Synthesis of 4-alkyl (aryl)-6-aryl-3-cyano-2(1H)-pyridinones and their 2-imino isosteres as nonsteroidal cardiotonic agents.
Thirty new 1,2-dihydropyridine derivatives of the general formula 4-alkyl (aryl)-6-aryl-3-cyano-2(1H)-pyridinones (1-15) and 4-alkyl (aryl)-6-aryl-3-cyano-2(1H)-iminopyridines (16-30) were synthesized using one-pot multicomponent reactions of the properly substituted acetophenone, appropriate aldehyde, ammonium acetate and ethyl cyanoacetate (1-15) or malononitrile (16-30) in ethanol. These target compounds (1-30) were evaluated for their cardiotonic activity using the spontaneously beating atria model, from reserpine-treated guinea pigs. The best pharmacological profile was obtained with 3-cyano-6-(3,4-dimethoxyphenyl)-4-(4-hydroxyphenyl)-2(1H)-pyridinone (9) which displaced selectivity for increasing the force of contraction (108.7 +/- 6.7,% change over control) rather than the frequency rate (40.8 +/- 5.3,% change over control) at a 5 x 10(-4) M concentration. The effects of structural changes upon activity are reported.
Abadi
A
A
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Al-Deeb
O
O
al-Afify
A
A
el-Kashef
H
H
D000818:Animals; D016275:Atrial Function; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D011728:Pyridones / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D013055:Spectrophotometry, Infrared
C120383:3-cyano-6-(3,4-dimethoxyphenyl)-4-(4-hydroxyphenyl)-2(1H)-pyridinone; D002316:Cardiotonic Agents; D011728:Pyridones