title: Benzofuran-morpholinomethyl-pyrazoline hybrids as a new class of vasorelaxant agents: synthesis and quantitative structure-activity relationship study.
abstract: The benzofuran-morpholinomethyl-pyrazoline hybrids 4a-e, 5a-e and 6a-j were synthesized via reaction of α,β-unsaturated carbonyl compounds 3a-e with hydrazine hydrate, semicarbazide or thiosemicarbazide. Applying the Mannich reaction to 5-(5-aryl-4,5-dihydro-1H-pyrazol-3-yl)-4-methoxybenzofuran-6-ols 7a-e with morpholine hydrochloride and paraformaldehyde afforded positional isomeric 7-morpholinomethyl derivatives 4a-e and N-morpholinomethyl derivatives 8a-e. All the synthesized compounds showed significant vasodilatation properties in isolated thoracic aortic rings of rats precontracted using the standard norepinephrine hydrochloride technique. Compounds 3d, 3e, 5a-c, 6b, 6c, 6f, 6h and 6i exhibited activity (IC50 0.3185-0.4577 mM) superior to that of prazocin (IC50 0.487 mM), while 5d, 6j and 8c showed comparable activity (IC50 0.4789-0.4951 mM). The quantitative structure-activity relationship study revealed a correlation between the observed vasorelaxant activities of the newly synthesized compounds and their different physicochemical parameters, especially solubility, in addition to structure connectivity and energetic quantities calculated from stored three dimensional (3D) conformations. Absorption, distribution, metabolism and elimination (ADME) evaluation showed good agreement with the biological results obtained.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University.
authors.forename: Ghaneya Sayed
authors.initials: GS
authors.lastname: Hassan
authors.forename: Doaa Ezzat
authors.initials: DE
authors.lastname: Rahman
authors.forename: Dalia Osama
authors.initials: DO
authors.lastname: Abdel  Saleh
authors.forename: Gehad Abdel Raheem
authors.initials: GA
authors.lastname: Abdel Jaleel
mesh_terms: D000465:Algorithms; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D017208:Rats, Wistar; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D001572:Benzofurans; D009025:Morpholines; D011720:Pyrazoles; D014665:Vasodilator Agents