ACE inhibitors hypothesis generation for selective design, synthesis and biological evaluation of 3-mercapto-2-methyl-propanoyl-pyrrolidine-3-imine derivatives as antihypertensive agents
Ismail, Mohamed A H; Nabil Aboul-Enein, M; Abouzid, Khaled; Ismail, Nasser S M; Abou El Ella, Dalal;
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.
Other data
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 | Authors | Ismail, Mohamed A H; Nabil Aboul-Enein, M; Abouzid, Khaled ; Ismail, Nasser S M; Abou El Ella, Dalal | Keywords | Molecular modeling;ACE inhibitors hypothesis generation;Hypotensive agents;3-Mercapto-2-methyl-propanoylpyrrolidines;ANGIOTENSIN-CONVERTING ENZYME;RECEPTOR ANTAGONISTS;HYPERTENSION | Issue Date | 15-May-2009 | Publisher | PERGAMON-ELSEVIER SCIENCE LTD | Journal | Bioorganic and Medicinal Chemistry | Volume | 17 | Issue | 10 | Start page | 3739 | End page | 3746 | ISSN | 0968-0896 | DOI | 10.1016/j.bmc.2009.03.008 | PubMed ID | 19403313 | Scopus ID | 2-s2.0-65449142952 | Web of science ID | WOS:000265683800027 |
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