Synthesis of new 4,5-3(2H)pyridazinone derivatives and their cardiotonic, hypotensive, and platelet aggregation inhibition activities.
4,5-dihydro-3(2H)pyridazinones such as CI-914, CI-930 and pimobendan along with tetrahydropyridopyridazine (endralazine) and perhydropyridazinodiazepine (cilazopril) have been used as potent positive inotropes, antihypertensives as well as platelet aggregation inhibitors. Accordingly, the present work involves the synthesis of 24 target compounds; 4,5-dihydro-3(2H)pyridazinones in addition to seven reported intermediates. The chemical structures of the new compounds were assigned by microanalysis, IR, 1H-NMR spectral analysis and some representatives by mass spectrometry. The positive inotropic effect of the final compounds and the intermediates 12a-12d as well as the reported intermediate compound 10 was determined in-vitro on isolated rabbit heart in comparison to digoxin. Data obtained revealed that twelve of the test compounds exhibited higher effective response than digoxin, nine compounds elicited comparable effects to digoxin and eight compounds were less active than digoxin. In addition, four compounds approved marked significant hypotensive effect better than that of the previously reported compound 10. Moreover, two compounds induced complete platelet aggregation inhibition. The last two compounds were also subjected to determination of their LD50 and they showed no signs of toxicity up to the dose level 300 mg/kg (i.p.), while the reported oral LD50 of digoxin is 17.78 mg/kg. Correlation of cardiotonic and hypotensive activities with structures of compounds was tried and pharmacophore models were computed to get useful insight onto the essential structural features required for inhibiting phosphodiesterase-III in the heart muscles and blood vessels.
Amin
Enas Nashaat
EN
Department of Pharmaceutical Organic Chemistry, Faculty of Medicine, Assiut University, Assiut 71526, Egypt.
Abdel-Alim
Abdel-Alim M
AA
Abdel-Moty
Samia G
SG
El-Shorbagi
Abdel-Naser A
AN
Abdel-Rahman
Mahran Sh
MSh
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D001792:Blood Platelets / Q000187:drug effects; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002855:Chromatography, Thin Layer; D019295:Computational Biology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007928:Lethal Dose 50; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D011817:Rabbits; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology
D000959:Antihypertensive Agents; D002316:Cardiotonic Agents; D007202:Indicators and Reagents; D010975:Platelet Aggregation Inhibitors; D011724:Pyridazines; D014665:Vasodilator Agents