Synthesis, Characterization and Anti-inflammatory Activity of New 5-(3,4-Dichlorophenyl)-2-(aroylmethyl) thio-1,3,4-oxadiaxoles

Abstract

Several 5-(3,4-dichlorophenyl)-2-(aroylmethyl)thio-1,3,4-oxadiazoles were synthesized and characterized by elemental analyses, IR and nuclear magnetic resonance spectra. All compounds were evaluated for anti-inflammatory activity by determining their ability to provide protection against carregeenan-induced edema in rat paw. In addition, ulcerogenic activity was determined. The anti-inflammatory data scoring showed that compounds 5e, 5f and 5g, at the dose of 100 mg/kg, exhibited anti-inflammatory activity, which for compound 5f was comparable to that of the reference drug Indometacin (CAS 53-86-1).

Key words

■ 1,3,4-Oxadiazoles, anti-inflammatory activity, S-alkylation, synthesis, X-ray crystallography

• Literature

• 1 Sorbera LA, Lesson PA, Castanar J, Castanar RM. Valdecoxib and parecoxib sodium. Analgesic, antiarthritic, cyclooxygenase-2 inhibitors. Drugs Future. 2001; 26: 133-140
• 2 Palomer A, Cabre F, Pascual J, Campos J, Trugillo MA, Entrena A et al. Identification of novel cyclooxygenase-2 selective inhibitors using pharmacophore models. J Med Chem. 2002; 45: 1402-1411
• 3 Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer JL et al. 4-[5-Methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2. J Med Chem. 2000; 43: 775-777
• 4 Tammara VK, Narurkar MM, Crider AM, Khan MA. Morpholinoalkyl ester prodrugs of diclofenac: Synthesis, in vitro and in vivo evaluation. J Pharm Sci. 1994; 83: 644-648
• 5 Smith CJ, Zhang Y, Kobolt CM, Muhammad J, Zwefel BS, Shaffer A et al. Pharmacological analysis of cyclooxy-genase-1 in inflammation. Proc Natl Acad Sci USA. 1998; 95: 13313-13318
• 6 Hawkey C, Laine L, Simon T, Beaulieu A, Maldonado-Cocco J, Acevedo E et al. Comparison of the effect of rofecoxib (a cyclo oxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis: A randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2000; 43: 370-377
• 7 Kalgutkar AS, Marnett AB, Crews BC, Remmel RP, Marnett LJ. Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indometacin, as selective cyclooxygenase-2 inhibitors. J Med Chem. 2000; 43: 2860-2870
• 8 Duflos M, Nourrisson MR, Brelet J, Courant J, Le Baut G, Grimaud N et al. N-Pyridinyl-indole-3-(alkyl)carboxam-ides and derivatives as potential systemic and topical inflammation inhibitors. Eur J Med Chem. 2001; 36: 545-553
• 9 Kalgutkar AS, Crews BC, Rowlinson SW, Garner C, Seibert K, Marnett LJ. Aspirin-like molecules that covalently inactivate cyclooxygenase-2. Science. 1998; 280: 1268-1270
• 10 Burbuliene MM, Jakubkiene V, Mekuskiene G, Udrenaite E, Smicius R, Vainilavicius P. Synthesis and anti-inflammatory activity of derivatives of 5-[(2-disubstitutedamino-6-meth-yl-pyrimidin-4-yl)-sulfanylmethyl]-3H-1,3,4-oxadiazole-2-thiones. Farmaco. 2004; 59: 767-774
• 11 Kadi AA, El-Brollosy NR, Al-Deeb OA, Habib EE, Ibrahim TM, El-emam AA. Synthesis, antimicrobial and anti-inflammatory activities of novel 2-(1-adamantyl)-5-substitut-ed-1,3,4-oxadiazoles and 2-(1-adamantylamino)-5-substituted-1,3,4-thiadiazoles. Eur J Med Chem. 2007; 42: 235-242
• 12 Palaska E, Sahin G, Kelicen P, Durlu NT, Altinok G. Synthesis and anti-inflammatory activity of 1-acylthiosemicarbazides, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones. Farmaco. 2002; 57: 101-107
• 13 Boschelli DH, Connor DT, Bornemeier DA, Dyer RD, Kennedy JA, Kuipers PJ et al. 1,3,4-Oxadiazole, 1,3,4-thiadiaz-ole, and 1,2,4-triazole analogs of the fenamates: in vitro inhibition of cyclo oxygenase and 5-lipoxygenase activities. J Med Chem. 1993; 36: 1802-1810
• 14 Jakubkiene V, Burbuliene MM, Mekuskiene G, Udrenaite E, Gaidelis P, Vainilavicius P. Synthesis and anti-inflammatory activity of 5-(6-methyl-2-substituted-4-pyrimidinyl-oxy-methyl)-1,3,4-oxadiazole-2-thiones and their 3-morpholinomethyl derivatives. Farmaco. 2003; 58: 323-328
• 15 Narayana B, Raj KKV, Ashalatha BV, Kumari NS. Synthesis of some new 2-(6-methoxy-2-naphtyl)-5-aryl-1,34-oxadiazoles as possible non-steroidal anti-inflammatory and analgesic agents. Arch Pharm Chem Life Sci. 2005; 338: 373-377
• 16 Raman K, Parmar SS, Salzman SK. Anti-inflammatory activity of substituted 1,3,4-oxadiazoles. J Pharm Sci. 1989; 78: 999-1002
• 17 Nargund LCG, Reddy GRN, Hariprasad V. Anti-inflammatory activity of substituted 1,3,4-oxadiazoles. J Pharm Sci. 1994; 83: 246-248
• 18 Raman K, Singh KH, Salzman SK, Parmar SS. Substituted thiosemicarbazides and corresponding cyclized 1,3,4-oxadiazoles and their anti-inflammatory activity. J Pharm Sci. 1993; 82: 167-169
• 19 Mullican MD, Wilson MW, Connor DT, Kostlan CR, Schrier DJ, Dyer RD. Design of 5-(3,5-di-tert-butyl-4-hydroxy-phenyl)-1,3,4-thiadiazoles, – 1,3,4-oxadiazoles, and – 1,2,4-triazoles as orally-active, nonulcerogenic antiinflammatory agents. J Med Chem. 1993; 36: 1090-1099
• 20 Winter CA, Risley EA, Nuss GW. Carrageenin-induced edema in hind paw of the rats as an assay for antiinflammatory drugs. Proc Soc Exp Biol Med. 1962; 111: 544-552
• 21 Liang-Zhong X, Guan-Ping Y, Shu-Mei Y, Kai Z, Shuang-Hua Y. 2-{5-[(1H-l,2,4-Triazol-l-yl)methyl]-1,3,4-oxadiazol-2-ylthio}-1-(2,4-dichlorophenyl)ethanone. Acta Cryst. 2005; E61: o3375-o3376
• 22 Picot D, Loll PJ, Garavito M. The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature. 1994; 367: 243-249
• 23 Kurumball RG, Stevens AM, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature. 1996; 384: 644-648