Hybrid Molecules The Privileged Scaffolds For Various

European Journal of Medicinal Chemistry 124 (2016) 500e536
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech
Review article
Hybrid molecules: The privileged scaffolds for various

pharmaceuticals
Shaveta, Sahil Mishra, Palwinder Singh*
UGC Sponsored Centre for Advanced Studies, Department of Chemistry, Guru Nanak Dev University, Amritsar, 143005, India
a r t i c l e i n f o a b s t r a c t
Article history: The practice of polypharmacology is not a new concept but the approaches which are being adopted for
Received 19 June 2014 administering the two or more drugs together are varied from time to time. Taking two or more drugs
Received in revised form simultaneously, co-formulation of two or more active agents in a single tablet and development of hybrid
21 July 2016
molecular entities capable to modulate multiple targets are the three popular approaches for multidrug
Accepted 17 August 2016
Available online 21 August 2016
therapy. The simultaneous use of more than one drug for the chemotherapy of a single disease demands
a lot of patient compliance. Hence the present form of polypharmacology is gaining popularity in the
form of hybrid molecules (multiple ligand approach). From the last 1-2 decades, the synthesis of hybrid
Keywords:
Hybrid molecules
molecules by the combination of different biologically relevant moieties has been under constant
Anti-fungal escalation along with their evaluation as diverse range of pharmacological agents and as potent drugs.
Anti-tubercular This review is focused on the biological potential of hybrid molecules with particular mention of those
Anti-malarial exhibiting anti-fungal, anti-tuberculosis, anti-malarial, anti-inflammatory and anti-cancer activities. A
anti-inflammatory comparison of the drug potency of the hybrid molecules with their individual counterparts is discussed
for quantifying the significance of the concept of molecular hybridisation.
© 2016 Elsevier Masson SAS. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
2. Hybrid molecules exhibiting anti-fungal activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
2.1. Hybrid molecules based on natural product pharmacophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
2.2. Hybrid molecules based on synthetic pharmacophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502
2.2.1. Hybrids based on triazole moiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503
2.2.2. Hybrids based on imidazole moiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504
2.2.3. Hybrids based on thiazole moiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504
3. Hybrids showcasing anti-tubercular activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
3.1. Hybrid molecules based on natural product pharmacophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
3.1.1. Hybrids of quinoline-triazole as anti-tuberculosis agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
3.1.2. Hybrids involving quinoline moiety with other bio-significant moieties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
3.1.3. Hybrids incorporating triazoles as anti-tuberculosis agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
3.1.4. Hybrids based on isatin moiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
3.1.5. Other natural pharmacophores used in hybridisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
3.2. Hybrids based on synthetic pharmacophores as anti-tuberculosis agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
4. Hybrids profiling anti-malarial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511
Abbreviations: ACTs, artemesinin based combination therapy; CQ, chloroquine; CC50, concentration required to reduce growth by 50%; EC50, half maximal effective
concentration; Fqa, ferroquine; GI50, 50% growth inhibitory concentration; IC50, 50% inhibitory concentration; mg, microgram; MIC, minimum inhibitory concentration; MIC50,
minimum concentration for 50% inhibition; mm, millimetre; mM, micromolar; nM, nanomolar; SI, selectivity index; TB, tuberculosis; MTB, mycobacterium tuberculosis; NO,
nitric oxide; OA, oleanolic acid; GSTp, glutathione S-transferase p; BPU, benzoylphenyl urea; SAR, structure activity relationship; BCG, Bacillus Calmette-Guerin; WHO, World
Health Organisation; LOX, lipoxygenase; COX, cyclooxygenase; ROS, reactive oxygen species; DHFR, dihydrofolate reductase; TOPO, Topoisomerase.
* Corresponding author.
E-mail address: palwinder_singh_2000@yahoo.com (P. Singh).
http://dx.doi.org/10.1016/j.ejmech.2016.08.039
0223-5234/© 2016 Elsevier Masson SAS. All rights reserved.
Shaveta et al. / European Journal of Medicinal Chemistry 124 (2016) 500e536 501
4.1. Hybrids based on natural pharmacophores as anti-malarial agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512

4.2. Hybrids based on synthetic pharmacophores as anti-malarial agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522
5. Hybrids exhibiting anti-inflammatory properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
5.1. Hybrids based on natural pharmacophoric groups as anti-inflammatory agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
5.2. Hybrids based on synthetic pharmacophores as anti-inflammatory agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527
5.2.1. Triazole based hybrids as anti-inflammatory agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527
5.2.2. NO-releasing hybrids as anti-inflammatory agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527
6. Hybrids exhibiting anti-cancer properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
6.1. Hybrids incorporating natural moieties as anticancer agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
6.2. Hybrids incorporating synthetic moieties as anticancer agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532
7. Conlusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534
1. Introduction recently been reviewed by Chaudhary et al. [3]. Nikkomycin and

polyoxin (Chart 1) were for the first time isolated from culture of
The efficacy of a drug is controlled by various physico-chemical Streptomyces sp and were found active as chitin synthase inhibitors.
parameters including absorption, distribution, mechanism of Till now, Nikkomycin Z is used as a potent drug for treating cocci-
interaction between the drug and its cellular target, metabolism, diomycosis, also known as valley fever.
excretion and toxicity. For the optimization of these parameters, it Based on the various options of modification, a lot of work on
is essential to have tailor-made design of the molecules. Since it is derivatization of 1 and 2 by incorporating other active drugs like
always advantageous to modify a known pharmacophore for the fluconazole, itraconazole for procuring hybrid molecules is re-
development of a new drug; the hybrid molecules, obtained by the ported. These molecules were found to exhibit additive efficacy.
combination of structural features of two differently active frag- Peptide-polyoxin/nikkomycin hybrids are reported as effective
ments, are the most popular chemical entities to work upon for antifungal agents (Chart 1, Table 1).
developing modified scaffolds with much improved and amazing Carvacrol (3), another naturally occurring monoterpenoid is an
properties in the area of biology as well as medicinal science. Taken effective antifungal and insecticidal agent while BPU is an insect
from the naturally available myriad of scaffolds with varied bio- growth regulator, inhibiting chitin synthesis. These two medici-
logical profiles, amalgamation of two molecular entities exhibits nally significant moieties were interestingly worked upon to syn-
unusual properties [1]. thesize their hybrids as reported by Pete et al. [4] (Chart 2).
The synthesis of hybrid molecules and their evaluation as Compounds 4 and 5 exhibited potent antifungal activities against
diverse range of pharmacological agents and as potent drugs has Candida albicans (Table 2) along with good insecticidal properties.
been under constant escalation for the last two decades. In the Also, the synthesized compounds were found to be non-haemolytic
present review, we have focused on the biological potential of as compared to carvacrol and amphotericin-B which otherwise
hybrid molecules with particular mention of those exhibiting anti- cause haemolysis. Hence, the new molecules were better and safer
fungal, anti-tuberculosis, anti-malarial, anti-inflammatory activ- than carvacrol and BPU's.
ities, and anti-cancer categories of pharmaceutical compounds. The Another naturally occurring moiety coumarin has attracted the
work of recent years on these classes of hybrid molecules is attention of researchers to exploit its extensive biological proper-
showcased concisely. Each type of the pharmacological entity is ties as a result of which warfarin, acenocoumarol, armillarisin A,
divided into two major subsections including the one covering the hymecromone and carbochromen were approved for therapeutic
hybrids synthesized from natural product pharmacophores and the purposes. In recent years, some reports have manifested that
other incorporating only the synthetically prepared pharmaco- coumarin backbone in combination with nitrogen-containing het-
phoric groups. The aim of this review was to make a succinct erocyclic moieties such as azetidine, thiazolidine, thiazole etc could
compilation of the recent findings in synthesis and evaluation of significantly increase the antimicrobial efficiency of the hybrid
hybrid molecules for various drug categories and to lend a hand to molecules. Keeping up the ideology, Zhou et al. [5] have reported
the entire scientific community (both experts and novice) for two series (6, 7; Chart 3) of hybrids of coumarin and triazoles and as
designing and developing improved pharmacological entities. checked against A. Fumigatus, they exhibited significantly improved
antifungal activities than fluconazole (Chart 3).
2. Hybrid molecules exhibiting anti-fungal activity Ronad et al. [6] also explored coumarin moiety and synthesized
its Schiff bases (8, Chart 4) with variedly substituted aromatic al-
Since humans and fungi undergo similar molecular processes, dehydes. The Schiff bases were further converted to their thiazo-
there is always risk of the toxicity of anti-fungal agents to human lidinone derivatives 9 and evaluated against various strains of fungi.
system. Moreover, the anti-fungal drugs suffer from a serious and Preliminary results showed better antifungal activities of thiazoli-
major side-effect of developing resistance in its early stage [2]. The dinone derivatives than that of Schiff bases. Al-Amiery et al. [7]
imidazoles and the triazoles in late 1980s and early 1990s, reported hybrids of coumarin-triazole thione/thiadiazole (10, 11;
respectively originated as efficient antifungal agents but soon Chart 5). The synthesized compounds were tested for antifungal
confronted the limitation of resistance development. So, the doors activities and indicated significant activities as compared to flu-
remained wide open for the development of more effective agents conazole. Bis-coumarin hybrids (12, 13; Chart 6) [8] were found to
capable of countering resistance of the serious fungal infections. be potent antifungal agents against C. albicans (ATCC 10231),
A. fumigatus (HIC 6094), T. rubrum (IFO 9185), and T. mentagrophytes
2.1. Hybrid molecules based on natural product pharmacophores (IFO 40996).
There is still scope for exploring the treasures of simple and
Nikkomycin (1) and polyoxin (2) based hybrid molecules have natural antifungal moieties. Such compounds (Chart 7) can be
502 Shaveta et al. / European Journal of Medicinal Chemistry 124 (2016) 500e536
Chart 1. Nikkomycin and polyoxin based hybrid molecules.
Table 1 hybridized with one another for procuring new molecules with
Antifungal activity of hybrids of Nikkomycin and polyoxin (Chart 1) against Candida better efficacy and improved pharmacological behaviour.
albicans.
Compound R MIC (mg/mL) IC50 (mg/mL)

2.2. Hybrid molecules based on synthetic pharmacophores
Nikkomycin Z e e 0.393
Polyoxin D e 320 e
Polyoxin-peptide hybrid CH2(CH2)8CH3 40e80 e
A number of reports are available for strategic incorporation of
Nikkomycin-peptide hybrid e 0.31 two synthetic moieties in one molecule keeping their inherent
properties intact, adding to enhancement in the biological profile
and reduction of side-effects, especially those pertaining to resis-
tance development. After the successful establishment of various
drugs like fluconazole, itraconazole, voriconazole, rovuconazole,
HO HO HO
O O S O
N N N N
H H H H
4 R 5 R
3; Carvacrol
Carvacrol-urea/thiourea hybrids
Chart 2. Carvacrol and benzoyl phenyl ureas.
Table 2 they reported another category of fluconazole hybrids with fur-

Antifungal activity of carvacrol and BPU hybrids against Candida albicans. anones (21; Chart 8) which showed significant antifungal activity
Compound R MIC (mg/mL) against C. albicans ATCC 24433, C. glabrata ATCC 90030, C. tropolis
ATCC 750 and C. neoformans ATCC 34664 with MIC50 values com-
Carvacrol e 128
4 H 32 parable to fluconazole [10]. A patent report [11] from the same
4 2-Cl 64 group provided access to hybrids of fluconazole with chalcones
4 4-Cl 16 where one of the compounds (22; Chart 8) exhibited MIC50 0.12 mg/
4 2-F e
mL against C. albicans.
4 2, 6-F 64
5 2-F 16
Zhou et al. [12] reported triazole based hybrids and quoted two
5 4-F 16 significant leads (23, 24; Chart 9) for antifungal activity with MIC
5 2, 6-F 16 30.00 and 22.85 mg/mL, respectively. The compounds exhibited
Chart 3. Coumarin derivatives.
ketoconazole, clotrimazole, econazole, miconazole, abafungin, etc. more potent antifungal activity against C. albicans ATCC 76615 than
as antifungal agents, azoles are among the major classes of syn- the clinically prevalent antifungal drug fluconazole (MIC 52.24 mg/
thetic scaffolds that are being exploited maximally to develop mL). While extending the work, the same group also synthesized
hybrid molecules for improved anti-fungal properties. bis-triazole hybrids (25; Chart 9) [13]. Their screening against
C. albicans showed two of the most effective compounds exhibiting
2.2.1. Hybrids based on triazole moiety more potent antifungal activity with MIC 0.25 mg/mL. Zhou et al.
Triazole is an antifungal agent with high potency and low [14] also demonstrated hybridisation of two potent antimicrobial
toxicity. Fluconazole has established an exceptional therapeutic drugs viz. fluconazole and clinafloxacin together in a single mole-
record due to its potent activity, excellent safety profile and cule and procured much effective antifungal agents. The most
favourable pharmacokinetic characteristics. But on prolonged use, active anti-fungal agent showed MIC 0.5 mg/mL, comparable to the
the development of resistance and also its failure in inhibiting standard drug fluconazole (26; Chart 9).
invasive Aspergillus sp are some of the facts that have pulled the Kategaonkar and co-workers [15] have synthesized
attention of researchers to further enhance its efficacy. A major chloroquinoline-triazole hybrids and evaluated them as antifungal
chunk of research was focused on the development of analogues of agents (27; Chart 10). In context to the hybridisation of quinolone-
fluconazole in the recent years and some outstanding achieve- triazole moieties, Thomas et al. [16] have prepared (1-(6-methoxy-
ments were obtained in this aspect. 2-methylquinoline-4-yl)-1H-1,2,3-triazol-4-yl] methanamine de-
Out of the recent publications on such type of work, Borate et al. rivatives (28; Chart 10) followed by their screening as potent anti-
[9] demonstrated hybrids of fluconazole with benzoxazinone/ fungal agents.
benzothiazinone moieties and found two compounds (20; Chart 8) Hybrids of substituted quinolinyls and 1,2,4-triazole-3-ols (29,
exhibiting excellent antifungal activity against C. albicans. Later on, 30; Chart 11) exhibited significant anti-fungal activities [17].
According to SAR studies, it was observed that the presence of CF3 and evaluated against various strains of Candida. One of the com-
at position 8 and biologically active amines at position 4 of quin- pounds (39; Chart 16) showed even better anti-C. mycoderma ac-
oline ring and bioactive moieties like eSH, -CH2CH2OCH3, phenyl, tivity with MIC 1 mg/mL as compared to standard drugs berberine
etc. at triazole ring of the compounds were responsible for and fluconazole.
increased anti-microbial activity. In one of the reports, Zhou et al.
[18] also demonstrated that sulphanilamide-1,2,3-triazole hybrids
2.2.3. Hybrids based on thiazole moiety
did not prove to be effective antifungal agents and exhibited poor
Since the bioactivity of thiazoles is also well established, many
antifungal activities against C. albicans and C. mycoderm.
researchers have incorporated these moieties in the development
of new chemical entities and evaluated for different pharmaco-
2.2.2. Hybrids based on imidazole moiety logical properties. Omar et al. [26] have incorporated thiazole,
Two series of pyrazole appended imidazoles (31; Chart 12) were thiozolidinone and adamantane to build hybrid molecules which
synthesized and evaluated against A. flavus, A. niger, C. albicans, M. show sensitivity towards A. niger (40; Chart 17). All the tested
gypsum and T. rubrum [19]. It was found that none of the com- compounds showed improved activity as compared to the standard
pounds showed promising anti-fungal activity but some com- drug ketoconazole.
pounds when tested against T. rubrum exhibited comparable Thiazolidinone-norfloxacin hybrids were evaluated against
activity with that of standard drug fluconazole. C. albicans ATCC 2091, A. niger ATCC 9029 and C. krusei ATCC 6258
Hybridisation of naphthilamide with imidazoles (Chart 13) [27]. One of the compounds exhibited comparable antifungal ac-
provided appreciable antifungal activities against C. albicans and C. tivity to that of fluconazole (41; Chart 18). Thiazole-benzotriazole
mycoderm [20]. The results indicated that triazole thione com- hybrids (42, Chart 19) were checked for their antifungal activities
pounds (34, Chart 13) were more potent than their imidazole an- against C. albicans and A. Niger [28]. The compounds with electron
alogues (33, Chart 13). One of the compounds was found equipotent withdrawing groups such as F, Cl showed enhanced inhibition of
to the standard drug fluconazole (4 mg/mL) when screened against fungal growth irrespective of their positions on the aromatic ring.
C. mycoderm. Triphenyl-imidazole hybrids (35; Chart 14) showed Saeed et al. [29] have accomplished the synthesis of
inhibitory activity comparable to the standard drug Griseofulvin sulphanilamide-thiourea hybrids which were screened for anti-
[21]. fungal activity against different strains viz. A. niger, A. flavus, A.
Kumar et al. [22] synthesized azole‒carbodithioate hybrids and pterus, and White rot. The most potent compound (43; Chart 20)
evaluated them against various strains of Candida sp (36, Table 3). exhibited excellent antifungal activity against all the tested strains
Anti-Candidasis data showed that the most active compound and showed maximum zone of inhibition comparable to that of
exhibited IC50 1.79, 3.33, 1.79 and 1.75 mg/mL, respectively against standard drug terbinafine. Compound 43 was identified as the most
PK3, PK9, PK13 and PK 30 strains of Candida. potent urease inhibitor with IC50 0.20 mM and was found to be 100-
A series of imidazolyl-thiazole amine hybrids were synthesized fold more potent than thiourea, the standard inhibitor.
by Reddy et al. [23]. Some of the hybrids (37; Chart 15) in these A hybrid molecule 44 (Chart 21) consisting of cinnamic acid and
series exhibited potent antifungal activity against standard drug oleanolic acid was synthesized by Habila et al. [30]. The in vitro
fluconazole. Hybrid molecules containing benzimidazole-pyrazole candidasis inhibition of the hybrid compound was studied against
and pyridine nucleus were synthesized by Desai et al. [24] and seven Candida sp. The compound exhibited a marked zone of in-
evaluated against various strains of fungi. Four compounds (38; hibition of growth against the tested organism which ranges from
Chart 15) were found to be most active with MIC of 100 mg/mL 22 ± 0.20 to 31 ± 0.10 mm. C. guielemondi is the most sensitive with
against A. clavatus strain of fungi. an inhibition zone of 31 ± 0.10 mm which is better than the stan-
Hybrids of berberine and metronidazole were synthesized [25] dard drug fluconazole (21 ± 0.8 mm) used as positive control.
Chart 4. Schiff bases of coumarin and coumarin-thiazole hybrids.

profiles.
3.1.1. Hybrids of quinoline-triazole as anti-tuberculosis agents

A series of hybrids of quinoline and triazoles (45; Chart 22) were
synthesized via click chemistry [31]. The synthesized compounds
were evaluated for their anti-tuberculosis activity against MTB
H37Rv. The most potent compound showed 76.41% reduction of
growth at dose 5 mg/mL. Thomas et al. [32] also reported hybrids of
quinolone and triazole (46; Chart 22). The formulated compounds
were tested against three strains of mycobacterium, viz., MTB
H37Rv, M. smegmatis (MS) and M. fortuitum (MF). Some of the
Chart 5. Coumarin e thiadiazole/triazole hybrids. compounds showed potent activity as compared to standard drug
isoniazid.
Therefore, in most of the cases, the improvement in the anti- 3.1.2. Hybrids involving quinoline moiety with other bio-significant
fungal activity was observed when fragments of two relevant moieties
molecules were combined together. However, further details need Synthesis of the hybrids of quinoline and carbohydrazides (47;
to be explored whether the hybrid molecule has the same cellular Chart 23) was performed by Eswaran et al. [33]. These compounds
target as its individual counterparts or it may find an additional were evaluated against MTB H37Rv, M. smegmatis (MS) and M.
target for showing its therapeutic effect. fortuitum (MF). The results indicated that presence of substituted
hydrazones and potent (3R)-3-amino-N,N- dimethyl-4-
3. Hybrids showcasing anti-tubercular activity (phenylthio) butanamide, respectively at positions 3 and 4 of
quinoline skeleton has tremendously enhanced the anti-
Tuberculosis (TB) is a chronic communicable disease. As per the tuberculosis activity.
present status, no such medication is available that completely Kantewari et al. [34] reported quinolone based hybrids incor-
eradicates this disease. Bacillus Calmette-Guerin (BCG) is the main porating carbazole moieties (48; Chart 24). Compounds having 9-F
vaccine used for the treatment of TB. This vaccine works only to substituent (Table 4) were found to be most active among all the
some extent in prevention of childhood TB but has not proved synthesized compounds when tested against MTB H37Rv strain.
effective in case of adults. Also, presently, a long duration treatment Three series of quinolone-hydrazide hybrids (49e51, Chart 25)
along with combination therapy is prescribed for the treatment of [35] were evaluated for their anti-tuberculosis activity against MTB
TB. Since WHO has announced TB as the case of emergency, it is H37Rv, M. smegmatis (ATCC 19420), M. fortuitum (ATCC 19542) and
high time to develop a drug for the complete demolition of TB. The MDR-TB strains. Most of the quinolone-carbohydrazides were
phenomenon of hybridisation is getting much explored for the found to be active against MTB strain while some of them possess
design and development of drugs from the already established drug activity against MS and MDR-MB strains (Table 5). The same group
molecules so that the efficacy may get improved along with the [36] also reported hybrids of quinolone and oxazolidine (52; Chart
decrease in the risk of side-effects associated with individual 26, Table 5) as potent anti-tuberculosis agents.
counterparts. Jardosh et al. [37] reported bisquinolone-isoniazide hybrids (53;
Chart 26) and after assessment for anti-tuberculosis activity, two
3.1. Hybrid molecules based on natural product pharmacophores compounds (53a and 53b) were found to be potent anti-
mycobacterial agents with 99% inhibition at a concentration of
Quinoline is a part of many natural alkaloids of medicinal use. 250 mg/mL. Shantakumar et al. [38] synthesized trichloromethyl
Much work has already been done and it is still under progress to substituted quinazolines. On evaluating against MTB strain, two
exploit the inherent properties of this natural product in devel- compounds (54, 55; Chart 27) showed equipotency with standard
oping improved pharmaceutical ingredient. Many of the anti- drugs pyrazinamide and streptomycin.
tubercular reports have described the synthesis of hybrids of Chander Shekhar et al. [39] prepared hybrids of quinoline car-
quinoline and its derivatives with other biologically significant boxylic acid and piperazine derivatives and evaluated them for
moieties and the evaluation of resulting molecules as anti- their anti-mycobacterial activity. The most active compound (56;
tubercular agents. Triazoles are another class of biologically active Chart 27) exhibited MIC 7.32 mg/mL against MTB H37Rv strain. Fused
moieties which are much explored as exhibiting various biological hybrids of pyrrolo-quinolines were synthesized by Bhattacharya
Chart 6. Bis-coumarin e thiazole hybrids.

Chart 7. Simple natural molecules e active antifungal agents.
Chart 8. Fluconazole e benzoxazinone/benzothiazinone hybrids.
Chart 9. Triazole based hybrid molecules.

Chart 10. Quinoline e triazole hybrids.
Chart 11. Quinoline e triazole hybrids.
resulted into lesser potency of the resulting molecule than the

standard drugs isoniazid and ethambutol but were found to be
more potent than pyrazinamide. According to SAR observation,
increase in anti-tubercular activity was attributed to the increase in
alkyl chain length appended to 1,2,3-triazole ring. Evaluation of
nitrofuran-triazole hybrids against MTB identified one compound
(60; Chart 30) [43] with excellent anti-tubercular activity (MIC
0.25 mg/mL) which was four times more potent than standard drug
Linezolid.
Chander shekhar et al. [44] fabricated piperazinyl and phenan-
thridine moiety within their hybrid molecules and carried out their
Chart 12. Imidazole e pyrazole hybrids. mycobacterial inhibitory activity. Some of the tested compounds
(61; Chart 30) showed excellent activity with MIC 1.56 mg/mL
against H37Rv strain of MTB. Further, extending their work [45],
et al. [40]. Two of the compounds (57, Chart 27) exhibited much they incorporated triazolyl moiety along with the previous com-
potent activity (MIC 3.3 mg/mL) than the standard drug ciproflox- pounds and evaluated the final compounds (62; Chart 30) for anti-
acin (MIC 4.7 mg/mL). mycobacterial activity. Promising results were obtained.
3.1.3. Hybrids incorporating triazoles as anti-tuberculosis agents 3.1.4. Hybrids based on isatin moiety
Clubbed 1,2,3-triazole hybrids from 1,2,3-triazole moiety and Isatin is a derivative of indole and is found in many plants
synthetic/natural product based tricycles (carbazole, dibenzofuran, including I. tinctoria, C. discolor, C. guianensis, etc. Also, Schiff bases
and dibenzothiophene) (Chart 28) were prepared by Patpi et al. of isatin are known for their various pharmaceutical properties.
[41]. These compounds exhibited potent in-vitro anti-mycobacterial Some recent reports regarding hybridisation of isatin into different
activity against MTB H37Rv (ATCC 27294 strain) with very low molecular entities are available. Hans et al. [46] synthesized
toxicity. The most active compound (58, Chart 28) showed anti- thiolactone-isatin hybrids (63; Chart 31) and evaluated them for
mycobacterial activity with minimum inhibitory concentration for their anti-tuberculosis activity. The compounds did not show much
100% inhibition (MIC) 1.89 mM and was 26 times more active than activity at 1 mg/mL but showed inhibition to some extent against
pyrazinamide (50.08 mM) and four times more active than etham- MTB H37Rv strain. Overall, not much influential results were ob-
butol (7.6 mM) and has low toxicity profile. tained. Aboul-Fadl et al. [47] synthesized Schiff base hybrids of
Integration of 2-(trifluoromethyl)-10H-phenothiazine and tri- isatin and nalidixic acid (64; Chart 31) and evaluated them for their
azole pharmacophores into a single molecule [42] (59; Chart 29) anti-mycobacterial activity. The most active compound showed
Chart 13. Naphthilamide e imidazole hybrids.
Chart 14. Triphenyl imidazoles.
Table 3 pyrrolothiazoles (65; Chart 31) showed equipotency to that of the

IC50 of compound 36 against various strains of C. albicans. standard drug ethambutol (MIC 7.6 mM) while it exhibited 6.7 times
Compound Azole R0 IC50 (mg/mL) higher potency than pyrazinamide (MIC 50.08 mM) [48]. Akhaja
et al. [49] synthesized a series of tetrahydropyrimidine-isatin hy-
C. albicans PK3 PK9 PK13 PK30
brids (66; Chart 32) and evaluated for anti-tuberculosis activity
36 CH3 1.26 1.79 3.33 1.79 1.75
against MTB H37Rv. Two compounds showed complete inhibition of
bacterial growth at 3.10e3.12 mg/mL.
Chloroquinoline-isatin hybrids (67, 68; Chart 32) [50] with MIC
Fluconazole e e 0.13 0.21 e e e
<10.41 mM were found more potent than standard drug cephalexin
(MIC 68.41 mM). From the same group, a recent report [51]
mentioned the synthesis of triazole tethered isatin-ferrocene and
MIC 0.625 mg/mL against Mycobacterium sp and was found to be 20 spiroisatin-ferrocene hybrids (69, 70; Chart 32) and evaluation of
times more potent than standard drug isoniazid (MIC 12.5 mg/mL). their biological activity. The final compounds and their immediate
Spiro hybrids of isatin-pyrrolidine, pyrollizine and precursors were evaluated for anti-mycobacterial activity and it
Chart 15. Imidazole e thiazole and imidiazole e pyrazole hybrids.
Chart 16. Hybrids of metroindazole and berberine.
was observed that on introducing ferrocene to the preliminary better than the standard drug pyrazinamide (IC90 > 20 mg/mL).
compounds, there is enhancement in anti-tubercular activity. Evaluation of hybrids of benzimidazole and carbohydrazide against
Bairwa et al. [52] exploited cinnamic acid and guanylhydrazones to MTB H37Rv and MDR-MTB strains identified one compound (76;
synthesize hybrid molecules and evaluated their anti-tubercular Chart 36) with better anti-tuberculosis activity as compared to
activity. The most active compound (71; Chart 33) exhibited MIC standard drug rifampicin [57].
6.5 mM against MTB H37Rv. Furthermore, a series of structurally novel hybrids of 2-
hydrazenyl benzothiazole and 4-(aryloxy) benzaldehyde (77;
3.1.5. Other natural pharmacophores used in hybridisation Chart 36) were synthesized by Telvekar et al. [58] and anti-
Hung et al. [53] synthesized phenyl substituted coumarin de- tubercular activity was evaluated against MTB H37Rv strain. It was
rivatives and evaluated them for their anti-tubercular activity. The noticed that presence of Cl (halogen group) at C-6 of benzothiazole
most potent compound (72; Chart 34) exhibited IC50 2 mM against ring helped in improving the activity profile against mycobacte-
MTB. Bhat et al. [54] synthesized terpene based Schiff bases by rium. Divakar et al. [59] have synthesized hybrids of benzimidazole
incorporating various hydrazide anti-mycobacterial drug de- and pyran derivatives and evaluated against MTB. All the com-
rivatives. On evaluating against MTB, one of the compounds (73; pounds (78; Chart 37) were found to be active against MTB at 10 mg/
Chart 34) showed promising activity (MIC 12 mg/ml) and having ml concentration. Combination of pyrazoline and carbazole in
more potency than standard drug isoniazid (12.5 mg/mL). compound 79 (Chart 37) [60] resulted into better anti-tubercular
activity than that of standard drugs streptomycin and pyr-
3.2. Hybrids based on synthetic pharmacophores as anti- azinamide (Table 6).
tuberculosis agents A series of dapsone-azetidinone (80; Chart 38) and dapsone-
thiazolidinone (81; Chart 38) hybrids was synthesized and the
Hybrids of ferrocene and hydrazones (74; Chart 35) were eval- compounds were screened for their anti-tubercular activity against
uated for anti-mycobacterial activity [55]. The most potent com- the human strain [61]. It was concluded from the results that the
pound, exhibiting MIC 2.5e5 mg/mL, was obtained by incorporating compounds bearing Cl, Br and I group showed better anti-
quinoline moiety which elucidates the importance of quinoline for tubercular activity than the other non-halogenated compounds.
anti-tubercular activity. Benzo [4,5]furo [2,3-c]chromen-6-one (82, Chart 39), the hybrid
Amongst the chromenyl-barbiturate hybrids, the most active of coumarin and benzofuran showed remarkable activity with MIC
compound 75 (Chart 35) [56] showed IC90 5.90 mg/mL which was 3.12 mg/mL against MTB strain H37Rv [62]. Khanage et al. [63]
Chart 19. Thiazole-benzotriazole hybrids.
0.78 mg/mL. Padhye et al. [65] synthesized isoniazide-pyruvate

hybrids and complexed them with Cu (II). The synthesized com-
plexes were then evaluated against MTB H37Rv strain. The com-
plexes (86; Chart 40) containing isonicotinyl group were found to
be most active anti-mycobacterial agents. Also, Rai et al. [66] syn-
thesized pyrido-quinazoline hybrids. The most active compounds
(87a-c; Chart 40) exhibit MIC 62.5, 50 and 40 mg/mL against MTB
H37Rv.
Triazole tethered b-lactam-ferrocene (88; Chart 41) [67] and b-
lactam-ferrocenyl chalcones (89; Chart 41) were evaluated against
MTB H37Rv strain. Surprisingly, none of the compounds was found
active enough to inhibit the growth of mycobacterium. Further, to
Chart 17. Thiazole based hybrid molecules.
improve the activity profile, the same group [68] synthesized a
modified library of compounds consisting of substituted triazoles at
the C-3 position and spacer of varied alkyl chain length (n ¼ 2 or 3)
within the previous molecules (90, 91; Chart 41). Unfortunately, the
changes made did not avail any inhibitory activity in the
compounds.
Seelam et al. [69] synthesized thiazolidinone hybrids with
phenothiazine. The most active compound 92 (Chart 42) displayed
MIC 3.12 mg/mL against MTB H37Rv whereas standard drug isoniazid
exhibited MIC 0.20 mg/mL. Also, Gudasi et al. [70] synthesized hy-
brids of salicylhydrazone and anthranilhydrazide and then pre-
pared their complexes with various transition metal ions to
evaluate their anti-tubercular activity. Complex of Co (II) (93; Chart
42) was found to be equipotent to that of standard drug isoniazid
against H37Rv strain of MTB.
Compound 94 (Chart 43), obtained through Schiff base combi-
nation of benzothiazole and pyrazolone moieties showed MIC
1.66 mg/mL against MTB [71]. Patel et al. [72] synthesized imidazo-
Chart 18. Thiazolidinone-norfloxacin hybrids. thiadiazole hybrid derivatives, amongst which compound 95 (Chart
43) with MIC 3.14 mg/mL was identified as potent anti-tubercular
agent against MTB. Kamal et al. [73] also synthesized a new class
synthesized hybrids of pyrazole and tetrazole with triazoles to yield of diarrylpyrrole-oxazolidinone hybrids. Two series of compounds
two series of compounds (83 and 84; Chart 39). Results of the were synthesized and checked for their anti-tubercular activity.
biological assay revealed that 4-chloro, 3-nitro, 4-methoxy and 2- Some of the compounds (96 and 97; Chart 43) exhibited significant
chloro substituted compounds showed anti-tubercular activity activity against certain strains of MTB including H37Rv, RiFR and
with MIC 6.25 mg/mL. XDR-1 strains.
Da Silva et al. [64] synthesized naphthoimidazoles and naph- Synthesis of nitropyrrole hybridized oxadiazole derivatives was
thoxazole derivatives. MIC was calculated for all the compounds accomplished for their evaluation for anti-tubercular activity [74].
against MTB H37Rv, rifampicin-resistant (RIFr, ATCC 35338) and Compounds 98(a-d) (Chart 44, Table 7) with MIC values 0.46, 0.72,
isoniazid-resistant (INHr, ATCC 35822) strains. Most of the com- 0.81 and 1.8 mg/mL against MTB H37Rv strain were identified as lead
pounds exhibited MIC 0.78e100 mg/mL against all the tested strains compounds. Another set of oxadiazole based hybrids were syn-
while the most active compound 85 (Chart 40) showed MIC value of thesized by Somani et al. [75]. They also evaluated them for anti-
Chart 20. Sulphanilamide-thiourea hybrids.
CH3 3. Hybrids profiling anti-malarial activity

H3C
Malaria is one of the terrible diseases caused by female anoph-
eles mosquito. In high risk areas, more than one malaria cases occur
OH
CH3 CH3 from a population of one thousand. According to a recent WHO
O O report [78], in 2015 alone, there were an estimated 214 million new
CH3 cases of malaria and 438000 people succumbed to death. About
O 80% of all malaria deaths occur in sub-Saharan Africa, and 77% occur
H3C CH3 in children under five. This has created an embarrassing situation
for the scientific community because of the inability to control a
44 highly preventable and treatable disease.
As far as malaria treatment is concerned, artemisinin based
Chart 21. Hybrid of cinnamic acid and oleanolic acid. combination therapy (ACTs) is prevalent as treatment against P.
Chart 22. Hybrids of quinoline and triazole.
tubercular activity. Two of the compounds (99a, b; Chart 44) were falciparum. In this combination therapy, two or three drug
found to show appreciable anti-tubercular activity. candidates are altogether used in the regimen so as to delay
In a recent review, Dutra et al. [76] have discussed the status of resistance onset. Although, no reports were available regarding
some hybrid molecules obtained by the combination of anti- any resistance development with artemisinins, recently [78],
tubercular drugs like isoniazid, ciprofloxacin, pyrazinamide, etc. parasite resistance to ACTs has been detected in four South East
Himaja et al. [77] synthesized four compounds by hybridizing Asian countries. Also pervasive spread of resistance against the
lamivudine (drug used for HIV-1 and Hepatitis B) with isonicotinic most deadly strain of P. falciparum demands the search and
acid and pyrazine-carboxylic acid (precursors of anti-tubercular development of much more effective and resistant immune
drugs). The resultant compounds (100e103; Chart 45) were eval- therapeutics.
uated against mycobacterium sp and all compounds showed very A lot of the work done on artemisinin based hybrids as well as
good activity at a minimum concentration 25 mL/mL. quinoline/aminoquinoline based hybrid molecules in the past few
Hence, the phenomenon of hybridisation of the molecules has years has been reviewed by Muregi et al. in 2010 [79]. They have
effectively been used in developing highly potent anti-tubercular covered hybrid compounds synthesized from natural as well as
agents. Some of these compounds are capable to act as leads for totally synthetic pharmacophores in a beautiful manner. Hence
their further refinement and development into anti-tuberculosis leaving the part covered in that review, here, we focused on the
drugs. recent developments in hybrid molecules for procuring anti-
malarial agents.
Chart 23. Hybrids of quinoline and carbohydrazide.
Chart 24. Quinoline e carbazole hybrids.
Table 4 4.1. Hybrids based on natural pharmacophores as anti-malarial

MIC of compound 48 against MTB strain. agents
Compound R X MTB
MIC (mg/mL)
Quinoline based drugs like chloroquine, quinine, mefloquine,
etc. are the backbone of anti-malarial treatment. Due to the early
48 F O 3.13
onset of resistance against these drug therapies, much emphasis is
48 F O 3.13
48 F NeCH3 3.13 being laid on the development of more effective drug entities as
Ethambutol e e 3.13 well as the modification of already prevalent anti-malarial drugs
especially chloroquine. Hybridisation approach is on a roll for swift
Chart 25. Quinolone-hydrazide hybrids.

Table 5 modification and development of quinoline based hybrid molecules

MIC of compounds 49e52 against MTB strain. as anti-malarial agents. In order to advance the hybridisation
Compound MIC (mg/mL) methodology, after introduction of quinoline moiety to trioxane
R1 MTB MS
moiety in trioxaquins [80], another antimalarial drug, ferroquine
(Fqa) (hybrid molecule with a ferrocenyl moiety inserted within the
49 1 1
side chain of chloroquine; molecule in phase 2 clinical trials) was
incorporated to synthesize trioxaferroquins [81]. Compounds
49 1 1
104e107 (Chart 46) were synthesized as trioxaferroquins and
evaluated against two chloroquine-resistant strains, FcB1 and
FcM29, and compared with the activity of the reference
compounds-artemisinin, chloroquine diphosphate, and trioxaquine
PA1103. All the compounds were found to be highly active
49 1 1
compared to the standard drug artemisinin while 105 was found to
be the most potent against FcM29 strain. In vivo examination also
directed towards its high activity and ability to clear parasitemia.
52 Dimethylamino 1 10 In a recent review, Kaur et al. [82] have revealed various reports
52 Diethylamino 1 10
regarding hybridisation of quinoline, substituted quinolines and
52 4-methyl piperazinyl 1 10
52 Morpholinyl 1 10 quinolone, isoquinolone derivatives. The review has covered
Isoniazid e 0.7 50 various advances in the field for the last ten years and has derived
structure activity relationship for the same. Wenzel et al. [83]
synthesized hybrids of chloroquine with ferrocene and evaluated
Chart 26. Bis-quinolone e Isoniazide hybrids.
Chart 27. Quinazoline and quinoline based hybrids.

Chart 28. Triazole based hybrid molecules.
them against various strains of P. falciparum. The most active

compounds (108, 109; Chart 47) showed better anti-malarial ac-
tivity as well as better cytotoxicity than the standard drug chloro-
quine (Table 8).
Chopra et al. [84] synthesized ferrocenyl-pyrimidine conjugates
and evaluated them against chloroquine susceptible NF54 strain of
the malaria parasite P. falciparum. The most active compound
bearing aromatic substituent at C-4 position of the pyrimidine core
and isopropyl ester group at C-5 position (110; Chart 47) was found
to show lC50 7.68 ± 0.50 mM.
Hermann et al. [85] have reported the synthesis of sugar
appended ferrocene-quinoline hybrids and evaluated for their
cytotoxicity as well as anti-malarial activity in both CQ-sensitive
and CQ-resistant strains of P. falciparum. For the chloroquine-
resistant Dd2-strain of P. falciparum, the IC50 for the most active
compound (111; Chart 47) was 36.2 nM which was much improved
over the standard drug chloroquine (IC50 527 nM). Recently, the
same group [86] designed another set of sugar appended
ferrocene-quinoline hybrids (112; Chart 47) and evaluated for their
anti-malarial activity. The compounds were found to be less active
than that of the previous report and it was postulated that it might
be due to the lack of additional amino groups in 112 in comparison
to the regularly substituted compound 111 which could lead to a
reduced uptake at the site of action of the drug. They also synthe-
sized another type of chloroquin-ferrocene hybrids (113; Chart 47)
[87]. Their evaluation against chloroquine resistant strains of P.
Chart 29. Phenothiazine e triazole based hybrids. falciparum indicated that most of these compounds were more
Chart 30. Piperazinyl e phenanthridine hybrids.

Chart 31. Thiolactone e isatin and isatin e nalidixic acid hybrids.
Chart 32. Isatin based hybrid molecules.
(MIC 0.125 mg/mL) while compound 115 (Chart 48), a quinoline-

tetrahydroisoquinoline derivative exhibiting MIC 0.031 mg/mL was
four times more potent than chloroquine. Compound 115 showed
the curative response to all the treated swiss mice infected with
CQ-resistant N67 strain of P. yoelii at the doses of 50 and 25 mg kg1
for four days by intraperitoneal route and was found to be orally
active at the dose 100 mg kg1 for four days. The same group also
synthesized hybrids of quinoline and triazines and found two
compounds (116; Chart 48) as active leads to develop into effective
anti-malarial dugs [89]. Compound 116 provided 100% protection
Chart 33. Cinnamic acid based hybrid molecules. to the treated mice at a dose of 50 mg kg1 for four days against CQ-
resistant N67 strain of P. yoelii.
Rawat et al. [90] synthesized hybrids of quinoline and triazines
active than the standard drug chloroquine. but in a different fashion so as to procure compounds like 117
Amongst the quinoline-piperazine derivatives [88], screened (Chart 48). Four compounds (117a-d) were found to be more potent
against NF54 strain of P. falciparum, compound 114 (Chart 48) with than chloroquine when tested for their anti-malarial activity
MIC 0.125 mg/mL was found to be equipotent to that of chloroquine against W2 strain of P. falciparum (Table 9). Cytotoxicity was also
checked for the compounds against a panel of three cell lines and
compound 117c was found to be more cytotoxic than CQ. Later on,
they incorporated triazole moiety in between quinoline and
triazine [91] and synthesized aminoquinoline-triazole hybrids. Out
of the five most active compounds (118a-e, Chart 49), none of the
compounds was comparable to the previously reported compounds
(117a-d).
Furthermore, Rawat et al. [92] synthesized hybrids of amino-
quinoline and pyrimidine moieties and tested for antimalarial ac-
tivity against both chloroquine (CQ)-sensitive (D6) and chloroquine
(CQ)-resistant (W2) strains of P. falciparum through an in vitro assay.
Chart 34. Pyridine based hybrid molecules. Eleven hybrids showed better antimalarial activity against both CQ-
Chart 35. Hybrids of ferrocene e hydrazones and chromenyl e barbiturate.
Chart 36. Hybrids of benzimidazole and carbohydrazide.
Chart 37. Benzimidazole e pyran and pyrazolone e carbazole hybrids.
sensitive and CQ-resistant strains of P. falciparum in comparison to

Table 6 standard drug CQ. Four molecules were more potent (119a-d; 78-
MIC of compound 79. fold; Chart 49) than CQ in D6 strain and eight molecules were found
Compound R MIC (mg/mL) to be 525-fold more active against resistant strain (W2). Most of
the compounds were not cytotoxic up to 60 mM concentration. Also,
79 o-chlorophenyl 5.0
79 m-chlorophenyl 4.5 the selective index for the antimalarial activity was very high for
79 p-chlorophenyl 3.5 most of the hybrids. Two compounds (119a and 119d) selected for
79 o-hydroxyphenyl 4.5 in vivo evaluation have shown excellent activity in a mouse model
79 p-hydroxyphenyl 3.5 of P. berghei without any toxicity (Table 10).
79 methyl 3.5
Streptomycin e 7.5
Amongst a library of aminoquinoline-aminopyrimidine de-
Pyrazinamide e 10 rivatives [93], the most active compound (120; Chart 50) showed
much better anti-malarial activity against CQ-resistant K1 strain
(IC50 3.6 nM) and showed comparable inhibition against CQ-
sensitive 3D7 strain to that of standard CQ (ICK1 50 201.8 nM;
Chart 38. Dapsone-azetidinone and dapsone-thiazolidinone hybrids.

Chart 39. Hybrid of coumarin e benzofuran and tetrazole e triazole.
Chart 40. Hybrids of naphthoimidazoles e naphthoxazole and pyrido e quinazoline.
IC3D7
50 1.4 nM). Singh et al. [94] synthesized a library of quinoline- most potent against both CQ-sensitive and resistant strains. From
pyrimidine hybrids along with anti-malarial results. The in vitro the same group, various series of hybrid compounds containing
evaluation of these hybrids against CQ sensitive D10 and CQ aminoquinoline-pyrimidine derivatives, pyrimidine carbonitrile-
resistant D2d strains of P. falciparum depicted activity in the nM quinoline derivatives and primaquin-pyrimidine hybrids [95e97]
range. Among others, compound 120 (Chart 50) was found to be were synthesized and evaluated for their antimalarial activities. It
Chart 41. Triazole tethered b-lactam-ferrocenes.

(122, Chart 51) was found to be potent against D10 strain similar to
the standard drugs PM and CQ and it was found superior in potency
to that of CQ against Dd2 strain.
Chibale et al. [99] have reported hybrids of aminoquinoline and
tetrazines and on evaluation for anti-malarial activity; they found
three compounds (123a-c, Chart 52, Table 11) as highly potent anti-
malarial agents. The in vitro evaluation was done against both the
CQ-sensitive (3D7) as well as CQ-resistant (K1 & W2) strains of P.
falciparum. Later on [100], they modified the library to yield com-
pounds like 124. They also showed some interesting results and
found three compounds (124a-c) as potent anti-malarial agents.
Chart 42. Thiazolidinone e phenothiazine hybrids. Chauhan et al. [101] modified the compounds synthesized by
Chart 43. Benzothiazole e pyrazolone and imidazo e thiadiazole hybrids.
Chibale and co-workers [65,66] and evaluated them for their anti-
malarial activity. Two of the compounds (125 a,b) showed prom-
ising in vitro activity results and when subjected to in vivo evalu-
ation, excellent results were obtained compared to standard drug
CQ. Chibale et al. also synthesized chalcone-chloroquinoline hy-
brids and demonstrated their anti-malarial activity in two of their
reports [102,103]. The hybrid compounds were evaluated for their
in vitro anti-malarial activity against the CQ-sensitive strain D10
and CQ-resistant strains Dd2 and W2 of P. falciparum. Out of the
library of compounds synthesized and evaluated, three compounds
Chart 44. Oxadiazole e pyrrole/pyridine hybrids.
(126, 127a, b; Chart 53, Table 12) were found to be highly active
against the tested strains of P. falciparum.
was concluded that hybrid 121 bearing m-nitrophenyl substituent Chloroquinoline-chalcone hybrids were evaluated against
at C-4 of pyrimidine displayed the highest antiplasmodial activity chloroquine sensitive strain (3D7) of P. falciparum [104]. Two
[IC50 56 nM] against the CQR (Dd2) strain, which was four fold compounds were found potent after in-vitro as well as in-vivo
greater than CQ. evaluation against plasmodium sp. In vivo antimalarial activity
N’Da et al. [98] also utilized quinoline and pyrimidine moieties against chloroquine resistant of P. yoelii strain N-67 in Swiss mice at
in their synthesis and procured a library of hybrid molecules and 100 mg kg1 day1 dose by oral route caused 99.9% suppression at
evaluated for anti-malarial activity. The most active compound the end of day 4 by the two compounds (128a, b, Chart 54) as
compared to standard drug CQ which causes 99% suppression only.
Similar effects were shown by the hybrids of aminoquinolines and
Table 7 chalcones [105]. Further modulating the hybrids, the pyrazoline
MIC of compound 98. derivatives of aminoquinolines were evaluated for anti-malarial
activity. The most active compound (129; Chart 54) showed an
Compound R MIC
IC50 14.1 mg/mL against NF54 strain of P. falciparum.
98a 2-fluorobenzyl 0.46 Kouznetsov et al. [106] synthesized a series of chloroquine based
98b 2-hydroxy-3,5-dinitrophenyl 0.72
98c 2-bromophenyl 0.81
hybrids incorporating either benzylamino group or thiazolidinone
98d 2-hydroxy-3-nitrophenyl 1.8 moiety. The synthesized compounds were screened for their anti-
Isoniazid e 0.40 malarial activity and evaluated against both CQ-sensitive 3D7 and
Chart 45. Lamivudine e isonicotinic acid hybrids.
multidrug-resistant Dd2 strains of P. falciparum. No compounds hybrids (135) and evaluated against various strains of P. falciparum.
were found active against 3D7 strain but some of the compounds The most active compounds (135a, b) showed IC50 in nM range and
(130, 131a-c; Chart 55, Table 13) with benzylamino fragment were also 135b showed strong activity on in vivo evaluation against P.
found to be more active than CQ against Dd2 strain. berghei causing 99% suppression at a dose of 30 mg/kg.
Singh et al. [107] synthesized aminoquinoline-Mannich base Andayi et al. [111] synthesized a series of chloroquinoline-
hybrids and evaluated for their anti-malarial activity. One of the hydroxypyridone hybrids and were tested against various strains
morpholine substituted 4-anilinoquinoline Mannich base deriva- of CQ-sensitive (K1 and W2) and CQ-resistant strain (3D7) of P.
tive (132; Chart 56) displayed strong suppressive activity against falciparum. The most potent compounds (136a-c; Chart 58) showed
CQ resistant P. yoelii infection in swiss mice. Quinoline appended anti-malarial activity against K1, 3D7 and W2, respectively as 136a
with 15-membered azalides (133a, b; Table 14) [108] showed (0.07, 0.03 and 0.08 mM); 136b (0.08, 0.01 and 0.02 mM) and 136c
improvement in activity against various strains of P. falciparum in (0.13, 0.004 and 0.10 mM) as compared to CQ (0.44, 0.01 and
comparison to standard drugs CQ and azithromycin (azalide 0.10 mM).
analogue). Rhodanine-aminoquinoline hybrids like 137 (Chart 58) also
Cornut et al. [109] synthesized quinoline and g-lactam based proved very effective against various strains of P. falciparum. An IC50
hybrids and evaluated against various strains of P. falciparum. The of 13.2 nM was observed against CQ-resistant K1 strain for the most
most active compound (134, Chart 57) exhibited IC50 19 and 42 nM active compound [112]. A novel series of thiosemicarbazone-
against 3D7 and W2 strain of P. falciparum, respectively. Overall, no triazole hybrids were efficiently synthesized by Kinfe et al. [113]
cytotoxicity was observed for the synthesized compounds. Also, and evaluated for their anti-malarial activity against the 3D7
Gemma et al. [110] synthesized quinoline and clotrimazole based strain of P. falciparum. None of the compounds was found to be
Chart 46. Ferroquine e chloroquine hybrids.

Chart 47. Hybrids of quinoline with ferrocene.
Table 8 more potent than standard drug chloroquine. Chadwick et al. [114]
Anti-malarial activity of compounds 108, 109 and 111. synthesized Mannich bases of tetraoxanes (138; Chart 59) and
evaluated for their anti-malarial activity. The hybrids were found to
Compound Dd2 IC50 (nM) anti-malarial MRC-5 IC50 (mM) cytotoxicity
exhibit higher potency in vitro and in vivo as well when compared
108 4.9 3.0 to standard drug artemisinin. Thomas et al. [115] designed furoxan-
109 5.2 1.0
111 36.2 e
amodiaquin based hybrid molecules to obtain a dual acting mole-
Chloroquine 527 64 cule that would demonstrate activity against a variety of parasitic
targets. The antimalarial drug amodiaquine was covalently joined
Chart 48. Quinoline e piperazine and quinoline e triazine hybrids.

Table 9
Anti-malarial activity of compounds 117 and 118.
Compound R R0 X/n P. falciparum (W2 clone) IC50 (mM)
117a Morpholine 3,5-dimethoxy aniline 1,3-propanediamine 0.22

117b Morpholine 3,5-dimethoxy aniline 1,8-octanediamine 0.35
117c Aniline aniline 1,2-ethylenediamine 0.25
117d N0 -(7-chloroquinolynyl-4-yl) ethane-1,2-diamine chloro 1,2-ethylenediamine 0.38
118a n¼2 1.73
118b -do- -N(Me)2 n¼1 1.15

118c -do- -do- n¼2 1.20
118d -do- n¼1 1.69
118e -do- -do- n¼2 0.73

CQ e e e 0.42
Chart 49. Triazole - quinoline e triazine hybrids.
Table 10
Anti-malarial activity of compound 119.
Compound n R P. falciparum (D6 clone) IC50 (mM)
119a 1 N-methyl piperazine 0.005

119b 2 -do- 0.007
119c 5 -do- 0.007
119d 2 N-ethyl piperazine 0.006
CQ e e 0.04
Pyrimethamine (PM) e e 0.01
Chart 50. Hybrids of aminoquinoline and pyrimidine.
Chart 51. Quinoline e pyrimidine hybrids.

Chart 52. Hybrids of aminoquinoline and tetrazines.
P. falciparum, Schistosomamansoni, and Ancylostoma ceylanicum.

Table 11 In a recent review on quinoline based antimalarial hybrid mol-
Anti-malarial activity of compounds 122e124 against P. falciparum strains.
ecules [116], some of the quinoline-containing chimeras exhibiting
Compound R R0 3D7 K1 W2 excellent antiplasmodial potential against both sensitive and
IC50 (mM) resistant Plasmodium species in vitro as well as in vivo have been
elaborated extensively by Vandekerckhove et al. Singh et al. [117]
123a CH3 H 0.001 0.002 0.0311
123b Cl Cl 0.0004 0.008 0.0305 also reviewed hybrids based on pyrimidine moiety in their recent
123c Cl H 0.002 0.001 0.0255 review with their antiplasmodial effects.
124a Diethylamino e 0.100 0.006 0.066
124b Pyrrolidine e 0.010 0.0096 0.077
124c Dimethylamino e 0.012 0.012 0.040 4.2. Hybrids based on synthetic pharmacophores as anti-malarial
125a Cl e 0.0106 0.1429 e agents
125b Br e 0.0117 0.233 e
CQ e e 0.0052 0.036 0.059
Chibale et al. [118] have synthesized a unique type of hybrid
molecules based on ferrocenyl-thiosemicarbazone and poly(-
propyleneimine) dendrimer scaffold. The synthesized hybrid
with a nitric oxide-releasing furoxan (139; Chart 59) to achieve compounds were evaluated for their anti-microbial activity against
multiple mechanisms of action. Using in vitro and ex vivo assays, the CQ-resistant (W2) strain of P. falciparum. The metallodendrimers
hybrid molecules showed activity against three parasites e (140; Chart 60) showed better anti-malarial activity (IC50 in mM
Chart 53. Hybrids of chalcone and chloroquinoline.
range) than ferrocenyl thioesters and free dendrimer polyamines.

Table 12 Another report from Verlinden et al. [119] described the synthesis
Anti-malarial activity of compound 126 and 127 against P. falciparum.
of bis-urea/thiourea and polyamine derivatives. All derivatives
Compound D10 Dd2 W2 showed growth inhibitory activity against P. falciparum at less than
IC50 (mM) 3 mM, with the majority having effective IC50 values in the
100e650 nM range (141, 142; Chart 60). This opens another front
126 0.04 0.07 0.09
127a 0.5 0.5 0.4
for the modification of such type of novel class of polyamine ana-
127b 0.6 0.5 0.3 logues to procure efficient anti-malarial agents.
CQ 0.017 0.097 0.069 Akhaja et al. [120] synthesized pyrimidine-isatin hybrids and
Chart 54. Chloroquinoline-chalcone and chloroquinoline e pyrazole hybrids.
Chart 55. Chloroquine based hybrids.
Table 13 activity. The most potent inhibitor from this series was found as
Anti-malarial activity of compound 130 and 131 against P. falciparum. compound 144 (Chart 61) with an EC50 of 28 nM and CC50 of 29 mM.
There was an increase in potency of nearly 1000 times compared to
Compound R R0 Dd2 IC50 (mM)
the starting compound a-thymidine (EC50 ¼ 23 mM). Nagle et al.
130 e e 0.44
[122] synthesized imidazole-piperazine hybrids and evaluated
131a H H 0.33
131b H OMe 0.30
them for their anti-malarial activities. They successfully optimized
131c Me H 0.35 a library of active anti-malarial agents. In order to further improve
CQ e e 0.50 their potency and metabolic stability profile, they modified the core
imidazolopiperazine scaffold, 145 and successfully got a lead
molecule having 8,8-dimethyl substituted piperazine ring moiety.
evaluated their anti-malarial activity against CQ-sensitive 3D7 The active molecule (146; Chart 62) was found to be much more
strain of P. falciparum. The most active compound (143; Chart 61) effective anti-malarial agent with enhanced oral exposure in vivo in
was found to be exhibiting much better anti-malarial activity (MIC mice.
0.035 mg/mL) as compared to standard drug CQ (MIC 0.125 mg/mL). Hybrids of cinnamic acid and chalcones showed promising anti-
Cui et al. [121] designed and synthesized hybrids of a-thymidine malarial activity against both CQ-resistant (W2) and CQ-sensitive
and urea derivatives and evaluated them for their anti-malarial (3D7) strain of P. falciparum. Four compounds (147; Chart 63)
Chart 56. Aminoquinoline e Mannich base hybrids.

Table 14 techniques may act at one or multiple targets, thus allowing for
Anti-malarial activity of compound 135. synergistic action.
Compound 3D7 W2 A review report from Chin Chung et al. [124] has described the
IC50 (nM)
synthesis of some new molecules by linking together three
different subunits: the carbamoyl from rivastigmine, the N-ben-
135a 11 9
zylpiperidine subunit of donezepil, and the arylhydrazone frag-
135b 3 2
CQ 16 431 ment of the anti-inflammatory compound LFQM19-27 to be used in
Chart 57. Quinoline e g-lactam based hybrids.
Chart 58. Chloroquinoline e hydroxypyridone/thiazone hybrids.
Chart 59. Amodiaquine and quinoline based hybrids.
were found to be more potent than standard drug chloroquine curing chronic disorders like Alzheimer's disease. Thalidomide
[123]. based hybrids have also been described therein. They have also
illustrated hybrid molecules comprising of various natural moieties
including coumarins, lipoic acid, ascorbic acid, etc. Some reports in
5. Hybrids exhibiting anti-inflammatory properties
the review revealed hybrids of aspirin with NO releasing as well as
H2S releasing counterparts.
Inflammation is related to several diseases, such as Alzheimer's
disease, asthma, atherosclerosis, rheumatoid arthritis, depression,
cancer; and disorders such as obesity and sexual dysfunction. 5.1. Hybrids based on natural pharmacophoric groups as anti-
Although inflammation is not the direct cause of these disorders inflammatory agents
but is accompanied by severe pain and sufferings. New anti-
inflammatory drugs developed using molecular hybridisation A series of novel biscoumarin-chalcone hybrids were
Chart 60. Ferrocenyl e thiosemicarbazone and poly(propyleneimine) dendrimers.
Chart 61. Isatin e pyrimidine/pyran hybrids.
Chart 62. Imidazole e piperazine hybrids.

synthesized by Sashidhara et al. [125]. The synthesized compounds

were evaluated for anti-inflammatory activity in carrageenan
induced paw oedema in albino rats. The volume of the paw was
measured plethysmographically immediately and after 3 h of the
injection of the irritant. The amount of oedema developed was
calculated from the difference in volumes. Percent inhibition of the
oedema between the control group and compound-treated groups
was calculated and was compared with the group receiving a
standard drug. Three compounds (148a-c; Chart 64) were found to
be showing good anti-inflammatory activity but not better than
standard drug ibuprofen. Compounds 148a, b and c exhibited 29%,
26% and 33% inhibition of the oedema at a dose of 100 mg/kg,
respectively whereas standard drug ibuprofen causes 59.5% inhi-
bition at the same dosage. Awadallah et al. [126] synthesized hy-
brids of quinazoline and pyrimidine and evaluated their anti-
inflammatory and ulcerogenic properties. Three compounds (149,
150a and b; Chart 64) showed potent anti-inflammatory activity
130.44, 114.03 and 116.73 mmol/kg, respectively at a dose of 50 mg/
kg against carrageenan induced rat paw oedema compared to the
Chart 63. Hybrids of cinnamic acid and chalcones. standard drug diclofenac (141.03 mmol/kg at 20 mg/kg dose). On
Chart 64. Bis-coumarin and bis-pyrimidine based hybrids.
checking the ulcerogenic effect (in terms of ulcer index-UI), com-

pounds 149 (UI 11.22) and 150b (UI 11.38) showed lesser ulcero-
genic effect than both standard drugs diclofenac (ulcerogenic, UI
17.02) and celecoxib (non-ulcerogenic, UI 12.51). On COX-2 selec-
tivity evaluation using COX-1/2 inhibition assay, the compounds
149 and 150a,b were found to be two fold selective for COX-2.
Hybrids of aspirin and NO/H2S releasing scaffolds (151; Chart
65) were found to have comparable activity to that of standard
drug aspirin [127]. Tale and Kamble et al. [128] synthesized hybrids
of flavone scaffold along with piperazine moiety. Synthesized
compounds were evaluated for their anti-inflammatory activity for
TNF-a and IL-6 cytokines. Some of the compounds showed excel-
lent results as compared to standard drug dexamethasone (152a,b,
Chart 65. Hybrids of aspirin and NO/H2S releasing scaffolds.
153a-c, Chart 66, Table 15). Table 15

Joseph et al. [129] designed a library of quinolone- Anti-inflammatory activity of compounds 152a-b and 153a-c.
thiazolidinone hybrids and shortlisted some of them for synthesis Compound R TNF-a IC-6
through molecular docking approach to act as NF-kB inhibitors. The % Inhibition at 10 mM
selected compounds were then synthesized and evaluated for anti-
152a 82 87
inflammatory activity by using carrageenan induced paw oedema
method. The most active compound (154; Chart 66) showed 25.16%
oedema inhibition as compared to 33.19% in case of standard drug
152b 80 84
indomethacin. However, indole-oxadiazole hybrids were synthe-
sized by Alla et al. [130] and evaluated for protection against
carrageenan induced rat paw oedema. The most potent compound
(155; Chart 66) showed 78.3% protection against oedema at a dose 153a 85 93
of 100 mg/kg which is quite better than that of standard drug
ibuprofen (72.8% protection against oedema).
Our group [131] has also contributed by designing chromone- 153b 87 93
indole/pyrazole based hybrid compounds and evaluated for their
anti-inflammatory activity by carrying out COX-1/2 inhibitory
immunoassay. Two compounds (156a,b; Chart 67) were found to 153c 85 91
have COX-2 inhibition at 29 nM and 20 nM, respectively as
compared to standard drug celecoxib (40 nM).
Dexamethasone - 71 84
Also, anti-nociceptive activity evaluation was carried out for
compound 156a by inhibiting capsaicin induced pain in mice.
Surprisingly, compound 156a showed much better relaxation from
pain by reducing the number of paw lickings by 76% at a dose of 5.2. Hybrids based on synthetic pharmacophores as anti-
10 mg/kg as compared to reduction of 68% paw lickings in case of inflammatory agents
standard drug diclofenac at a dose of 25 mg/kg. Getting inspired
from the fabulous results, another set of compounds [132] was Triazole is one of the chief multidisciplinary scaffolds that owe
designed and synthesized to carry out their anti-inflammatory many biological properties inherited in it and anti-inflammatory is
evaluation. This time hybrids by joining three moieties viz., one of them. As a result, it is quite explored in designing hybrid
indole, pyrazole and chromone were synthesized. Four out of the molecules, incorporating triazoles with other relevant moieties and
tested compounds (157a,b and 158a,b; Chart 67) showed signifi- evaluated as anti-inflammatory agents.
cant selectivity index (SI, Table 16), better than the standard drugs
diclofenac, indomethacin and chrysin while three compounds 5.2.1. Triazole based hybrids as anti-inflammatory agents
(157a,b and 158b) when checked for their anti-nociceptive activity Xu et al. [135] synthesized triazole-diaryl hybrids and evaluated
showed remarkable analgesic effect as compared to standard drug their anti-inflammatory activity from xylene induced ear oedema
diclofenac. Also, based upon the previous report [134], our group in mice. They optimized four compounds (160a,b and 161a,b; Chart
designed [133] and synthesized amino acid appended indoles as 69, Table 17) with potent anti-inflammatory activity compared to
effective 5-LOX inhibitors. Two compounds (159a,b; Chart 68) were standard drug celecoxib.
showing highly potent 5-LOX inhibitory activity with IC50 9.7 and In order to develop new anti-inflammatory agents with
8.6 nM, respectively. improved pharmacological profile and reduced risk of side-effects,
Tozkoparan et al. [136] designed and synthesized a series of com-
pounds incorporating triazole moiety along with ibuprofen scaf-
fold. The resulting compounds were evaluated in vivo for their anti-
inflammatory activity using carrageenan induced hind paw
oedema model in mice. Most of the synthesized compounds
showed moderate to high anti-inflammatory activity at a dose of
50 mg/kg while one of the compounds (162, 56% inhibition; Chart
69) showed comparable activity to that of ibuprofen (55% inhibi-
tion of carrageenan induced hind paw oedema in mice). Also, most
of the compounds were found to have less ulcerogenic effect as
compared to standard drugs indomethacin and ibuprofen.
5.2.2. NO-releasing hybrids as anti-inflammatory agents

Several hybrid molecules have been designed so as to release NO
during its metabolic breakdown during ADME. A series of nitric
oxide (NO) donating triazole-oxime hybrids were synthesized and
evaluated for their anti-inflammatory activity by Abou-Rahma et al.
[137]. Anti-inflammatory activity revealed several compounds with
comparable results to that of indomethacin while compound 163
(Chart 70) showed the most promising anti-inflammatory activity
with 82% inhibition of carrageenan induced oedema in mice after
4 h of administration comparable to 83% inhibition in case of
indomethacin. Also, compound 161 showed much improved ulcer
Chart 66. Flavone e piperazine, quinolone-thiazolidinone and indole-oxadiazole index than indomethacin. Further extending the work, the same
hybrids. group [138] designed and synthesized another series of compounds
Chart 67. Chromone e indole/pyrazole based hybrids.
Table 16 incorporating same counterparts but in a different manner. They

IC50 values of compounds 157 and 158 for COX-1/2. were also evaluated for their anti-inflammatory and ulcerogenic
Compound n IC50 (mM) SI (IC50COX-1/IC50COX-2) properties. The most promising anti-inflammatory activity was
exhibited by compound 164 (Chart 70) which showed 79% inhibi-
COX-2 COX-1
tion of carrageenan induced paw oedema in mice after 4 h com-
157a 3 0.7 118 168.5 parable to standard drug indomethacin.
157b 4 6.2 90 14.5
158a 3 7.9 102 12.9
Also, Fruttero et al. [139] synthesized NO-releasing hybrids of R-
158b 3 7.3 115 15.7 roscovotine. The synthesized compounds were evaluated as po-
Indomethacin e 0.96 0.08 0.08 tential pro-resolution agents of inflammation with their ability to
Diclofenac e 0.02 0.07 3.5 promote human neutrophil apoptosis. In particular, derivatives
Chrysin e 25.5 39.3 1.5
165a and 165b (Chart 71) were found to be significantly more
biologically active than the lead. This suggested an essential
contribution of the release of NO from the NO-mimetic compounds
to their enhanced biological activity.
Bothara et al. [140] synthesized hybrids involving N-phenylene
aminobenzoate derivatives along with NO-releasing molecular
entities and evaluated for anti-inflammatory, analgesic and ul-
cerogenic potential. Compound 166 (Chart 71) showed significant
anti-inflammatory, analgesic and non-ulcerogenic activity.
Isoxazole-mercaptobenzimidazole hybrids were synthesized by
Kankala, Vadde and Vasam et al. [141]. The synthesized hybrid
compounds were evaluated for their in vivo analgesic as well as
anti-inflammatory activities. Two compounds (167a, b; Chart 72,
Table 18) were found to be exhibiting potent activity compared to
standard drugs diclofenac and pentazocine.
Chart 68. Amino acid appended indoles. Adhikari et al. [142] synthesized pyridinyl-hydrazone hybrids
and evaluated the synthesized compounds for their anti-
Chart 69. Triazole e diaryl hybrids.

Table 17 inflammatory activity. Anti-inflammatory activities of the com-

Inhibitory effect of compounds on xylene-induced ear oedema in mice. pounds were evaluated using carrageenan induced paw oedema in
Compound R R0 %Inhibition mice. Two most potent compounds exhibited 66.46% (168a; Chart
160a F NH2SO2 75.0
72) and 65.86% (168b; Chart 72) inhibition after 3 h as compared
160b Cl NH2SO2 80.0 to 65.26% inhibition in case of standard drug diclofenac. Their
161a Br CH3SO2 70.8 analgesic activity was also comparable to the standards.
161b Cl NH2SO2 77.2 Xu et al. [143] synthesized triazole and hydroxyurea based
celecoxib e e 64.9
hybrid molecules and evaluated for potential anti-inflammatory
Chart 70. Triazole e aryl hybrids.
Chart 71. NO-releasing hybrids of R-roscovotine.
Chart 72. Hybrids of N-phenylene aminobenzoate and NO-releasing molecular entities.
Table 18
Anti-inflammatory and analgesic activity of compound 167.
Compound Anti-inflammatory (% inhibition after 3 h) Analgesic (% inhibition at 100 mg/kg)
167a 60.76 13.92

167b 58.46 13.87
Diclofenac 45.76 e
Pentazocine e 14.10 mg/kg
activity. The biological data revealed that all the compounds

showed dual COX-2/5-LOX inhibitory activities in vitro and com-
pound 169 (Chart 72) showed optimal inhibitory activities (COX-
2(IC50) 0.15 mM and 5-LOX (IC50) 0.85 mM) along with selectively
inhibiting COX-2 relative to COX-1 with selectivity index
(SI ¼ 0.012) comparable to celecoxib (SI ¼ 0.015). It also displayed
promising analgesic activity in acetic acid-induced writhing
response and hot-plate assay.
6. Hybrids exhibiting anti-cancer properties
A recent review by Berube et al. [144] has incorporated the latest

information about the development of hybrid molecules as anti-
cancer agents. They have divided the review into two sections
that take into account hybrid anticancer molecules synthesized by;
i) merging or blending haptophoric moieties of different drugs and
Chart 73. Hybrids of isoflavene and propranolol. ii) combining two or several entire drugs together. Nepali et al.
[145] have also commented on the hybrid molecules for anti-cancer
Chart 74. Benzimidazole e coumarin/pyrimidine hybrids.
Chart 75. Coumarin e monastrol hybrids.

Chart 76. Hybrids of pyrazole-quinoline-pyridine; hybrids from O2-(2,4-dinitrophenyl)- diazeniumdiolate and OA.
Chart 77. Hybrids based on curcumin and thalidomide.
Chart 78. Thiazolidinone e isatin and indole e pyrimidine based hybrids.
activity. Other recent literature reports that incorporate various 6.1. Hybrids incorporating natural moieties as anticancer agents
natural and synthetic moieties within single molecules have been
discussed here. Kumar et al. [146] have designed and synthesized hybrids of
isoflavene and propranolol because both the moieties are inherited
with anti-cancer properties. The hybrid compounds were analysed
against SHEP neuroblastoma and MDA-MB-231 breast adenocar-
cinoma cell lines and were found to exhibit potent anti-
proliferative activities. The most potent compounds (170a and
170b; Chart 73, GI50 in mM) showed higher activity profiles than
that of both the standard drugs isoflavene and propranolol.
Paul et al. [147] synthesized coumarin-benzimidazole hybrids
and evaluated their anti-cancer activity. The compounds were
screened against 60 cell line panel of human cancer cells. Out of the
Chart 79. Isothiocyanate e pterostilbene hybrids. screened compounds, one compound (171; Chart 74) was found to
be inhibiting more than 50% cancer growth at leukaemia, colon well as when used in combination. Adding to this, mechanistic
cancer and breast cancer cell lines. In another report [148], the studies in U266 cells demonstrated that the two hybrids (178 and
same group synthesized hybrids of substituted quinazoline and 179) can induce the production of reactive oxygen species (ROS)
benzimidazole moieties and carried out their similar studies. One of and cause G1/S arrest, thus leading to apoptosis and cell death.
the compounds (172; GI50 0.81 mM; Chart 74) exhibited more ac- On the other hand, Lesyk et al. [155] synthesized thiazolidinone-
tivity compared to both monomeric analogues, quinazoline and isatin based hybrids and evaluated for their anti-cancer activity. The
benzimidazole, respectively. synthesized compounds were evaluated for in vitro cell line
Amongst the coumarin-monastrol hybrids (173; Chart 75) [149] screening at National cancer institute (NCI). The two most active
and trioxane-egonol hybrids [150], compound 174 (IC50 0.57 mM; compounds (180a, b; Chart 78) exhibited a mean growth inhibition
Chart 75) was the most potent against the tested multidrug- of 44.28 and 32.09%, respectively. Also, Crooks et al. [156] synthe-
resistant leukaemia CEM/ADR5000 cells and also possesses a de- sized hybrids of N-benzylated indole and barbiturates and carried
gree of cross-resistance of 2.34. out their anti-cancer screening against 60 cell line panel of human
Zhu et al. [151] synthesized hybrids of pyrazole-quinoline and cancer. On in vitro anti-cancer screening, four compounds (181a-d;
pyridine and evaluated their anti-proliferative activity. The most Chart 78) were identified as lead compounds with GI50 in nM range
potent compound (175; Chart 76) showed an IC50 0.18 mM against against certain cell lines. Compound 181a showed GI50 20 nM
A549 cell line of human alveolar basal epithelial cancer and showed against OVCAR-5 cell line of ovarian cancer while it showed GI50
IC50 0.51 mM against EGFR inhibitory assay. 40 nM against MDA-MB-468 cell line of breast cancer. Another
A series of hybrids from O2-(2,4-dinitrophenyl)- dia- compound 181b exhibited GI50 40 nM against A498 cell line of renal
zeniumdiolate and OA were designed and synthesized by Zhang cancer. While compounds 181c and 181d exhibited GI50 30 nM
et al. [152] and were biologically evaluated as novel nitric oxide against MDA-MB-468 cell line of breast cancer.
(NO)-releasing prodrugs that could be activated by glutathione S- Roy et al. [157] synthesized a novel class of hybrid compounds
transferase p (GSTp) over-expressed in a number of cancer cells. It by introducing isothiocyanate moiety in pterostilbene and evalu-
was discovered that the most active compound (176; Chart 76) ated for their anti-cancer activity in hormone-dependent breast
released high levels of NO selectively in HCC cells but not in the cancer cell line (MCF-7) in vitro and Ehrlich ascetic tumor bearing
normal cells and exhibited potent anti-proliferative activity in vitro mice model in vivo. The novel compound (182; Chart 79) showed
as well as remarkable tumor-retarding effects in vivo. Dholakia et al. better in vitro anti-cancer activity (IC50 25 mM) in comparison to the
[153] synthesized nucleobases based hybrids with barbiturates and reference compound pterostlibene (IC50 65 mM). The compound
carried out their anti-cancer activities against HepG2, WI-38, VERO also inhibited tumor growth in tumor bearing mice.
and MCF-7 cell lines. The most active compound (177; Chart 77)
showed cytotoxicity at all the tested cell lines with IC50 18, 24, 16 6.2. Hybrids incorporating synthetic moieties as anticancer agents
and 16 mM against WI-38, VERO, MCF-7 and HEPG-2 cell lines,
respectively but lesser than the standard drug 5-fluorouracil (IC50 Behr et al. [158] synthesized pyrrolidine-ferrocene hybrids and
10, 8, 10 and 5 mM, respectively). Zhang et al. [154] designed and evaluated anti-proliferative potential against MDA-MB-231 breast-
synthesized hybrids based on curcumin and thalidomide for eval- cancer cell line. The best compound (183; Chart 80) showed a
uation against multiple myeloma MM1S, RPMI8226, U266 cells and strong anti-proliferative effect, with up to 100% inhibition of the
lung cancer A549 cells in humans. Two of the hybrid compounds proliferation of MDA-MB-231 cancer cells at 50 mm concentration.
(178 and 179; Chart 77) exhibited significantly improved lethal Top and Jaouen et al. [159] synthesized hydroxyferrocifen hy-
effects towards all three human MM cell models compared to both brids and evaluated for their anti-cancer activity against triple-
the parent moieties thalidomide and curcumin when used alone as negative breast cancer cells. On anti-proliferative activity
Chart 80. Pyrrolidine/alkylidene e ferrocene hybrids.
Chart 81. Triazole e dithiocarbamate hybrids.

Table 19 and carboxylic acids against breast cancer cells while bisamides
Anti-proliferative activity of compounds 185 and 186. showed very poor activity. Liu et al. [160] synthesized novel
Compound R IC50 (mM) triazole-dithiocarbamate hybrids and evaluated their anti-
MGC-803 MCF- 7 SMMC-7721 EC-9706
proliferative activity against four selective human cancer cell
a
lines. One of the compounds (185; Chart 81) was found to be more
185 e 0.73 5.67 11.61PC-3 2.44EC-109a
potent than standard drug 5-fluorouracil against all the tested cell
5-FU e 7.01 7.54 27.07PC-3a 3.34 EC-109a
186a o-Fluoro 1.62 1.86 7.13 20.84 lines. Further, extending the work [161], they added urea moiety to
186b p-Fluoro 0.76 1.66 5.97 12.19 the previous compounds and a modified library was obtained. The
a
Designates the IC50 value at the subscripted cell lines. new hybrids were evaluated for their anti-proliferative activity
against four selective human cancer cell lines (MGC-803, MCF-7,
SMMC-7721 and EC-9706). The most active compounds 186a and
186b (Chart 81, Table 19) showed a broad spectrum anti-
proliferative activity against the tested cell lines with IC50 in the
range of 1.62e20.84 mM and 0.76e13.55 mM, respectively.
Abuo-Rahma et al. [162] synthesized hybrid molecules
comprising of piperazinyl, ciprofloxacin and chalcone moieties in
single molecules and carried out their anti-cancer and TOPO-I/II
inhibitory activity. One dose anti-cancer results revealed com-
pounds with high potency of cancer growth inhibition. In terms of
GI50, one of the compounds (187; Chart 82) showed pronounced
selectivity (6.71) for leukaemia cancer.
Chart 82. Piperazinyl e ciprofloxacin e chalcone hybrids.
Our group has also worked on synthesizing small hybrid mol-
ecules based on two biologically significant moieties. Based on the
evaluation against breast cancer cell lines MDA-MB-231, the lowest previous report [163] characterising indole-barbiturate based
IC50 value was found for the hydroxamic acid hybrid (184; 1.3 mM; hybrid molecules as lead compounds with much effective anti-
Chart 80). It was observed that the hydroxamic acids of both cancer activities, more hybrid compounds were synthesized
phenolic series were more anti-proliferative than primary amides (188e193; Chart 83) [164] by reacting together chromone, indole,
pyrazole and barbiturate moieties. Their evaluation for anti-cancer
Chart 83. Chromone, indole, pyrazole and barbiturate based hybrid molecules.
activity was performed at NCI, USA over 60 cell line panel of human A. Mohan, R.R. Iyer, R. Ramakrishnan, A.C. Tawte, D.D. Rao, PCT Int. Appl.
(2012). WO 2012172562 A2 20121220.
cancer cells. The most active compound (192; R ¼ H, R’ ¼ 2, 6-
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Hybrid Molecules The Privileged Scaffolds For Various

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European Journal of Medicinal Chemistry 124 (2016) 500e536

Contents lists available at ScienceDirect

European Journal of Medicinal Chemistry

Hybrid molecules: The privileged scaffolds for various

4.1. Hybrids based on natural pharmacophores as anti-malarial agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512

1. Introduction recently been reviewed by Chaudhary et al. [3]. Nikkomycin and

Chart 1. Nikkomycin and polyoxin based hybrid molecules.

Compound R MIC (mg/mL) IC50 (mg/mL)

Table 2 they reported another category of ﬂuconazole hybrids with fur-

Chart 3. Coumarin derivatives.

Chart 4. Schiff bases of coumarin and coumarin-thiazole hybrids.

3.1.1. Hybrids of quinoline-triazole as anti-tuberculosis agents

Chart 6. Bis-coumarin e thiazole hybrids.

Chart 7. Simple natural molecules e active antifungal agents.

Chart 8. Fluconazole e benzoxazinone/benzothiazinone hybrids.

Chart 9. Triazole based hybrid molecules.

Chart 10. Quinoline e triazole hybrids.

Chart 11. Quinoline e triazole hybrids.

resulted into lesser potency of the resulting molecule than the

Chart 13. Naphthilamide e imidazole hybrids.

Chart 14. Triphenyl imidazoles.

Table 3 pyrrolothiazoles (65; Chart 31) showed equipotency to that of the

Chart 15. Imidazole e thiazole and imidiazole e pyrazole hybrids.

Chart 16. Hybrids of metroindazole and berberine.

Chart 19. Thiazole-benzotriazole hybrids.

0.78 mg/mL. Padhye et al. [65] synthesized isoniazide-pyruvate

Chart 20. Sulphanilamide-thiourea hybrids.

CH3 3. Hybrids proﬁling anti-malarial activity

Chart 22. Hybrids of quinoline and triazole.

Chart 23. Hybrids of quinoline and carbohydrazide.

Chart 24. Quinoline e carbazole hybrids.

Table 4 4.1. Hybrids based on natural pharmacophores as anti-malarial

Chart 25. Quinolone-hydrazide hybrids.

Table 5 modiﬁcation and development of quinoline based hybrid molecules

Chart 26. Bis-quinolone e Isoniazide hybrids.

Chart 27. Quinazoline and quinoline based hybrids.

them against various strains of P. falciparum. The most active

Chart 30. Piperazinyl e phenanthridine hybrids.

Chart 31. Thiolactone e isatin and isatin e nalidixic acid hybrids.

Chart 32. Isatin based hybrid molecules.

(MIC 0.125 mg/mL) while compound 115 (Chart 48), a quinoline-

Chart 35. Hybrids of ferrocene e hydrazones and chromenyl e barbiturate.

Chart 36. Hybrids of benzimidazole and carbohydrazide.

Chart 37. Benzimidazole e pyran and pyrazolone e carbazole hybrids.

sensitive and CQ-resistant strains of P. falciparum in comparison to

Chart 38. Dapsone-azetidinone and dapsone-thiazolidinone hybrids.

Chart 39. Hybrid of coumarin e benzofuran and tetrazole e triazole.

Chart 40. Hybrids of naphthoimidazoles e naphthoxazole and pyrido e quinazoline.

Chart 41. Triazole tethered b-lactam-ferrocenes.

Chart 43. Benzothiazole e pyrazolone and imidazo e thiadiazole hybrids.

Chart 45. Lamivudine e isonicotinic acid hybrids.

Chart 46. Ferroquine e chloroquine hybrids.

Chart 47. Hybrids of quinoline with ferrocene.

Chart 48. Quinoline e piperazine and quinoline e triazine hybrids.

Compound R R0 X/n P. falciparum (W2 clone) IC50 (mM)

117a Morpholine 3,5-dimethoxy aniline 1,3-propanediamine 0.22

118b -do- -N(Me)2 n¼1 1.15

118e -do- -do- n¼2 0.73

Chart 49. Triazole - quinoline e triazine hybrids.

Compound n R P. falciparum (D6 clone) IC50 (mM)

119a 1 N-methyl piperazine 0.005

Chart 50. Hybrids of aminoquinoline and pyrimidine.

Chart 51. Quinoline e pyrimidine hybrids.