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Tugas Kimia Medisinal

Kelompok 3
Magister Farmasi Sains dan Teknologi
Fakultas Farmasi
Universitas Gadjah Mada
1. Sudarman
2. Suhaera
3. Putri
4. Syamsu Nur
5. Andi Tenri NurW
Introduction

Antibiotik adalah segolongan moleku,


baik alami maupun sintetik,
yang mempunyai efek
menekan atau
menghentikan suatu proses
biokimia di dalam
organisme, khususnya
dalam proses infeksi oleh
bakteri.
Antibiotika bekerja seperti pestisida
dengan menekan atau memutus
satu mata rantai metabolisme,
Penggunaan antibiotika khususnya hanya saja targetnya adalah
berkaitan dengan pengobatan bakteri. Antibiotika berbeda
penyakit infeksi, meskipun dalam dengan desinfektan karena cara
bioteknologi dan rekayasa genetika
juga digunakan sebagai alat seleksi kerjanya. Desinfektan membunuh
terhadap mutan atau transforman. kuman dengan menciptakan
lingkungan yang tidak wajar bagi
kuman untuk hidup.
Introduction

PYRAZOLINES ISOXALINES

Kedua senyawa tersebut merupaka


senyawa heterosiklik yang berbeda
mengandung nitrogen, sulfur dan oksigen
sebagai atom hetero yang dapat memiliki
peran penting dalam aktivitas biologis
anti-tumor

Introduction

anti-inflamasi
Antiparasitary
antikonvulsan
antimikroba
Pyrazoline antinociceptive
antimalaria
penghambatan nitrat oksida sintase,
inflamasi arthritis
antidepresan
antikanker
antibakteri
analgesik
antioksidan
antiamoebic,
sitotoksik antijamur
antimikroba
antimycobacterial
Isoxazoline antikonvulsan
Antihepatotoksik
anti-inflamasi
Antibiotik
anti-virus
analgesik
Aktivitas antitumor
Chemistry
Result
IR
The IR spectra of all the compounds showed absorption bands in the regions
1517e1614 cm1 corresponding to CN stretching because of ring closure.
The infrared spectra of (6aec) also revealed CO band at 1642e1600 cm1.

HNMR
In the1 H NMR spectra of all compounds the three hydrogen atoms
attached to the C-4 and C-5 carbon atoms of the heterocyclic ring gave
an ABX spin system.
Thepyrazoline/isoxazoline structures were unambigously proved bythe
measured chemical shifts. In compounds (2aee) and (4aee), H-4(trans)
and H-4 (cis) appeared as double doublets and H-5 either appeared as
multiplets or double doublets.
CONT
In4aand4ethe peak for H-4 (cis) of pyrazolines could not be
picked out because of its merger with solvent peak. In
compounds (6a-c) H-5 (cis) appeared as multiplets and H-4
appeared either as multiplets or double doublets. The peak
for H-5 (trans) could not be identified because of merging
with solvent peak

The methyl and aromatic protons were observed at expected


ppm. All structures were further supported by13 C NMR
spectra which showed the chemical shift values of carbon
atoms of heterocyclic ring C-3 at (126.46e159.21 ppm), C-
4 at (31.02e54.86 ppm) and C-5 at (56.26e76.60 ppm).
Pharmacology

In vitro antimicrobial activity


Method
Antifungal and antibacterial
activities were evaluated by using
agar well diffusion method
synthesized compounds
- antifungal activity against Candida albicans, Aspergillus
fumigatus, Aspergillus versicolor and Aspergillus flavus,
- in-vitro antibacterial activity against Gram-negative
Escheriochia coli and Gram-positive Staphylococcus aureus

standard references

Ciprofloxacin(25 mg/disc) and


fluconazole (20 mg/disc)
Pharmacology

MIC of all active compounds against


tested fungal strains
Technique
Minimum inhibitory concentration (MIC) of all active
compounds
was measured in vitro using two fold serial dilution
technique

Concentration result

The results of minimum inhibitory concentration against


tested fungi, ranging from 3.12 to 50
Pharmacology

MIC values of all the active compounds are comparable with


standard drug fluconazole.

As revealed from MIC values compounds 2b, 4c, 4d and 6aec


exhibited highest antifungal activity among all the investigated
compounds.
Molecular docking study

All 21 molecules were docked against the


generatedtarget.

Only 12 molecules docked within the


generated target grid.

The fluconazole-bound CYP51 from


Mycobacterium tuberculosis (MTCYP51)
(PDB No: 1EA1) resolved at 2.2 A was the
rst authentic drug target for cytochrome
P450
The active pocket of CYP The binding interactions of
consists of amino acid fluconazole in binding
residues as Tyr76, Phe78, pocket of CYP 450
Leu321, ILE323, Val435,
Met433, Leu324, Met79,
Ala256, Phe255, Arg96
and Hem 460
The glide docking scores of the synthesised
compounds
Compound 2b showed H-bond
formation with residue ARG-90 Compound 6a did not show
and MET - 433. Furthermore any H-bond formation but
there was pep stacking with it showed pep stacking
PHE-78 and TYR-76 and p- observed with TYR e 76.
cation stacking was observed
with HEM - 460.
Compound 6b Compound 2d showed H-
showed no H-bond bond formation with residue
formation but p- ARG e 96, pep stacking with
PHE-78, TYR-76 and p-cation
cation stacking was stacking with HEM - 460.
observed with ARG -
96.
Conclusion

Compounds 2b, 4c, 4d and 6aec exhibited


comparable activity against all tested fungal strains.
MIC values of all the active compounds are
comparable with standard drug fluconazole. A set of
twelve compounds (2aee, 4aed and 6aec) showed
better glidescore against the standard drug
fluconazole.
All the compounds possessed the required binding
energy to dock itself with the binding pocket of
CYP51 ranging from 8.37 to 1.73 kcal/mol.
The antifungal activity of these compounds was fully
supported by the in silico molecular docking study.
Experimental Protocol
- Melting points were uncorrected and measured using
Chemistry Electrothermal IA 9100 apparatus
- Fourier Transform Infra Red (FTIR) spectra were measured on a
Brukers Vector 22 spectrophotometer in film; vmax
max
values are given in cm-1-1

H NMR spectra were recorded on a Bruker


11 13
13C NMR spectra was recorded on
Spectrospin DPX 300-MHz spectrometer using a Bruker spectrospin DPX at 75 MHz
DMSO-d66 as a solvent and tetramethyl silane using deuterated DMSO as a solvent and
(TMS) as an internal standard. tetramthyl silane (TMS) as internal
Chemical shifts are given in d (ppm) scale, standard.
coupling constants (J values) are expressed in
Hz.

Mass spectra (MS) were scanned by using a FAB Purity of the compounds was checked
ionization JEOL-JMS-DX 303 system equipped with a on TLC plates (silica gel G) which were
direct inlet probe system. The m/z values of the more visualized by exposing to iodine
intense peaks are mentioned. vapours.
6.2. General procedure for the synthesis of 3, 5-diaryl)-2- pyrazolines 2a-e

6.2. General procedure for the synthesis of 3, 5-diaryl)-2- pyrazolines 2a-e

General procedure for the synthesis of 3, 5-diaryl)-2- pyrazolines 2a-e

Appropriate chalcones or flavanone (0.001 mol) and hydrazine hydrate (98%, 0.001
mol) were dissolved in ethanol (20-30 ml) and refluxed for 24 h

After completion of the reaction the reaction mixture was concentrated to 10-15 mL

It was left at room temperature to give crystalline compound. It was filtered and
crystallized with ethanol to give pure compound.
6.3. General procedure for the synthesis of 3, 5-diaryl-1-(psulfamylphenyl)-2-pyrazolines
3a-h

3, 5-diaryl-1-(p-sulfamylphenyl)-2-pyrazolines were prepared as per the previously


reported method by us

6.4 General procedure for the synthesis of 3, 5-diaryl-2- isoxazolines 4a-e

Appropriate chalcone or flavanone (0.001 mol) and hydroxylamine hydrochloride (0.002 mol)
and KOH (0.002 mol) were dissolved in ethanol (25 ml) and refluxed for 6-8 h.

After completion of the reaction monitored by TLC the reaction mixture was acidified
with acetic acid. The resulting solid was washed with water
and crystallized with alcohol to give pure compound.
General procedure for the synthesis of 3-aroyl-4-
aryl-2- pyrazolines 6a-c

Appropriate chalcone (50 mg) was treated with freshly prepared diazomethane gas
dissolved in ether (20 ml) at 0oC and reaction mixture was kept overnight at room
temperature to give crystalline compound.

It was recrystallized with acetone to give pure compound. Diazomethane gas was
prepared through reported method.
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