Synthesis and evaluation of novel 2-pyridone derivatives as inhibitors of phosphodiesterase3 (PDE3): a target for heart failure and platelet aggregation.
Twenty-six 2-pyridone derivatives (8a-8z), which are structurally analogous to amrinone and milrinone two important cardiotonic drugs, are synthesized and characterized. The synthesis of 2-pyridone derivatives involves addition, followed by cyclization between Baylis-Hillman acetates (7a-7k) and enamino esters or nitriles (3a-3e). Thus synthesized pyridones were subjected to PDE3 inhibitory activity, 14 pyridones were found to be hits out of 26 pyridones synthesized and out of 14 hits, there are 5 pyridones found to be lead compounds having excellent PDE3 inhibitory activity. Further we have carried out computational analysis to understand protein/enzyme and 2-pyridone derivative interactions to identify amino acid residues involved in the vicinity of binding and compared with milrinone drug.
Organic Chemistry Division II, Indian Institute of Chemical Technology, Uppal Road Tarnaka, Hyderabad 500607, India.
Mettu
M
Ravinder
Budde
B
Mahendar
Saidulu
S
Mattapally
Kommi Venkata
KV
Hamsini
Thatikonda Narendar
TN
Reddy
Chilappa
C
Rohit
Kolupula
K
Srinivas
Sanjay Kumar
SK
Banerjee
Vaidya Jayathirtha
VJ
Rao
D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D058987:Phosphodiesterase 3 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D002316:Cardiotonic Agents; D058987:Phosphodiesterase 3 Inhibitors; D011728:Pyridones; C017679:2-hydroxypyridine