A REVIEW ON THE BIOLOGICAL ACTIVITIES OF 1,3,4- OXADIAZOLE

About Author:
Alex Martin
Department of Pharmaceutical Chemistry,
St. Joseph’s College of Pharmacy
University of Health Sciences, Cherthala-688524 (Kerala), India.
aalexmartin@rediffmail.com

Abstract
Oxadiazole is a five membered heterocyclic ring which is a versatile lead compound for designing potent bioactive agents. It exists in four isomeric forms. One of its four isomers 1,3,4-oxadiazole exhibited a wide range of biological activities which includes anti-bacterial, anti-tubercular, anticonvulsant, hypoglycemic, anti-allergic, enzyme inhibitor, vasodilatory, antifungal, cytotoxic, anti-inflammatory, analgesic, hypolipidemic, anticancer, insecticidal activities etc. The present review has basic information about 1,3,4-oxadiazole and its biological activities.

Oxadiazoles is a heterocyclic ring and is considered to be derived from furan by the replacement of two methane (-CH=) groups by two nitrogen (-N=) atoms. There are four possible isomers of Oxadiazole, depending on the positions of hetero atoms and they are named as 1,2,3; 1,2,4; 1,2,5; 1,3,4-oxadiazoles. 1,2,4-Oxadiazole, 1,2,5-Oxadiazole, and 1,3,4-Oxadiazole are known, but the 1,2,3-isomer is unstable and reverts to the diazoketone tautomer. The stable oxadiazoles appear in a variety of pharmaceutical drugs including raltegravir, butalamine, fasiplon, oxolamine, and pleconaril.

REFERENCE ID: PHARMATUTOR-ART-1906

Literature review reveals that the 1,3,4-oxadiazole undergo a number of reactions such as Electrophilic substitution, Nucleophilic substitution, Thermal and Photochemical. This has been exploited in the preparation of 1,3,4-oxadiazole therapeutic molecules for various applications. In view of this, an attempt has been made to review the biological activities of 1,3,4-oxadiazole.

Antimicrobial activity

Radha et al ¹synthesized 5-(benzothiazol-2-yl-thiomethyl)-1,3,4-oxadizole from mercaptobenzothiazole which showed moderate anti-bacterial and anti-inflammatory activities.

The bactericidal activity of 1,3,4-oxadiazoles was screened by Kataky et al ² by the synthesis of 2-amino-5-(2,4-dichlorophenyl)-1,3,4-oxadiazoles. This will give 1,3,4-oxadiazole-2-iminobenzylidine with appropriate araldehydes. The products exhibited good anti-bacterial activity.

Various 5-substituted-1,3,4-oxadiazol-2-hydrazides were synthesized by Kalluraya B. et al ³ by the reaction of oxadiazole with hydrazine hydrate. The oxadiazole hydrazide when condensed with 5-substituted-2-furfural gave hydrazones. These compounds were found to be active against gram positive and gram negative bacteria.

2-(5’-thioxo-1,3,4-oxadiazolin-2-yl) indoles were synthesized by Sonar VN et al ⁴ by the reaction of indole-2-carbohydrazides with CS₂ and KOH. Screening of these compounds has shown that they posses moderate activity against S. aureus, E. coli, P. vulgaris and B. subtilis.

Nailesh Joshi et al ⁵ synthesized some 2,5-disubstituted-1,3,4-oxadiazoles . The compounds have been tested for their anti-microbial and anti-fungal activity.

2-(3,4-dihydro-3-2H-1,4-benzoxazin-2-yl)methyl-5-(alkyl/arylthio)-1,3,4-oxadiazoles have been synthesized by Y. Jayamma et al ⁶ and screened for their anti-microbial activity.

The synthesis of 2-arylamino-5-(p-nicotinamidophenyl)-1,3,4-oxadiazoles was carried out by Vimal R. Shah et al ⁷ from ethyl p-nicotinamidobenzoate which in turn was obtained by the treatment of nicotinic acid with thionyl chloride followed by the reaction with ethyl p-aminobenzoate in pyridine. The anti-bacterial activity of the compound was determined by the cup plate method.

A series of 1,3,4-oxadiazoles were prepared by Kapoor et al ⁸ by the cyclisation of respective hydrazides. They were screened for their anti-bacterial, anti-fungal and anti-mycobacterial activities by agar well diffusion method.

Antitubercular activity

Chaudary B.R et al ⁹synthesized 1,4-benzothiazinyl-1,3,4-oxadiazoles by the condensation of 1,4-benzothiazinylthiosemicarbazides in the presence of an alkali. The compounds exhibited anti-tubercular activity.

Parekh et al ¹⁰synthesized 2,5-disubstituted-1,3,4-oxadiazoles and studied their anti-microbial activity against several microbes and anti-tubercular activity against Mycobacterium tuberculosis.

A novel series of 2-(substituted phenyl)amino-5-[4-(4-methoxybenzoylamino)phenyl]-1,3,4- oxadiazoles were synthesized and were evaluated for their anti-tubercular activity by Kucukguzel SG et al ¹¹. The compounds were found to possess moderate anti-tubercular activity.

Some novel 1,3,4-oxadiazole derivatives have been synthesized by Pattan R. Shashikant et al ¹² and the compounds were evaluated for their anti-tubercular activity against H₃₇R_V strain and compared to the standard drug Streptomycin. Compound A.1) have shown promising activity and compound A.2) and A.3) have shown moderate activity.

Anti-inflammatory activity
S.N. Sawhney et al ¹³reported the synthesis of twenty compounds belongings to five different series namely, 2-(2-methylthiazol-4-yl)-5-aryl-1,3,4-oxadiazoles, 2-(2-methylthiazol-4-yl)-5-substituted-amino-1,3,4-thiadiazoles and 5-(2-methylthiazol-4-yl)-3-mercapto-4-substituted-4H-1,3,4-oxadiazoles as potential anti-inflammatory agents.

A series of 5-[2-(3,5-dimethoxy-4-hydroxyphenyl)ethyl]-1,3,4-oxadaiazoles were synthesized by Mullican H.D et al ¹⁴with the aim of discovering dual inhibitors of 5-lipooxygenase and cyclooxygenase with improved pharmacokinetic properties. The compounds were screened by carageenin rat paw edema method and showed good anti-inflammatory properties.

The synthesis of 5-(6-methyl-2-substituted-4-pyrimidinyloxymethyl)-2,3-dihydro-1,3,4-oxadiazol-2-thiones and their morpholinomethyl derivatives were carried out by Virginija Jakubkiene et al ¹⁵. The synthesized compounds were evaluated for their anti-inflammatory activity and some of these were more active than acetylsalicylic acid.

Harish kumar et al ¹⁶prepared a series of 1,3,4-oxadiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxyaceticacid and evaluated these compounds for their anti-inflammatory, analgesic and lower ulcerogenic potential. The compounds were found to posses strong anti-inflammatory properties.

Mohd. Amir et al ¹⁷synthesized a series of 1,3,4-oxadiazole derivatives and 1,2,4-triazine-5-one derivatives. All the compounds were screened for their anti-inflammatory activity by using Carageenin-induced rat paw edema method. Compounds A (1) and A (2) among all the synthesized compounds showed maximum anti-inflammatory activity.

Anticancer activities

Loetchutiant et al ¹⁸synthesized a novel series of 5-(substituted aryl)-3-(4-hydroxyphenyl)-1,3,4-oxadiazole-2-(3H)-thiones by the cyclocondenstaion of 1-(4-hydroxyphenyl)-2-aroylhydrazines with thiophosgene. The synthesized compounds were evaluated for their anti-proliferative activity against micro-organisms. IC₅₀ values ranges from 24 to 94 mM and the compounds were found to have comparable efficacy with that of apigenin and genistein.

Saddi et al ¹⁹have reported the synthesis of 5-(1-(4-chlorophenyl)-4-hydroxy-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-one (A) and 5-(1-(4-chlorophenyl)-4-hydroxy-1H_pyrazol-3-yl)2-phenyl-1,3,4-oxadiazole derivatives (B). The compounds were screened for their anti-cancer activity.

Ouyang et al ²⁰synthesized and evaluated various 1,3,4-oxadiazole derivatives as to their ability to inhibit tubule polymerization and block the mitotic division of tumor cells. Compound A exhibited potent activity. In-vitro studies of compound A indicated that at nano concentrations it interrupted mitotic division in breast carcinoma and squamous cell tumors, which included multi-drug resistant cells.

Dalip kumar et al ²¹prepared a series of novel 5-(3’-indolyl)-2-(substituted)-1,3,4-oxadiazoles and screened them for their in-vitro anti-cancer activity against human cancer cells from prostate (PC₃,DU145 and LnCaP), breast (MCF7 and MDMDA231) and pancreas(PaCa2). The compound 1.a) with two phenyl group exhibited moderate activity against MCF7 and activity against other cell lines. Also N-methylation of indole ring nitrogen dramatically improved the cytotoxic activities.

Qing-Zhong Zheng et al ²²synthesized a series of 2-chloropyridine derivatives possessing 1,3,4-oxadiazole moiety. The compounds showed anti-proliferative activity against gastric cancer cell SGC-7901, which was more potent than the positive control.

REFERENCES:
1.Radha R.B and Rao B.U.T. (1990). Synthesis and Biological activities of benzthiazolothiomethyl-oxadiazoles, thiadiazoles and triazoles. Indian Journal of Chemistry, 29, 995 – 998.
2.Duita MM and Kataky (1992). Synthesis and biological activities of Azadianesarylphosphate/ thiophosphate derivatives of 1,3,4-oxadiazoles and thiadiazoles. Indian Journal of Chemical Society, 69, 599 – 601.
3.Kalluraya B , Ramesh C and Shivaram HB (1995). Synthesis and anti-microbial activity of various 5-substituted-1,3,4-oxadiazole-2-hydrazides. Indian Journal of Pharmaceutical Sciences, 5, 37 – 39.
4.Sonar VN , Yadav LDS and Sandhya S. (1995). New Mannich bases from oxadiazolyl indoles and their anti-bacterial activities. Indian Journal of Heterocyclic Chemistry, 4, 203 – 205.
5.Nailesh J., Korgaokar S. and Parekh H. (1996). Synthesis and anti-microbial activity of substituted 1,3,4-oxadiazoles. Indian Journal of Heterocyclic Chemistry, 5, 241 – 242.
6. Jayamma Y., Sarangapani M. and Reddy V.M. (1996). Synthesis and evaluation of biological activity of novel heterocycles. Indian Journal of Heterocyclic Chemistry, 6, 111 – 114.
7. Shah V.R., Vadodaria M. and Parikh A.R. (1997). Synthesis of 1,3,4-oxadiazoles having nicotinamide moiety as potential anti-microbial agents. Indian Journal of Chemistry, 36, 101 – 103.
8.Kapoor RP and Batra H (1997). Synthesis of some oxadiazoles and thiadiazoles of potential biological importance. Indian Journal of Heterocyclic Chemistry, 6, 1 – 4.
9.Chaudary BR , Shinde DB and Shigara MS (1995). Synthesis of some 1,.4-benzothiazinyl thiosemicarbazides, triazoles, oxadiazoles, thiadiazoles and evaluation of their anti-tubercular activities. Indian Journal of Heterocyclic Chemistry, 4 , 187 – 189.
10.Parekh H.H., Preethi K.R., Niraj S.S. and Rajeev D.V. (1999). Synthesis and anti-microbial activity of 2,5-disubstituted-1,3,4-oxadiazoles. Indian Journal of Chemistry, 38, 572 – 574.
11.Kucukguzel S.G., Oric E.E., Rollas S., Sachin F. and Ozbek A. (2002). Synthesis, Characterization and biological activity of novel 4-thiadiazolidinones, 1,3,4-oxadiazoles and some related compounds. European Journal of Medicinal Chemistry, 37, 197 – 206.
12.Shashikant P.R., Rabara P.A., Pattan S. and Jayashri (2009). Synthesis and evaluation of some novel substituted-1,3,4-oxadiazole derivatives for anti-tubercular activity. Indian Journal of Chemistry, 48, 1453 – 1456.
13.Sawhney S.N. , Gupta A. and Sharma P.K. (1991). Synthesis of some new 2-(2-methylthiazol-4-yl)-1,3,4-oxadiazoles and 5-(2-methylthiazol-4-yl)-3-mercapto-1,2,4-triazoles as potent anti-inflammatory agents. Indian Journal of Heterocyclic Chemistry, 1 , 8 – 16.
14.Mullican MD, Wilson MW, Connor DT, Kostlan CR, Schrier DJ and Dyer RD (1993). Design of 5-(3,5-ditertbutyl-4-hydroxyphenyl)-1,3,4-oxadiazoles and -1,3,4- thiadiazoles and -1,2,4-triazoles as orally active , non-ulcerogenic and anti-inflammatory agents. Journal of Medicinal Chemistry,36 , 1090 – 1099.
15.Jakubkiene V., Barbuliene M.M., Kiene G.K., Naite E.U., Gaidelis P. and Vainilavicius P. (2003). Synthesis and anti-inflammatory activity of 5-[6-methyl-2-substituted-4-pyrimidinyloxymethyl)-1,3,4-oxadiazol-2-thiones and their morphilinomethyl derivatives. Il Farmaco, 58, 323 – 328.
16.Kumar H., Javed S.A., Khan S.A. and Amir M. (2008). 1,3,4-oxadiazole/ thiadiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxy acetic acid : Synthesis and preliminary evaluation of biological properties. European Journal of Medicinal Chemistry, 43, 2688 – 2698.
17.Amir M., Kumar H., Javed S.A. and Khan S.A. (2008). Synthesis, characterization and screening of novel 1,3,4-oxadiazole derivatives for analgesic, anti-inflammatory and anti-microbial activity. European Journal of Medicinal Chemistry, 43, 2688 – 2698.
18.Loetchutiant C., Chau F. and Mankhetkom S. (2003). Synthesis and evaluation of 5-aryl-3-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-(3H)-thiones as P Glycoprotien inhibitors. Chem. Pharma Bull, 51, 728 – 730.
19.Saddi M.S.A., Rustam S.A.F. and Allah H.M.F. (2005). In-vitro anti-tumour screening of some polysubstituted pyrazole analogues. Saudi Pharma Journal, 13, 89 – 96.
20.Ouyang X., Patnitsk E.L., Pattaropong V., Chen X., Kiselyov A.S., Velangar A., Kaurkami J., Labelle M. and Smith L. (2006). Oxadiazole derivatives as a novel class of anti-mitotic agents : Synthesis, inhibition of tubulin polymerization and activity in tumor cell lines. Biorg. Med. Chem. Lett., 16, 1191 – 1196.
21.Kumar D., Sundaree S., Johnson E.O. and Shah K. (2009). An efficient synthesis and biological study of novel indolyl-1,3,4-oxadiazoles as potent anti-cancer agents. Biorganic and Medicinal Chemistry Letters, 19, 4492 – 4494.
22.Zheng Q.Z., Zhang X.M., Cheng Y.X.K., Jiao Q.L. and Zhu H.L. (2010). Synthesis, biological evaluation and docking studies of 2-chloropyridine derivatives possessing 1,3,4-oxadiazole moiety as potential anti-tumour agents. Biorganic and Medicinal Chemistry, 18, 7836 – 7841.