Design of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3,4-thiadiazoles, -1,3,4-oxadiazoles, and -1,2,4-triazoles as orally active, nonulcerogenic antiinflammatory agents

Abstract

To discover dual inhibitors of 5-lipoxygenase (LO) and cyclooxygenase (CO) with improved pharmacokinetic properties, we have designed and synthesized series of 1,2,4-triazole, 1,3,4-oxadiazole, and 1,3,4-thiadiazole di-tert-butylphenol derivatives which exhibit a wide range of log P (2.3 to > 4) and pKa (5.5-12) values. From this work 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)- thione, choline salt (12a, CI-986) was found to be a potent inhibitor of 5-LO (IC50 = 2.8 microM) and CO (IC50 = 0.8 microM), orally active in rat models of inflammation and nonulcerogenic.

Synthesis and Characterization of Novel 1,3-Thiazole and 2-Amino-1,3,4-Thiadiazole Derivatives

“…In addition, C(5) and C(4) of the thiazole ring were observed at 100.48-100.87 and 148.21-148.28 ppm, respectively. The exo N(2')=C(2) carbon data of the thiazole ring appeared at 161.31-161.37 ppm in the 13 C NMR spectra [29]. The signals of the thione group (C=S) from the compounds 3a-e disappeared, and new signals were observed at 60.17-60.27 ppm (-OCH 2 ), 14.10-14.20 ppm (-CH 3 ), 12.41-12.54 ppm (-OCH 2 CH 3 ).…”

Molecular Docking Study of Some Novel Imidazo [2,1-B] [1,3,4]-Thiadiazole Derivatives

“…1,2 and thiadiazole [3][4][5] moieties are accompanying with diverse applications in the field of pharmacy owing to the -N-C=N and toxophoric -N=C-S-groups. The fusion of heterocycles, the possibilities of reducing harmful effects of cytotoxic agents on the immune system also seems very attractive.…”

“…Thiazole (sulfathiazole, cefixime), Imidazo [2,1-b] thiazole and their bioisosteric derivatives such as thiadiazole (acetazolamide), imidazo [2,1-b] [1,3,4] thiadiazole are regarded as safer and better drug molecules that are found to possess diversified biological activities like anti-bacterial 2 , diuretic, antifungal, and leishmanicidal 6 . The anti-tumor potential of 2-amino [1,3,4] thiadiazole skeleton was recognized in early 1950's and subsequently, its fusion with imidazo [2,1-b] ring system has resulted in compounds with antibacterial 3 , anticancer 5 , cardiotonic and cytotoxic activities 7 .…”

“…The anti-tumor potential of 2-amino [1,3,4] thiadiazole skeleton was recognized in early 1950's and subsequently, its fusion with imidazo [2,1-b] ring system has resulted in compounds with antibacterial 3 , anticancer 5 , cardiotonic and cytotoxic activities 7 .…”

Biological Evaluation of 2, 5-Di (4 Aryloylaryloxy Methyl) - 1, 3, 4-Oxadiazoles Derivatives as Antimicrobial Agents

“…The compounds with the backbone of benzophenones have been reported to possess various biological activities such as anticancer [8] antimicrobial [9] antioxidant [10]. 1,3,4-Oxadiazole ring is associated with many types of biological properties such as anti-inflammatory [11][12][13], hypoglycemic [14], antifungal and antibacterial [15][16][17][18][19] activities. 1,3,4-Oxadiazoles and its derivatives have a broad range of biological and pharmacological properties and are widely used as starting materials for the synthesis of a broad range of heterocyclic compounds and substrates for the drug synthesis.…”