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SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF NEW SUBSTITUTED


AZETIDINONYL INDOLYLTRIAZOLE DERIVATIVES

Singh I1, Singh N, Kaur H, Vishwakarma P, Sharma M, Kumar S, Saxena K K,

Kumar A** and Kumar A*

*Medicinal Chemistry Division, Department of Pharmacology, L.L.R.M. Medical College,

Meerut 250004, U. P. India.


**
Department of SPM , L.L.R.M. Medical College, Meerut 250004, U. P. India.

ABSTRACT

Cyclocondensation of 4-[2‫׳‬-substituted alkyl/aryl-5‫׳‬-methoxy-3‫׳‬-indolylideno]-3-ethanethioat-5-(substituted


phenyl)-1,2,4-triazoles (3a-3h) and 4-[2‫׳‬-substituted alkyl/aryl-5‫׳‬-methoxy-3‫׳‬-indolylideno]-3-benzothioat-5-
(substituted phenyl)-1,2,4-triazoles (4a-4h) with chloroacetyl chloride give 4-[3‫׳׳‬-chloro-2‫׳‬2)-‫׳׳‬-substituted
alkyl/aryl-5‫׳‬-methoxy-3‫׳‬-indolylideno)-4‫׳׳‬-oxoazetidinyl]-3-ethanethioat-5-(substituted phenyl)-1,2,4-triazoles
(5a-5h) and 4-[3‫׳׳‬-chloro-2‫׳‬2)-‫׳׳‬-substituted alkyl/aryl-5‫׳‬-methoxy-3‫׳‬-indolylideno)-4‫׳׳‬-oxoazetidinyl]-3-
benzothioat-5-(substituted phenyl)-1,2,4-triazoles (6a-6h) respectively. All the synthesized compounds were
screened for their antibacterial activity and compared with reference drugs Ciprofloxacin and Gattifloxacin.
The compound 5h was the most potent compound of this series. This compound exhibited promising
antibacterial activity against S. aureus (26mm), E.coli (24mm), P. vulgaris (22mm) and K.pneumoniae
(23mm). Structure of all the synthesized compounds have been characterized by elemental (C,H,N) and
spectral (IR and 1HNMR ) analysis.

Keywords: Triazoles, Indolyltriazoles, Azetidinonyltriazoles, antibacterial activity, acute toxicity.

____________________________

1
Part of the Ph.D. thesis work

*Corresponding author. Tel.: 91-0121-2764084, Mob.: +919917053074

E-mail address: rajputak@gmil.com (A. Kumar), Fax: +91 121 2760888


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INTRODUCTION

Triazole derivatives are the nitrogen containing heterocyclic compounds displaying a wide variety of

biological and pharmacological activities like antibacterial1,2, antifungal3,4, anti-inflammatory5, antihistaminic6,

antitubercular7, analgesic8, anticancer9 specially antibacterial activity. It is interesting to note from chemical

literature that various indole10 and azetidinone 11,12 derivatives were also found to possess wide spectrum of

antibacterial activity. In light of above observations it was thought worthwhile to synthesized some new

substituted triazole derivatives by incorporation of indole and azetidinone moieties with the hope to get better

antibacterial agents.

MATERIALS & METHODS

The melting point of compounds were determined in open capillaries and are uncorrected. The homogeneity

of the synthesized compounds was routinely checked by thin layer chromatography on silica gel-G plates. The

IR spectra were recorded on a Beckman Acculab-10 spectrometer (ν max in cm-1) and the 1H NMR spectra

were recorded by Brucker DPX-300MHz using CDCl3 as solvent.

General procedure for synthesis of 4-amino-5-(substituted phenyl)-3-mercapto-1,2,4-triazoles (1a-1b)

In methanolic solution of substituted aromatic acid hydrazides (1.0 mole), potassium hydroxide (1.5 mole)

and carbon di sulfide (1.0 mole) were added and stirred vigorously for 2-3 h. After stirrring excess of

hydrazine hydrate was added and the mixtures were further refluxed for 4 h. The completion of the reaction

was checked by TLC. The reaction mixtures were cooled and poured into ice water and neutralized with

concentrated HCl. The solids thus obtained were filtered, washed with water and recrystallized from

appropriate solvents to obtained coumpounds 1a and 1b.

General procedure for synthesis of 4-[2‫׳‬-substituted alkyl/aryl-5‫׳‬-methoxy-3‫׳‬-indolylideno]-3-mercapto-

5-(substituted phenyl)-1,2,4-triazoles (2a-2h)


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To a solution of 4-amino-5-(substituted phenyl)-3-mercapto-1,2,4-triazoles 1a-1b (0.5 mole) in methanol (50

mL), 2-substituted-5-methoxyindolaldehydes (0.5 mole) were added separately in presence of glacial acetic

acid. The reaction mixtures were refluxed for 10 h. The solvents were distilled off at reduced pressure and the

solids thus obtained were recrystallized from appropriate solvents to yielded compounds 2a-2h.

General procedure for synthesis of 4-[2‫׳‬-substituted alkyl/aryl-5‫׳‬-methoxy-3‫׳‬-indolylideno]-3-

ethanethioat-5-(substituted phenyl)-1,2,4-triazoles (3a-3h)

To a the mixtures of compounds 2a-2h (0.08 mole) in dry ether, acetylchloride (0.16 mole) was added

dropwise with stirring separetelly. The reaction mixtures were refluxed for 5 h. The solvents were distilled off

separetelly and the reaction mixtures were poured onto crused ice. The solids thus obtained were washed with

water and recrystallized from appropriate solvents.

General procedure for synthesis of 4-[2‫׳‬-substituted alkyl/aryl-5‫׳‬-methoxy-3‫׳‬-indolylideno]-3-

benzothioat-5-(substituted phenyl)-1,2,4-triazoles (4a-4h)

A mixture of compounds 2a-2h (0.08 mole) in dry ether, benzoylchloride (0.16 mole) was added dropwise

with stirring separetelly. The reaction mixtures were refluxed for 6 h. Excess of solvent of each mixtures

were distilled off and poured onto crused ice. The solids thus obtained were washed with water and

recrystallized from appropriate solvents to give compounds 4a-4h

General procedure for synthesis of 4-[3‫׳׳‬-chloro-2‫׳‬2)-‫׳׳‬-substituted alkyl/aryl-5‫׳‬-methoxy-3‫׳‬-indolylideno)-

4‫׳׳‬-oxoazetidinyl]-3-ethanethioat-5-(substituted phenyl)-1,2,4-triazoles (5a-5h)

A mixtures of compounds 3a-3h (0.01 mole) in dry dioxane (50 mL), the chloro acetyl chloride (0.015 mole)

was added in presence of triethylamine (0.008 mole). The reaction mixtures were stirred at 0 0C. Each

mixtures were further stirred at room temperature then kept aside for 48 h. The reaction mixtures were poured
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into water. The solids thus obtained were filtered, dried and recrystallized from appropriate solvents to

furnish compounds 5a-5h.

General procedure for synthesis of 4-[3‫׳׳‬-chloro-2‫׳‬2)-‫׳׳‬-substituted alkyl/aryl-5‫׳‬-methoxy-3‫׳‬-indolylideno)-

4‫׳׳‬-oxoazetidinyl]-3-benzothioat-5-(substituted phenyl)-1,2,4-triazoles (6a-6h)

A mixtures of compounds 4a-4h (0.01 mole) in dry dioxane (50 mL), the chloro acetyl chloride (0.015 mole)

was added in presence of triethylamine (0.008 mole). The reaction mixtures were stirred at 0 0C. Each

mixtures were further stirred at room temperature then kept aside for 50 h. The reaction mixtures were poured

into water. The solids thus obtained were filtered, dried and recrystallized from appropriate solvents.

1a. IR (KBr): 3320 (NH2), 3114 (CH aromatic), 2713 (SH), 1682 (C=N), 1612 (C-C of aromatic
ring), 1295 (N-N) cm-1. 1HNMR (CDCl3 + DMSO-d6) δ in ppm: 11.30 (s, 1H, SH exchangeable
with D2O), 8.87 (s, 2H, NH2 exchangeable with D2O), 7.70-8.32 (m, 5H, ArH).

1b. IR (KBr): 3420 (OH), 3321 (NH2), 3115 (CH aromatic), 2712 (SH), 1680 (C=N), 1613 (C-C
of aromatic ring), 1296 (N-N) cm-1. 1HNMR (CDCl3 + DMSO-d6) δ in ppm: 12.52 (s, 1H, OH
exchangeable with D2O), 11.39 (s 1H, SH exchangeable with D2O), 8.88 (s, 2H, NH2
exchangeable with D2O), 7.71-8.31 (m, 4H, ArH).

2a. IR (KBr): 3250 (NH straching), 3145 (CH aromatic), 2711 (SH), 1682 (C=N), 1614 (C-C of
aromatic ring), 1295 (N-N), 1228 (OCH3) cm-1. 1HNMR (CDCl3 + DMSO-d6) δ in ppm: 11.37 (s,
1H, SH exchangeable with D2O), 8.81 (s, 1H, N=CH- indole), 7.72-8.32 (m, 8H, Ar-H), 7.50 (s,
1H, C=CH of pyrole ring of indole), 7.24 (s, 1H, NH exchangeable with D2O), 3.48 (s, 3H,
OCH3).

2b. IR (KBr): 3428 (OH), 3255 (NH str), 3146 (CH aromatic), 2712 (SH), 1680 (C=N), 1615
(C-C of aromatic ring), 1296 (N-N), 1230 (OCH3) cm-1. 1HNMR (CDCl3 + DMSO-d6) δ in ppm:
12.53 (s, 1H, OH exchangeable with D2O), 11.35 (s, 1H, SH exchangeable with D2O), 8.87 (s,
1H, N=CH- indole), 7.71-8.31 (m, 7H, Ar-H), 7.55 (s, 1H, C=CH of pyrole ring of indole), 7.23
(s, 1H, NH exchangeable with D2O), 3.46 (s, 3H, OCH3).

2c. IR (KBr): 3145 (CH aromatic), 2850 (CH3 of indole), 2715 (SH), 1685 (C=N), 1618 (C-C of
aromatic ring), 1298 (N-N), 1232 (OCH3) cm-1. 1HNMR (CDCl3 + DMSO-d6) δ in ppm: 11.32 (s,
1H, SH exchangeable with D2O), 8.89 (s, 1H, N=CH- indole), 7.71-8.30 (m, 8H, Ar-H), 7.21 (s,
1H, NH exchangeable with D2O), 3.43 (s, 3H, OCH3), 2.23 (s, 3H, CH3 of indole).

2d. IR (KBr): 3430 (OH), 3147 (C-H aromatic), 2854 (CH3 of indole), 2718 (SH), 1684 (C=N),
1619 (C-C of aromatic ring), 1297 (N-N), 1231 (OCH3) cm-1. 1HNMR (CDCl3 + DMSO-d6) δ in
5

ppm: 12.55 (s, 1H, OH exchangeable with D2O), 11.33 (s, 1H, SH exchangeable with D2O), 8.87
(s, 1H, N=CH - indole), 7.71-8.31 (m, 7H, Ar-H), 7.20 (s, 1H, NH exchangeable with D2O), 3.42
(s, 3H, OCH3), 2.24 (s, 3H, CH3 of indole).

2e. IR (KBr): 3150 (CH aromatic), 2720 (SH), 1683 (C=N), 1620 (C-C of aromatic ring), 1299
(N-N), 1236 (OCH3) cm-1.1HNMR (CDCl3 + DMSO-d6) δ in ppm: 11.31 (s, 1H, SH
exchangeable with D2O), 8.85 (s, 1H, N=CH -indole), 7.70-8.31 (m, 13H, Ar-H), 7.23 (s, 1H,
NH exchangeable with D2O), 3.45 (s, 3H, OCH3).

2f. IR (KBr): 3428 (OH), 3154 (CH aromatic), 2722 (SH), 1681 (C=N), 1625 (C-C of aromatic
ring), 1296 (N-N), 1233 (OCH3) cm-1. 1HNMR (CDCl3 + DMSO-d6) δ in ppm: 12.53 (s, 1H, OH
exchangeable with D2O), 11.32 (s, 1H, SH exchangeable with D2O), 8.83 (s, 1H, N=CH- indole),
7.70-8.30 (m, 12H, Ar-H), 7.21 (s, 1H, NH exchangeable with D2O), 3.43 (s, 3H, OCH3).

2g. IR (KBr): 3156 (CH aromatic), 2718 (SH), 1683 (C=N), 1632 (C-C of aromatic ring), 1298
(N-N), 1235 (OCH3), 760 (C-Cl) cm-1. 1HNMR (CDCl3 + DMSO-d6) δ in ppm: 11.35 (s, 1H, SH
exchangeable with D2O), 8.84 (s, 1H, N=CH -indole), 7.72-8.30 (m, 12H, Ar-H), 7.24 (s, 1H,
NH exchangeable with D2O), 3.45 (s, 3H, OCH3).

2h. IR (KBr): 3426 (OH), 3158 (CH aromatic), 2720 (SH), 1685 (C=N), 1635 (C-C of aromatic
ring), 1297 (N-N), 1234 (OCH3), 763 (C-Cl) cm-1. 1HNMR (CDCl3 + DMSO-d6) δ in ppm: 12.52
(s, 1H, OH exchangeable with D2O), 11.30 (s, 1H, SH exchangeable with D2O), 8.83 (s, 1H,
N=CH- indole), 7.70-8.30 (m, 11H, Ar-H), 7.21 (s, 1H, NH exchangeable with D2O), 3.44 (s,
3H, OCH3).

3a. IR (KBr): 3360 (NH), 3155 (CH aromatic), 1720 (C=O), 1690 (C=N), 1638 (C-C of
aromatic ring), 1299 (N-N), 1235 (OCH3), 681 (C-S-C) cm-1. 1HNMR (CDCl3 + DMSO-d6) δ in
ppm: 8.86 (s, 1H, N=CH- indole), 7.72-8.31 (m, 8H, Ar-H), 7.55 (s, 1H, C=CH of pyrole ring of
indole), 7.20 (s, 1H, NH exchangeable with D2O), 3.45 (s, 3H, OCH3), 2.24 (s, 3H, CH3).

3b. IR (KBr): 3350 (NH), 3154 (CH aromatic), 1730 (C=O), 1689 (C=N), 1635 (C-C of
aromatic ring), 1294 (N-N), 1233 (OCH3), 685 (C-S-C) cm-1. 1HNMR (CDCl3 + DMSO-d6) δ in
ppm: 12.54 (s, 1H, OH exchangeable with D2O), 8.82 (s, 1H, N=CH- indole), 7.70-8.30 (m, 7H,
Ar-H), 7.56 (s, 1H, C=CH of pyrole ring of indole), 7.21 (s, 1H, NH exchangeable with D2O),
3.44 (s, 3H, OCH3), 2.23 (s, 3H, CH3).

3c. IR (KBr): 3355 (NH), 3159 (CH aromatic), 1735 (C=O), 1685 (C=N), 1631 (C-C of
aromatic ring), 1293 (N-N), 1237 (OCH3), 683 (C-S-C) cm-1. 1HNMR (CDCl3 + DMSO-d6) δ in
ppm: 8.81 (s, 1H, N=CH indole), 7.71-8.30 (m, 8H, Ar-H), 7.23 (s, 1H, NH exchangeable with
D2O), 3.46 (s, 3H, OCH3), 2.28 (s, 3H, CH3), 2.24 (s, 3H, CH3 of indole).

3d. IR (KBr): 3431 (OH), 3342 (NH), 3157 (CH aromatic), 2880 (CH3), 1733 (C=O), 1683
(C=N), 1636 (C-C of aromatic ring), 1295 (N-N), 1231 (OCH3), 688 (C-S-C) cm-1 . 1HNMR
(CDCl3 + DMSO-d6) δ in ppm: 12.52 (s, 1H, OH exchangeable with D2O), 8.83 (s, 1H, N=CH-
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indole), 7.70-8.31 (m, 7H, Ar-H), 7.21 (s, 1H, NH exchangeable with D2O), 3.42 (s, 3H, OCH3),
2.29 (s, 3H, CH3), 2.22 (s, 3H, CH3 of indole).

3e. IR (KBr): 3340 (NH), 3155 (CH aromatic), 2900 (CH3), 1731 (C=O), 1681 (C=N), 1637 (C-
C of aromatic ring), 1297 (N-N), 1233 (OCH3), 685 (C-S-C) cm-1. 1HNMR (CDCl3 + DMSO-d6)
δ in ppm: 8.81 (s, 1H, N=CH- indole), 7.72-8.30 (m, 13H, Ar-H), 7.20 (s, 1H, NH exchangeable
with D2O), 3.45 (s, 3H, OCH3), 2.30 (s, 3H, CH3).

3f. IR (KBr): 3428 (OH), 3350 (NH), 3157 (CH aromatic), 2890 (CH3), 1732 (C=O), 1685
(C=N), 1635 (C-C of aromatic ring), 1295 (N-N), 1235 (OCH3), 681 (C-S-C) cm-1. 1HNMR
(CDCl3 + DMSO-d6) δ in ppm: 12.55 (s, 1H, OH exchangeable with D2O), 8.83 (s, 1H, N=CH-
indole), 7.70-8.30 (m, 12H, Ar-H), 7.22 (s, 1H, NH exchangeable with D2O), 3.47 (s, 3H,
OCH3), 2.27 (s, 3H, CH3).

3g. IR (KBr): 3355 (NH), 3158 (CH aromatic), 1733 (C=O), 1683 (C=N), 1625 (C-C of
aromatic ring), 1298 (N-N), 1235 (OCH3), 761 (C-Cl), 682 (C-S-C) cm-1. 1HNMR (CDCl3 +
DMSO-d6) δ in ppm: 8.85 (s, 1H, N=CH- indole), 7.71-8.32 (m, 12H, Ar-H), 7.20 (s, 1H, NH
exchangeable with D2O), 3.48 (s, 3H, OCH3), 2.25 (s, 3H, CH3).

3h. IR (KBr): 3340 (NH), 3156 (CH aromatic), 1731 (C=O), 1687 (C=N), 1628 (C-C of
aromatic ring), 1291 (N-N), 1237 (OCH3), 765 (C-Cl), 683 (C-S-C) cm-1. 1HNMR (CDCl3 +
DMSO-d6) δ in ppm: 12.53 (s, 1H, OH exchangeable with D2O), 8.82 (s, 1H, N=CH-indole),
7.70-8.30 (m, 11H, Ar-H), 7.21 (s, 1H, NH exchangeable with D2O), 3.44 (s, 3H, OCH3), 2.24 (s,
3H, CH3).

4a. IR (KBr): 3348 (NH), 3157 (CH aromatic), 1738 (C=O), 1686 (C=N), 1630 (C-C of
aromatic ring), 1295 (N-N), 1231 (OCH3), 687 (C-S-C) cm-1. 1HNMR (CDCl3 + DMSO-d6) δ in
ppm: 8.84 (s, 1H, N=CH- indole), 7.71-8.30 (m, 13H, Ar-H), 7.53 (s, 1H, C=CH of pyrole ring
of indole), 7.20 (s, 1H, NH exchangeable with D2O), 3.47 (s, 3H, OCH3).

4b. IR (KBr): 3429 (OH), 3346 (NH), 3158 (CH aromatic), 1736 (C=O), 1685 (C=N), 1635 (C-
C of aromatic ring), 1294 (N-N), 1232 (OCH3), 684 (C-S-C) cm-1 . 1HNMR (CDCl3 + DMSO-
d6) δ in ppm: 12.54 (s, 1H, OH exchangeable with D2O), 8.81 (s, 1H, N=CH -indole), 7.70-8.31
(m, 12H, Ar-H), 7.57 (s, 1H, C=CH of pyrole ring of indole), 7.23 (s, 1H, NH exchangeable with
D2O), 3.46 (s, 3H, OCH3).

4c. IR (KBr): 3345 (NH), 3155 (CH aromatic), 2853 (CH3), 1732 (C=O), 1684 (C=N), 1632 (C-
C of aromatic ring), 1290 (N-N), 1233 (OCH3), 685 (C-S-C) cm-1. 1HNMR (CDCl3 + DMSO-d6)
δ in ppm: 8.82 (s, 1H, N=CH- indol), 7.70-8.30 (m, 13H, Ar-H), 7.21 (s, 1H, NH exchangeable
with D2O), 3.47 (s, 3H, OCH3), 2.24 (s, 3H, CH3 of indole).

4d. IR (KBr): 3427 (OH), 3344 (NH), 3157 (CH aromatic), 2851 (CH3), 1734 (C=O), 1683
(C=N), 1630 (C-C of aromatic ring), 1295 (N-N), 1234 (OCH3), 682 (C-S-C) cm-1. 1HNMR
(CDCl3 + DMSO-d6) δ in ppm: 12.53 (s, 1H, OH exchangeable with D2O), 8.80 (s, 1H, N=CH-
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indole), 7.70-8.31 (m, 12H, Ar-H), 7.23 (s, 1H, NH exchangeable with D2O), 3.45 (s, 3H,
OCH3), 2.23 (s, 3H, CH3 of indole).

4e. IR (KBr): 3346 (NH), 3154 (CH aromatic), 1737 (C=O), 1685 (C=N), 1633 (C-C of
aromatic ring), 1297 (N-N), 1232 (OCH3), 681 (C-S-C) cm-1. 1HNMR (CDCl3 + DMSO-d6) δ in
ppm: 8.81 (s, 1H, N=CH- indole), 7.71-8.32 (m, 18H, Ar-H), 7.21 (s, 1H, NH exchangeable with
D2O), 3.48 (s, 3H, OCH3).

4f. IR (KBr): 3428 (OH), 3345 (NH), 3156 (CH aromatic), 1733 (C=O), 1684 (C=N), 1631 (C-
C of aromatic ring), 1293 (N-N), 1234 (OCH3), 683 (C-S-C) cm-1. 1HNMR (CDCl3 + DMSO-d6)
δ in ppm: 12.54 (s, 1H, OH exchangeable with D2O), 8.82 (s, 1H, N=CH- indole), 7.71-8.30 (m,
17H, Ar-H), 7.20 (s, 1H, NH exchangeable with D2O), 3.45 (s, 3H, OCH3).

4g. IR (KBr): 3343 (NH), 3152 (CH aromatic), 1735 (C=O), 1685 (C=N), 1636 (C-C of
aromatic ring), 1294 (N-N), 1231 (OCH3), 763 (C-Cl), 682 (C-S-C) cm-1. 1HNMR (CDCl3 +
DMSO-d6) δ in ppm: 8.81 (s, 1H, N=CH- indole), 7.71-8.31 (m, 17H, Ar-H), 7.22 (s, 1H, NH
exchangeable with D2O), 3.46 (s, 3H, OCH3 ).

4h. IR (KBr): 3426 (OH), 3349 (NH), 3158 (CH aromatic), 1734 (C=O), 1686 (C=N), 1632 (C-
C of aromatic ring), 1294 (N-N), 1236 (OCH3), 760 (C-Cl), 683 (C-S-C) cm-1 . 1HNMR (CDCl3
+ DMSO-d6) δ in ppm: 12.55 (s, 1H, OH exchangeable with D2O), 8.87 (s, 1H, N=CH- indole),
7.70-8.30 (m, 16H, Ar-H), 7.20 (s, 1H, NH exchangeable with D2O), 3.44 (s, 3H, OCH3).

5a. IR (KBr): 3342 (NH), 3150 (CH aromatic), 1737 (C=O), 1687 (C=N), 1638 (C-C of
aromatic ring), 1295 (N-N), 1233 (OCH3), 762 (C-Cl), 680 (C-S-C) cm-1. 1HNMR (CDCl3 +
DMSO-d6) δ in ppm: 7.70-8.31 (m, 8H, Ar-H), 7. 55 (s, 1H, C=CH of pyrole ring of indole), 7.21
(s, 1H, NH exchangeable with D2O), 6.70 (d, 1H, N-CH- indole), 4.60 (d, 1H, CH-Cl), 3.45 (s,
3H, OCH3), 2.28 (s, 3H, CH3).

5b. IR (KBr): 3340 (NH), 3152 (CH aromatic), 1734 (C=O), 1681 (C=N), 1643 (C-C of
aromatic ring), 1280 (N-N), 1250 (OCH3), 761 (C-Cl), 681 (C-S-C) cm-1. 1HNMR (CDCl3 +
DMSO-d6) δ in ppm: 12.53 ( s, 1H, OH exchangeable with D2O), 7.71-8.30 (m, 7H, Ar-H), 7.50
(s, 1H, C=CH of pyrole ring of indole), 7.23 (s, 1H, NH exchangeable with D2O), 6.76 (d, 1H,
N-CH- indole), 4.65 (d, 1H, CH-Cl), 3.43 (s, 3H, OCH3), 2.23 (s, 3H, CH3).

5c. IR (KBr): 3335 (NH), 3155 (CH aromatic), 2891 (CH3), 1735 (C=O), 1685 (C=N), 1644
(C-C of aromatic ring), 1283 (N-N), 1245 (OCH3), 760 (C-Cl), 687 (C-S-C ) cm-1. 1HNMR
(CDCl3 + DMSO-d6) δ in ppm: 7.71-8.32 (m, 8H, Ar-H), 7.21 (s, 1H, NH exchangeable with
D2O), 6.72 (d, 1H, N-CH -indole), 4.71 (d, 1H, CH-Cl), 3.40 (s, 3H, OCH3), 2.27 (s, 3H, CH3),
2.21 (s, 3H, CH3 of indole).

5d. IR (KBr): 3428 (OH), 3352 (NH), 3154 (CH aromatic), 2885 (CH3), 1754 (C=O), 1682
(C=N), 1643 (C-C of aromatic ring), 1285 (N-N), 1243 (OCH3), 763 (C-Cl), 685 (C-S-C) cm-1.
1
HNMR (CDCl3 + DMSO-d6) δ in ppm: 12.52 (s, 1H, OH exchangeable with D2O), 7.71-8.30
8

(m, 7H, Ar-H), 7.20 (s, 1H, NH exchangeable with D2O), 6.70 (d, 1H, N-CH- indole), 4.72 (d,
1H, CH-Cl), 3.45 (s, 3H, OCH3), 2.28 (s, 3H, CH3), 2.22 (s, 3H, CH3 of indole).

5e. IR (KBr): 3382 (NH), 3155 (CH aromatic), 2891 (CH3), 1753 (C=O), 1681 (C=N), 1650 (C-
C of aromatic ring), 1289 (N-N), 1245 (OCH3), 760 (C-Cl), 687 (C-S-C) cm-1. 1HNMR (CDCl3 +
DMSO-d6) δ in ppm: 7.70-8.32 (m, 13H, Ar-H), 7.21 (s, 1H, NH exchangeable with D2O), 6.71
(d, 1H, N-CH- indole), 4.62 (d, 1H, CH-Cl), 3.47 (s, 3H, OCH3), 2.27 (s, 3H, CH3).

5f. IR (KBr): 3429 (OH), 3386 (NH), 3152 (CH aromatic), 1757 (C=O), 1685 (C=N), 1636 (C-
C of aromatic ring), 1288 (N-N), 1253 (OCH3), 759 (C-Cl), 681 (C-S-C) cm-1. 1HNMR (CDCl3 +
DMSO-d6) δ in ppm: 12.55 (s, 1H, OH exchangeable with D2O), 7.70-8.30 (m, 12H, Ar-H), 7.22
(s, 1H, NH exchangeable with D2O), 6.70 (d, 1H, N-CH- indole), 4.60 (d, 1H, CH-Cl), 3.45 (s,
3H, OCH3), 2.24 (s, 3H, CH3).

5g. IR (KBr): 3372 (NH), 3157 (CH aromatic), 2891 (CH3), 1755 (C=O), 1683 (C=N), 1643 (C-
C of aromatic ring), 1284 (N-N), 1249 (OCH3), 761 (C-Cl), 688 (C-S-C) cm-1. 1HNMR (CDCl3 +
DMSO-d6) δ in ppm: 7.71-8.32 (m, 12H, Ar-H), 7.21 (s, 1H, NH exchangeable with D2O), 6.71
(d, 1H, N-CH-indol), 4.61 (d, 1H, CH-Cl), 3.45 (s, 3H, OCH3), 2.26 (s, 3H, CH3).

5h. IR (KBr): 3432 (OH), 3377 (NH), 3155 (CH aromatic), 1751 (C=O), 1684 (C=N), 1640 (C-
C of aromatic ring), 1281 (N-N), 1245 (OCH3), 764 (C-Cl), 686 (C-S-C) cm-1. 1HNMR (CDCl3 +
DMSO-d6) δ in ppm: 12.54 (s, 1H, OH exchangeable with D2O), 7.71-8.30 (m, 11H, Ar-H), 7.20
(s, 1H, NH exchangeable with D2O), 6.70 (d, 1H, N-CH- indole), 4.63 (d, 1H, CH-Cl), 3.44 (s,
3H, OCH3), 2.24 (s, 3H, CH3).

6a. IR (KBr): 3382 (NH), 3157 (CH aromatic), 1757 (C=O), 1689 (C=N), 1637 (C-C of
aromatic ring), 1287 (N-N), 1249 (OCH3), 760 (C-Cl), 684 (C-S-C) cm-1. 1HNMR (CDCl3 +
DMSO-d6) δ in ppm: 7.72-8.31 (m, 13H, Ar-H), 7.58 (s, 1H, C=CH of pyrole ring of indole),
7.23 (s, 1H, NH exchangeable with D2O), 6.71 (d, 1H, N-CH- indole), 4.64 (d, 1H, CH-Cl), 3.42
(s, 3H, OCH3).

6b. IR (KBr): 3416 (OH), 3382 (NH), 3158 (CH aromatic), 1758 (C=O), 1687 (C=N), 1635 (C-
C of aromatic ring), 1285 (N-N), 1246 (OCH3), 762 (C-Cl), 683 (C-S-C) cm-1. 1HNMR (CDCl3 +
DMSO-d6) δ in ppm: 12.55 (s, 1H, OH exchangeable with D2O), 7.71-8.31 (m, 12H, Ar-H), 7.56
(s, 1H, C=CH of pyrole ring of indole), 7.21 (s, 1H, NH exchangeable with D2O), 6.72 (d, 1H,
N-CH- indole), 4.60 (d, 1H, CH-Cl), 3.43 (s, 3H, OCH3).

6c. IR (KBr): 3382 (NH), 3155 (CH aromatic), 2882 (CH3), 1755 (C=O), 1686 (C=N), 1634 (C-
C of aromatic ring), 1286 (N-N), 1247 (OCH3), 763 (C-Cl), 684 (C-S-C) cm-1. 1HNMR (CDCl3 +
DMSO-d6) δ in ppm: 7.72-8.30 (m, 13H, Ar-H), 7.20 (s, 1H, NH exchangeable with D2O), 6.75
(d, 1H, N-CH- indole), 4.61 (d, 1H, CH-Cl), 3.45 (s, 3H, OCH3), 2.21 (s, 3H, CH3 of indole).

6d. IR (KBr): 3386 (NH), 3158 (CH aromatic), 2895 (CH3), 1754 (C=O), ), 1682 (C=N), 1635
(C-C of aromatic ring), 1288 (N-N), 1246 (OCH3), 760 (C-Cl), 683 (C-S-C) cm-1. 1HNMR
(CDCl3 + DMSO-d6) δ in ppm: 12.54 (s, 1H, OH exchangeable with D2O), 7.71-8.30 (m, 12H,
9

Ar-H), 7.22 (s, 1H, NH exchangeable with D2O), 6.70 (d, 1H, N-CH-indole), 4.60 (d, 1H, CH-
Cl), 3.44 (s, 3H, OCH3), 2.27 (s, 3H, CH3 of indole).

6e. IR (KBr): 3387 (NH), 3159 (CH aromatic), 1756 (C=O), 1689 (C=N), 1644 (C-C of
aromatic ring), 1289 (N-N), 1249 (OCH3), 761 (C-Cl), 681 (C-S-C) cm-1. 1HNMR (CDCl3 +
DMSO-d6) δ in ppm: 7.73-8.32 (m, 18H, Ar-H), 7.20 (s, 1H, NH exchangeable with D2O), 6.75
(d, 1H, N-CH-indole), 4.62 (d, 1H, CH-Cl), 3.46 (s, 3H, OCH3).

6f. IR (KBr): 3429 (OH), 3380 (NH), 3155 (CH aromatic), 1753 (C=O), 1682 (C=N), 1643 (C-
C of aromatic ring), 1287 (N-N), 1248 (OCH3), 762 (C-Cl), 683 (C-S-C) cm-1. 1HNMR (CDCl3 +
DMSO-d6) δ in ppm: 12.53 (s, 1H, OH exchangeable with D2O), 7.72-8.31 (m, 17H, Ar-H), 7.23
(s, 1H, NH exchangeable with D2O), 6.72 (d, 1H, N-CH-indol), 4.60 (d, 1H, CH-Cl), 3.43 (s, 3H,
OCH3).

6g. IR (KBr): 3485 (NH), 3153 (CH aromatic), 1685 (C-C of aromatic ring), 1683 (C=N), 1655
(C=O), 1286 (N-N), 1247 (OCH3), 763 (C-Cl), 684 (C-S-C) cm-1. 1HNMR (CDCl3 + DMSO-d6)
δ in ppm: 7.71-8.31 (m, 17H, Ar-H), 7.21 (s, 1H, NH exchangeable with D2O), 6.70 (d, 1H, N-
CH-indole), 4.62 (d, 1H, CH-Cl), 3.41 (s, 3H, OCH3).

6h. IR (KBr): 3487 (NH), 3429 (OH), 3152 (CH aromatic), 1684 (C-C of aromatic ring), 1681
(C=N), 1651 (C=O), 1285 (N-N), 1245 (OCH3), 761 (C-Cl), 682 (C-S-C) cm-1. 1HNMR (CDCl3
+ DMSO-d6) δ in ppm: 12.56 (s, 1H, OH exchangeable with D2O), 7.71-8.30 (m, 16H, Ar-H),
7.23 (s, 1H, NH exchangeable with D2O), 6.74 (d, 1H, N-CH-indol), 4.65 (d, 1H, CH-Cl), 3.42
(s, 3H, OCH3).

PHARMACOLOGICAL EVALUATION (ANTIBACTERIAL ACTIVITY)

All the synthesized compounds were tested for their antibacterial activity. The effect of

unknown compounds were compared with the standard drug Ciprofloxacin and Gattifloxacin and

propylene glycol treated group served as control. All the newly synthesized compounds were also

screened for their approximate lethal dose (ALD50).

Cup-Plate Method (CUPS): This activity was performed by following the method of Chuinckshank

et. al.13 in albino rats. Nutrient agar was poured onto the sterilized petri dishes (20-25 mL each pertri
10

dish). The poured material was allowed to set (1-1.5 h) and thereafter the “CUPS” (10 mm diameter)

were made by punching into the agar surface with a sterile cork borer and scooping out the punched

part of the agar. Into these cups the test compound solution was added with the help of sterile syringe.

The plates were incubated at 370C for 48hr and the results were noted. A solvent control (10%

DMSO in methanol) was also run to not the activity of the blank (solvent). The above said standard

drugs were also screened under similar conditions for comparison.

Approximate lethal dose (ALD50): The LD50 was determined in albino rats weighing 100-120 gm of

either sex by the method of Smith14. The test compounds were administered by i.p. route in one group

and the same volume of propylene glycol in another group of animals consisting six rats in graded

doses. The animals were allowed to take food and water adlibidum. After 24 h of drug administration

percent mortality in each group was observed. From the data obtained ALD50 was calculated.

RESULTS AND DISCUSSION

All the newly synthesized compounds were screened for antibacterial activity. The compounds

have shown antibacterial activity (Table IIa, IIb, IIc). Compounds 1a & 1b exhibited mild

antibacterial activity. Incorporation of different aromatic aldehydes via NH2 linkage of

substituted triazoles (1a & 1b) yielded compounds 2a-2h. Among the compound 2a-2h,

Compound 2h exhibited zone of inhibition 10 mm against S. aureus , 13 mm against P. vulgaris ,

12mm K. pneumonia. This compound has shown moderate antibacterial activity. Resulted

compound revealed that 2a and 2b devoid of antibacterial activities. Compounds 2d, 2e, 2f and

2g exhibited mild antibacterial activity. The characteristics feature of the synthesized compound

3a-3h is ethanethioate moiety and compounds 4a-4h is benzothioate moiety. Compounds 3a,

3b, 3c, 3d, and 3g have shown mild to moderate antibacterial activity. Compound 3e was devoid

of antibacterial activity. Compounds 4b, 4c, 4d, 4e, 4f, 4g and 4h have shown less antibacterial

activity than compounds 3a-3h having ethanethioate moiety.


11

Cyclization of compound 3a-3h and 4a-4h with choloroacetylchloride in presence of

triethylamine yielded corresponding azetidinones 5a-5h having ethanethioate and 6a-6h having

benzothioate moiety increased the antibacterial activity. Among the compounds 5a-5h,

compound 5f exhibited good activity against E. coli and P. vulgaris. Moreovers compound 5h

showed zone of inhibition 26 mm against S. aureus, 24 mm against E. coli, 22 mm against P.

vulgaris , 23 mm against K. pneumoniae. The later compound showed more potent antibacterial

activity than standard drugs, which prove that this compound is the most active compound of this

series. Compounds 5a, 5b, 5c, 5d, and 5e have shown significant antibacterial activity.

Among the compounds 6a-6h, compound 6d exhibited zone of inhibition 18 mm against S.

aureus and 20 mm against P, vulgaris . Compound 6f exhibited zone of inhibition 23 mm against

S. aureus, 21 mm against E. coli, 20 mm against K. pneumoniae. The compound 6h exhibited

equipotent antibacterial activity against S. aureus as compared to the reference drug

gattifloxacin. The synthesized compounds were also tested for approximate lethal dose ALD50

and were found to exhibit a higher value of ALD50 i.e. more than 1000mg/kg i.p. except

compound 5h which exhibited ALD50 of more than 2000mg/kg i.p. (maximum dose tested) thus

indicating the safer nature of the compound.

While considering all the newly synthesized compounds of this series we may conclude that

1 Azomethine linkage enhances antibacterial activities.

2 It is interesting to point out that compound 5h have more potency than the other

substituted triazol derivatives.

3 O-hydroxy and p-chloro substitution is beneficial for the biological activity.

4 Compound 6h possessed equipotent antibacterial activity in comparison to gattifloxacin

and ciprofloxacin (i.z. 25mm and 20mm).


12

REFERENCES

1. Phillips O.A., Udo E.E., Abdel-Hamid M.E., Varghese R.: Synthesis and antibacterial
activity of novel 5-(4- methyl-1H-1,2,3-triazole) methyl oxazolidinones, Eur. J.
Med. Chem., 2009, 44(8), 3217-3227.
2. Gadaginamath S.G., Patil A.S.: Synthesis and antimicrobial activity of some new 2-amino-
methyl-5- (4-phenyl- -mercapto- 1,2,4- triazol-3- yl) methoxyindole derivatives, Indian J.
Chem., 1999, 38B(9), 1070-4.

3. Shukla D.K., Srivastava S.D.: Synthesis of some new 5-[2-{(1,2,3-benzotriazole)-1-yl-


methyl}-1'-(4'-substituted aryl-3'-chloro-2'-oxo azetidine)]-amino-1,3,4-
thiadiazoles: Antifungal and antibacterial agents, Indian J. of Chem., 2008,
47B, 3, 463-469.

4.Guru N., Srivastava S.D.: Synthesis of some new 1-[5'-{(2-benzothiazolylthio) methyl}-1',3'4'-


thiadiazol2'-yl]-4- substituted-3-chloro-2-azetidinones: Antimicrobial agent, J.Sci. Ind.
Res., 2001, 60(7), 601-5.

5. Rani P., Srivastava V. K., Kumar A.: Synthesis and anti-inflammatory activity of
heterocyclic indole derivatives, Euro. J. Medi. Chem., 2004, 39(5), 449-452.

6. Omar A., Mohsen M.E., El-Dine, Shams A.S., Labouta I.M., El-Tombary A.A.:
Synthesis and evaluation for antimicrobial and antihistaminic properties of new
thiosemicabazide and triazole derivatives of triazolo[4,3-a]quinazolin-5(4H)-
ones. Alexandria J, Pharma, Sci., 1991, 5, 213-215.

7. Thaker M.K., Kachhadia V.V., Joshi S.H.: Synthesis of 4-thiazolidinones and 2-


azetidinones bearing benzo(b) thiophenes nucleus as potential antitubercular and
antibacterial agents, Indian J. Chem., 2003, 42B(6), 1544-7.

8. Dundar Y., Cakir B., Kupeli E.,Sahin M.F., Noyanalpan N.: Synthesis of some new 1-
Acylthiosemicarbazides and 1,2,4-triazol-5-thiones and their analgesic and anti-
Inflammatory activities, Turk J. Chem., 2007, 31, 301-313.

9. Heindel N.D.,Minatelli J.A.: Synthesis and antibacterial and anticancer evaluation of α-


methylene-γ-butyrolactones, J. pharm. Sci., 1981, 70(1), 84-86.

10. Mohboobi S., Eichhorn E., Winkler M., Sellmer A., Mollmann U.: Antibacterial activity of a
novel series of 3-bromo-4-(1H-3-indolyl)-2,5-dihydro-1H-2,5-pyrrolidione derivatives-An
extended structure-activity relationship study, Eur. J. Med. Chem., 2008, 43(3), 633-656.

11. Bhusare R.S. Shinde B.A. Pawar P.R. Vibhute B. Y.: Synthesis and antimicrobial activity of
heterocyclic schif bases, 4-thiazolidinones and 2-azetidinones, Indian J. Pharm. Sci.,
2004,3,228-31.
13

12. Desai K.G., Desai K.R.: Rapid and efficient synthesis of some biological active 2-
azetidinone under microwave irradiation, Indian J. Chem., 2005, 44B, 2093- 2096.

13. Chuinckshank R., Dugid J.P., Swain R.H.A.: Medical Microbiology, 1975, 2.

14. Smith Q.E.: Pharmacological Screening Tests Progressive, Medicinal Chemistry


Butterworths, London, 1960, Vol. 1, 1-33.

Table 1Ia: Antibacterial activity of the compounds: 4-amino-5-substituted phenyl -

3-mercapto-1,2,4-triazoles (1a-b),4-(2‫׳‬-substituted-5‫׳‬-methoxy-3‫׳‬-indolylideno)-5-

substituted phenyl -3-mercapto-1,2,4-triazoles (2a-h).

R N N
N N
R SH OCH3
N
N SH N
NH2 (2a-h) R' N
(1a-b) H
14

Table I1b: Antibacterial activity of the compounds: 4-[2‫׳‬-substituted-5‫׳‬-methoxy-3‫׳‬-

Indolylideno]- 3-ethanethioat-5-(substituted phenyl)-1,2,4-triazoles (3a-h),4-[2‫׳‬-

substituted-5‫׳‬-methoxy-3‫׳‬- indolylideno]-3-benzothioat-5-(substituted phenyl)-1,2,4-

triazoles (4a-h).

Compound Bacterial growth inhibition (diameter) ALD50

No. R R‫׳‬ Mg/kg i.p.

S. aureusE. coli P. vulgarisK. pneumoniae

1a H - 6mm - - - >1000

1b 2-OH - 5mm 6mm - - >1000

2a H H - - - - >1000

2b 2-OH H - - - - >1000

2c H CH3 - - - - >1000

2d 2-OH CH3 8mm - - 9mm >1000

2e H C6H5 - - 7mm - >1000

2f 2-OH C6H5 9mm 8mm - - >1000

2g H C6H4Cl 8mm - 7mm - >1000

2h 2-OH C6H4Cl 10mm - 13mm 12mm >1000


15

R N N R N N
O O
N S OCH 3 N S OCH3
N N
(3a-h) R' N R' N (4a-h)
H H

ALD50

Compound
R R‫׳‬ Bacterial growth inhibition (diameter) Mg/kg
i.p.
No.

S. aureusE. coli P. vulgarisK. pneumoniae

3a H H - - 9mm - >1000

3b 2-OH H 10mm - 11mm - >1000

3c H CH3 - - - 10mm >1000

3d 2-OH CH3 13mm - - 12mm >1000

3e H C6H5 - - - - >1000

3f 2-OH C6H5 14mm 16mm - - >1000

3g H C6H4Cl - 12mm - 11mm >1000

3h 2-OH C6H4Cl 14mm - 16mm 15mm >1000

4a H H - 10mm - - >1000

4b 2-OH H - - - - >1000

4c H CH3 - - 8mm - >1000

4d 2-OH CH3 9mm - - 10mm >1000

4e H C6H5 - - - - >1000

4f 2-OH C6H5 - 11mm - 12mm - >1000

4g H C6H4Cl - 10mm - - >1000

4h 2-OH C6H4Cl 12mm - - 12mm >1000


16

Table IIc: Antibacterial activity of the compounds: 4-[3‫׳׳‬-chloro-2‫׳‬2)-‫׳׳‬-substituted-5‫׳‬-methoxy-

3‫׳‬-indolylideno)-4‫׳׳‬-oxoazetidinyl]-3-ethanethioat-5-substituted phenyl-1,2,4-triazoles

(5a- h), 4-[3‫׳׳‬-chloro-2‫׳‬2)-‫׳׳‬-substituted-5‫׳‬-methoxy-3‫׳‬-indolylideno)-4‫׳׳‬-oxoazetidinyl-3

benzothioat-5-substituted phenyl-1,2,4-triazoles (6a-h).


17

R N N R N N
O O
N S OCH3 N S
OCH3
N
(5a-h) N
O N
Cl R' H O N (6a-h)
Cl R' H

Comp. R R‫׳‬ Bacterial growth inhibition (diameter) ALD50

No. S. aureusE. coli P. vulgarisK. pneumoniae


Mg/kg i.p.

5a H H 16mm - - - >1000

5b 2-OH H - 17mm 18mm - >1000

5c H CH3 20mm - 19mm 18mm >1000

5d 2-OH CH3 - - 20mm - >1000

5e H C6H5 19mm 18mm - - >1000

5f 2-OH C6H5 - 22mm 20mm - >1000

5g H C6H4Cl 24mm - - 21mm >1000

5h 2-OH C6H4Cl 26mm 24mm 22mm 23mm >2000

6a H H - - 14mm 15mm >1000

6b 2-OH H 15mm - - - >1000

6c H CH3 17mm 16mm - - >1000

6d 2-OH CH3 18mm - 20mm - >1000

6e H C6H5 - 15mm 16mm - >1000

6f 2-OH C6H5 23mm 21mm - 20mm >1000

6g H C6H4Cl - 20mm - 21mm >1000

6h 2-OH C6H4Cl 25mm - 20mm - >1000

Ciprofloxacin - 20mm 22mm 20mm 21mm >1000

Gattifloxacin - 25mm 22mm 20mm 21mm >1000


18
19

Co R R‫׳‬ m. Yiel Recrystalli Molecular Elimental Analysis


mN p d sation formula
o. (0C (%) %C %H %N
) solvent

Calc Foun Calcd Foun Calc Foun


d d . d d. d

1a H -‫׳‬ 24 94 Ethanol C8H8N4S 49. 49.8 4.19 4.3 29. 29.


6 98 5 0 14 25

1b OH - 25 93 Methano C8H8N4OS 46. 46.2 3.87 3.6 26. 26.


4 l 18 6 6 90 82

2a H H 23 92 Acetone C18H15N5OS 61. 61.8 4.33 4.2 20. 20.


6 87 5 5 04 05

2b OH H 24 90 DMF- C18H15N5O2 59. 59.4 4.14 4.0 19. 19.


7 water S 16 0 5 17 34

2c H CH3 21 89 Methano C19H17N5OS 62. 62.8 4.71 4.3 19. 19.


0 l 79 9 2 27 37

2d OH CH3 22 90 Ethanol C19H17N5O2 60. 60.3 4.52 4.6 18. 18.


1 S 14 2 5 46 72

2e H C6H5 22 87 Methano C24H19N5OS 67. 67.5 4.50 4.6 16. 16.


9 l 74 6 0 46 75

2f OH C6H5 23 86 Acetone C24H19N5O2 65. 65.0 4.34 4.5 15. 15.


4 S 29 8 0 86 55

2g H 4-ClC6H4 24 85 Ethanol C24H18ClN5O 62. 62.7 3.94 3.8 15. 15.


4 S 67 5 4 23 54

2h OH 4-ClC6H4 25 86 Methano C24H18ClN5O 60. 60.7 3.81 3.6 14. 14.


8 l 2S 56 8 2 71 95

3a H H 19 84 DMF- C20H17N5O2 61. 61.4 4.38 4.5 17. 17.


0 water S 37 9 7 89 68

3b OH H 21 82 Acetone C20H17N5O3 58. 58.6 4.21 4.5 17. 7.3


0 S 96 7 3 19 5

3c H CH3 21 81 Methano C21H19N5O2 62. 62.5 4.72 4.9 17. 17.


2 l S 21 5 5 27 57

3d OH CH3 21 80 Ethanol C21H19N5O3 59. 59.5 4.54 4.8 16. 16.


4 S 84 6 4 62 38

3e H C6H5 21 83 DMF- C26H21N5O2 66. 66.9 4.53 4.6 14. 14.


6 water S 79 8 4 98 68
20

Table I. physical and analytical data of compounds 1a-1b, 2a-2h, 3a-3h,4a-4h,5a-5h, and 6a-6h.
21

R
CONHNH2

CS2 / KOH
NH2 NH2.H2 O

N N
R
N SH
NH 2
(1a-1b)
OCH 3
CHO

R' NH

N N
R

N SH OCH3

N CH

R' NH
(2a-2h)

CH3 COCl C6 H5 COCl

N N N N
R R

N S COCH3 OCH3 N S COC6 H5 OCH3

N CH N CH

R' NH R' NH
(3a-3h) (4a-4h)

ClCH 2COCl ClCH2 COCl

N N N N
R R

N S COCH3 OCH3 N S COC6H5 OCH3

N CH SCHEME I N CH

R' NH R' NH
O Cl O Cl
(5a-5h) (6a-6h)

R = H, OH
R' = H, CH3, C6 H5, C6 H4 Cl
SCHEME I
22

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