title: New hybrid molecules combining benzothiophene or benzofuran with rhodanine as dual COX-1/2 and 5-LOX inhibitors: Synthesis, biological evaluation and docking study.
abstract: New molecular hybrids combining benzothiophene or its bioisostere benzofuran with rhodanine were synthesized as potential dual COX-2/5-LOX inhibitors. The benzothiophene or benzofuran scaffold was linked at position -2 with rhodanine which was further linked to various anti-inflammatory pharmacophores so as to investigate the effect of such molecular variation on the anti-inflammatory activity. The target compounds were evaluated for their in vitro COX/LOX inhibitory activity. The results revealed that, compound 5h exhibited significant COX-2 inhibition higher than celecoxib. Furthermore, compounds 5a, 5f and 5i showed COX-2 inhibitory activity comparable to celecoxib. Compound 5h showed selectivity index SI=5.1 which was near to that of celecoxib (SI=6.7). Compound 5h displayed LOX inhibitory activity twice than that of meclofenamate sodium. Moreover, compounds 5a, 5e and 5f showed significant LOX inhibitory activity higher than that of meclofenamate sodium. Compound 5h was screened for its in vivo anti-inflammatory activity using formalin-induced paw edema and gastric ulcerogenic activity tests. The results revealed that, it showed in vivo decrease in formalin-induced paw edema volume higher than celecoxib. It also displayed gastrointestinal safety profile as celecoxib. The biological results were also consistent with the docking studies at the active sites of the target enzymes COX-2 and 5-LOX. Also, compound 5h showed physicochemical, ADMET, and drug-like properties within those considered adequate for a drug candidate.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt. Electronic address: mostafa.elmiligy@alexu.edu.eg.
authors.forename: Mostafa M M
authors.initials: MMM
authors.lastname: El-Miligy
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
authors.forename: Aly A
authors.initials: AA
authors.lastname: Hazzaa
authors.affiliation: Faculty of Pharmacy, Omar-Almukhtar University, Libya.
authors.forename: Hanan
authors.initials: H
authors.lastname: El-Messmary
authors.affiliation: Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
authors.forename: Rasha A
authors.initials: RA
authors.lastname: Nassra
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
authors.forename: Soad A M
authors.initials: SAM
authors.lastname: El-Hawash
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005557:Formaldehyde; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D012236:Rhodanine / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001572:Benzofurans; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D013876:Thiophenes; C088015:benzothiophene; D005557:Formaldehyde; D012236:Rhodanine; D001094:Arachidonate 5-Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C105430:benzofuran
keywords: Benzofuran; Benzothiophene; COX/LOX inhibition; Rhodanine