Novel class of benzimidazole-thiazole hybrids: The privileged scaffolds of potent anti-inflammatory activity with dual inhibition of cyclooxygenase and 15-lipoxygenase enzymes. Issue 7 (1st April 2020)

• Record Type: Journal Article
• Authors: Maghraby, Mohammed T.-E.; Abou-Ghadir, Ola M.F.; Abdel-Moty, Samia G.; Ali, Asmaa Y.; Salem, Ola I.A.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 7(2020)
• Publication Date: 2020-04-01
• Subjects: Benzimidazole-thiazole hybrids -- Anti-inflammatory agents -- Dual COX-2 /15-LOX inhibitors -- Ulcerogenic effect -- Molecular docking; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115403
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Design and synthesis of novel dual COX-2 and 15-LOX benzimidazole-thiazole hybrids. Potent COX-2 inhibition with high selectivity comparable to celecoxib. Hybrid linked to 1, 3-thiazoline 15b was the best COX-2/15-LOX inhibitor. High in vivo edema inhibition with superior gastrointestinal safety profile. Molecular docking exposed significant structural binding features. Abstract: The present study includes design and synthesis of new molecular hybrids of 2-methylthiobenzimidazole linked to various anti-inflammatory pharmacophores through 2-aminothiazole linker, to investigate the effect of such molecular variation on cyclooxygenase (COX) and 15-lipoxygenase (15-LOX) enzymes inhibition as well as in vivo anti-inflammatory activity. The chemical structures of new hybrids were confirmed using different spectroscopic tools and elemental analyses. Benzimidazole-thiazole hybrids linked to acetyl moiety 13, phenyl thiosemicarbazone 14, 1, 3-thiazolines 15a-c and 4-thiazolidinone 16 exhibited significant COX-2 inhibition (IC50 = 0.045–0.075 µM) with significant COX-2 selectivity indices (SI = 142–294). All hybrids revealed potent 15-LOX inhibitory activity (IC50 = 1.67–6.56 µM). Benzimidazole-thiazole hybrid 15b was the most potent dual COX-2 (IC50 = 0.045 µM, SI = 294) inhibitor approximate to celecoxib (COX-2; IC50 = 0.045 µM, SI = 327), with double inhibitory activity versus 15-LOX enzyme (IC50 = 1.67 µM) relative to quercetin (IC50 = 3.34 µM). Three hybrids (14, 15b & 16 ) were selected for in vivo screening using carrageenan-induced paw edema method. Benzimidazole-thiazole hybrid linked to 4-thiazolidinone 16 showed the maximum edema inhibition at both 3 h and 4 h intervals as well (~119% and 102% relative to indomethacin, respectively). The gastric ulcerogenic effect of benzimidazole-thiazole hybrid 16 was estimated compared with indomethacin showing superior gastrointestinal safety profile. In bases of molecular modeling; all new active hybrids were subjected to docking simulation into active sites of COX-2 and 15-LOX enzymes to study the binding mode of these novel potent dual COX-2/15-LOX inhibitors.