title: ACE inhibitors hypothesis generation for selective design, synthesis and biological evaluation of 3-mercapto-2-methyl-propanoyl-pyrrolidine-3-imine derivatives as antihypertensive agents.
abstract: A series of new 3-mercapto-2-methyl-propanoyl-pyrrolidine derivatives (V, VIa-e) were designed. A new validated ACE inhibitors pharmacophore model (hypothesis) was generated for the first time in this research from the biologically active (frozen) conformation of Lisinopril-Human ACE complex that was downloaded from PDB, using stepwise technique of CATALYST modules. The molecular modeling compare-fit study of the designed molecules (V, VIa-e), with such ACE inhibitors hypothesis was fulfilled, and several compounds showed significant high simulation fit values. The compounds with high fit values were synthesized and biologically evaluated in vivo as hypotensive agents. It appears that the in vivo hypotensive activity of compounds V, VIa, VIb, and VIe was consistent with their molecular modeling results, and compound VIe showed the highest activity in comparison to Captopril.
authors.affiliation: Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, ElKhalifa ElMaamoon St., 11566 Abbasseya, Cairo, Egypt. mhismaeel@yahoo.com
authors.forename: Mohamed A H
authors.initials: MA
authors.lastname: Ismail
authors.forename: M
authors.initials: M
authors.lastname: Nabil Aboul-Enein
authors.forename: Khaled A M
authors.initials: KA
authors.lastname: Abouzid
authors.forename: Dalal A
authors.initials: DA
authors.lastname: Abou El Ella
authors.forename: Nasser S M
authors.initials: NS
authors.lastname: Ismail
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002384:Catalysis; D002415:Cats; D003198:Computer Simulation; D030562:Databases, Protein; D015195:Drug Design; D008956:Models, Chemical; D008958:Models, Molecular; D011422:Propionates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D011422:Propionates; D011759:Pyrrolidines; C541665:ethyl-2-(1-(3-mercapto-2-methylpropanoyl)-2-(4-methoxybenzyl)pyrrolidin-3-ylidene amino)propanoate