title: Design and synthesis of benzimidazole analogs endowed with oxadiazole as selective COX-2 inhibitor.
abstract: New molecules of benzimidazole endowed with oxadiazole were designed and synthesized from 2-(2-((pyrimidin-2-ylthio)methyl)-1H-benzo[d]imidazol-1-yl)acetohydrazide as 1-((5-substituted alkyl/aryl-1,3,4-oxadiazol-2-yl)methyl)-2-((pyrimidin-2-ylthio)methyl)-1H-benzimidazoles (5a-r) with the aim to acquire selective cyclooxygenase (COX-2) inhibitor activity. The synthesized compounds were screened by in vitro cyclooxygenase assays to determine COX-1 and COX-2 inhibitory potency and the results showed that they had good-to-remarkable activity with an IC50 range of 11.6-56.1 µM. The most active compounds were further screened for their in vivo anti-inflammatory activity by using the carrageenan-induced rat paw edema model. In vitro anticancer activities of the hybrid compounds were assessed by the National Cancer Institute (NCI), USA, against 60 human cell lines, and the results showed a good spectrum. Compound 5l exhibited significant COX-2 inhibition with an IC50 value of 8.2 µM and a percent protection of 68.4%. Compound 5b evinced moderate cytotoxicity toward the UO-31 cell line of renal cancer. A docking study was performed using Maestro 9.0, to provide the binding mode into the binding sites of the cyclooxygenase enzyme. Hopefully, in the future, compound 5l could serve as a lead compound for developing new COX-2 inhibitors.
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Jamia Hamdard (Hamdard University), New Delhi, India.
authors.forename: Ankita
authors.initials: A
authors.lastname: Rathore
authors.forename: Mujeeb Ur
authors.initials: MU
authors.lastname: Rahman
authors.forename: Anees Ahamad
authors.initials: AA
authors.lastname: Siddiqui
authors.forename: Abuzer
authors.initials: A
authors.lastname: Ali
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shaharyar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002351:Carrageenan; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017076:Computer-Aided Design; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D020128:Inhibitory Concentration 50; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D017208:Rats, Wistar; D018570:Risk Assessment; D013276:Stomach Ulcer / Q000139:chemically induced; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D052246:Cyclooxygenase 2 Inhibitors; D010069:Oxadiazoles; D002351:Carrageenan; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C489691:Ptgs2 protein, rat
keywords: Benzimidazole; Cyclooxygenase 1 and 2; Indomethacin; Oxadiazole; Selectivity index