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

Autor: Maghraby MT; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt., Abou-Ghadir OMF; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt., Abdel-Moty SG; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt., Ali AY; Histology and Cell Biology Department, Faculty of Medicine, Assiut University, Assiut 71111, Egypt., Salem OIA; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. Electronic address: ola.salim@pharm.aun.edu.eg.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2020 Apr 01; Vol. 28 (7), pp. 115403. Date of Electronic Publication: 2020 Feb 26.
DOI: 10.1016/j.bmc.2020.115403
Abstrakt: 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 (IC 50  = 0.045-0.075 µM) with significant COX-2 selectivity indices (SI = 142-294). All hybrids revealed potent 15-LOX inhibitory activity (IC 50  = 1.67-6.56 µM). Benzimidazole-thiazole hybrid 15b was the most potent dual COX-2 (IC 50  = 0.045 µM, SI = 294) inhibitor approximate to celecoxib (COX-2; IC 50  = 0.045 µM, SI = 327), with double inhibitory activity versus 15-LOX enzyme (IC 50  = 1.67 µM) relative to quercetin (IC 50  = 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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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