Novel class of benzimidazole-thiazole hybrids: The privileged scaffolds of potent anti-inflammatory activity with dual inhibition of cyclooxygenase and 15-lipoxygenase enzymes

• Published in: Bioorganic & medicinal chemistry Vol. 28; no. 7; p. 115403
• Main Authors: Maghraby, Mohammed T.-E., Abou-Ghadir, Ola M.F., Abdel-Moty, Samia G., Ali, Asmaa Y., Salem, Ola I.A.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.04.2020; Elsevier
• Subjects: Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Arachidonate 15-Lipoxygenase - metabolism; Benzimidazole-thiazole hybrids; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Biochemistry & Molecular Biology; Carrageenan - toxicity; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacology; Drug Design; Dual COX-2 /15-LOX inhibitors; Edema - chemically induced; Edema - drug therapy; Life Sciences & Biomedicine; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; Male; Molecular docking; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Rats; Science & Technology; Structure-Activity Relationship; Thiazoles - chemistry; Thiazoles - pharmacology; Ulcerogenic effect; Ulcerogenic effect; Benzimidazole-thiazole hybrids; Dual COX-2 /15-LOX inhibitors; Anti-inflammatory agents; Molecular docking; DESIGN; COX-2; Dual COX-2/15-LOX inhibitors; INFLAMMATION; DRUGS; BIOLOGICAL EVALUATION; AGENTS; UPDATE; DERIVATIVES; 5-LOX
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2020.115403

[Display omitted] •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. 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.