title: Design and Development of Novel 4-(4-(1H-Tetrazol-5-yl)-1H-pyrazol-1-yl)-6-morpholino-N-(4-nitrophenyl)-1,3,5-triazin-2-amine as Cardiotonic Agent via Inhibition of PDE3.
abstract: The classical phosphodiesterase 3A (PDE3A) inhibitors provide relaxation of the vasculature system via increasing the cellular level of cyclic adenosine monophosphate (cAMP) and proved to be useful in the management of congestive heart failure. Consequently, the present paper deals with the development of novel pyrazole derivatives tethered with substituted 1,3,5-triazine derivatives in search for novel PDE3 inhibitors. The synthesis of designed inhibitors was realized in a multi-step reaction and the structures were ascertained with the help of various spectroscopic techniques. Subsequently, these analogs were tested for their inhibitory activities against PDE3 enzymes, where they exhibited considerable inhibition, revealing 9g as the most promising inhibitor of the class. In a docking study, the morpholine fragment of compound 9g was efficiently engulfed in the small pocket of the active site lined by Gly940 and Pro941. The substituted aromatic ring of the core scaffold was found to be positioned deep in the cavity bordered by Tyr829, Asn830, Leu850, Glu851, and Thr893. Moreover, it considerably improved the contractility of cardiac muscles without altering the heart beat frequency in experimental subjects.
authors.affiliation: Department of Cardiovasology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, P. R. China.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Mao
authors.affiliation: Department of Kidney Rheumatology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P. R. China.
authors.forename: Qiao-Ling
authors.initials: QL
authors.lastname: Li
authors.affiliation: Department of Cardiovasology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, P. R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Cardiovasology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, P. R. China.
authors.forename: Yang-Li
authors.initials: YL
authors.lastname: Sun
authors.affiliation: Department of Cardiovasology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, P. R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000737:chemistry / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D062105:Molecular Docking Simulation; D009200:Myocardial Contraction / Q000187:drug effects; D058987:Phosphodiesterase 3 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017208:Rats, Wistar; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C000613240:4-(4-(1H-tetrazol-5-yl)-1H-pyrazol-1-yl)-6-morpholino-N-(4-nitrophenyl)-1,3,5-triazin-2-amine; D002316:Cardiotonic Agents; D058987:Phosphodiesterase 3 Inhibitors; D014227:Triazines; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517290:Pde3a protein, rat; C517294:Pde3b protein, rat
keywords: 1,3,5-Triazine; Docking; PDE3 inhibitor; Synthesis