Research Methodology Seminar

Synthesis and Biological Activities of Azole Derivatives

by Janardan Sannapaneni Reg. No 11PHD0074

Research Supervisor: Dr. Akella Sivaramakrishna

Organic Chemistry Division School of Advanced Sciences

Contents

Background Significance of Azole compounds Mechanism of Action Reported synthetic routes Proposed research work Results and Discussion

Back ground

An azole is a class of five-membered nitrogen heterocyclic ring compounds containing at least one other non-carbon atom of either nitrogen, sulfur, or oxygen. The parent compounds are aromatic and have two double bonds One, and only one, lone pair of electrons from each heteroatom in the ring is part of the aromatic bonding in an azole.

Basic Azole rings

S N Thiazole

H N N

H N
pyrazole

N
O N

imidazole

O N

isoxazole

oxazole

Azoles
N

H N S O
N N

N H

5-(Pyridine-4-yl)-1, 3, 4 -oxadiazole-2-(3H)-thione
Anti amoebic

1-aryl-4-(4, 5-dihydro1H-imidazolo-2-yl)-1Hpyrazoles
Anti lesmanial activity

OH N N N NH F N N R F
1

Fluconazole analogue Anti fungal activity

Y. Yan, S. Yu, X. Chai, H. Hu, and Q. Wu, Arch Pharm Res., Vol 34, No 10, (2011) 1649-1656 6

Significance

These compounds showing good activities like Antibacterial and Antifungal, Antiamoebic and anti Lesmanial activities. Many azoles are used as antifungal drugs, inhibiting the fungal enzyme 14-demethylase which produces ergosterol (an important component of the fungal plasma membrane). Antifungals Clotrimazole Posaconazole Ravuconazole Econazole Ketoconazole Voriconazole
Triazole-based Fluconazole Itraconazole

Mechanism of Action

Reported Synthesis
N
CS2, KOH/H , Reflux 10h
+

H N S O

O NH N
C6 H5NCS, C2H5OH, reflux 1h
N

N 1 NH2
O NH NH S NH

2N NaOH, ref lux 2h

H 2 SO 4 , rt 1h,

N SH N N

N S

N NH

S. M. Siddiqui, A. Salahuddin, A. Azam., European journal of Medicinal Chemistry., 49 (2012) 411-416

Procedure

5-(Pyridine-4-yl)-1, 3, 4-oxadiazole-2-(3H)-thione (1) was synthesized by the cyclization of isonicotinic acid hydrazide using carbon disulfide in presence of KOH. (2), (3) was synthesized through an intermediate compound namedN-Phenyl-2-(pyridine-4-ylcarbonyl)hydrazine carbothiamide (4) which was obtained by the reaction of isoniazid with phenylisothiocyanate. The compound (2) was obtained by the cyclization of compound 3 in the presence of 2N NaOH and the compound (3) was obtained by the acid catalysed intramolecular dehydrative cyclization of compound(4)
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N CN NH2 . HCl NH i R 5 6 N N N N ii iii CN N N N H

NH2

R 7

R 8

i.Sodiumacetate,ethanal,0.5h reflux ii.t-butylnitrile THF 2h, reflux iii.Ethylenediamine, CS212-14h,1100C

M. S. D. Santos, M. L. V. Oliveira, A. M. R. Bernardino, R. M. D. Leo, V. F. Amaral, F.T. D. Carvalho, L. L. Leon, M. M. Canto- cavalheiro., Bioorganic and Medicinal Chemistry Letters 21 (2001) 7451-7454.

Procedure

The synthesis of 1-aryl-4-(4, 5-dihydro-1H-imidazolo-2-yl)-1Hpyrazoles (8) was synthesized by the treatment of arylhydrazine hydrochlorides (5) reacted with ethoxymethylene malononitrile and sodium acetate in ethanol

Reflux the reaction mixture to form 5-amino-1-aryl-1Hpyrazole-4-carbonitriles (6) and the compounds were converted to the 1- aryl-1H-pyrazole-4-cabonitriles (7) by the aprotic deamination using t-butyl nitrile and tetrahydrofuran
After refluxing the target molecule can b obtained by the reaction of 1-aryl-1H-pyrazole-4-cabonitriles with carbon disulfide and 1, 2 di amino ethane
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Proposed Synthesis
+ 2 H2N NH2 O Benzil O N NH2 N NH2
H2/Metal

HN NH2

NH NH2 i

ii H2N N N NC iii N CN NC N N N N CN N NH2

H2N

N N N

NH2 N N H

N NH

i.Sodiumacetate,ethanal,0.5h reflux ii.t-butylnitrile THF 2h, reflux iii.Ethylenediamine, CS212-14h,1100C

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Results and Discussion

S.No 1 Time factor(h) 1 1 1 2 2 2 2 3 3 3 Inhibitory action of the drug (mg) 0.49 0.48 0.476 0.51 0.514 0.512 0.478 0.48

0.487

The calculated F (34.85532) value is much Smaller than critical F (5.143253) value so the null hypothesis was rejected. The P value is 0.000497718 so the test is significant. By observing above calculations the null hypothesis was rejected i. e there is a huge change in the inhibition action of the drug at 14 regular intervals of time

Conclusion

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Thank You All