Synthesis of new 4,5-3(2H)pyridazinone derivatives and their cardiotonic, hypotensive, and platelet aggregation inhibition activities

Abstract

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.

A structural and functional perspective into the mechanism of Ca2+-sensitizers that target the cardiac troponin complex

“…In a recent study, Amin et al . identified a few more pharmacophores necessary to elicit cardiotonic activity [60]. They found that carbonyl groups attached to the hydrazone greatly improved the cardiotonic activity of the compounds.…”

A Review on Pyridazinone Ring Containing Various Cardioactive Agents

“…The cardiotonic, antihypertensive, and antiplatelet actions were also tested. The positive inotropic actions were exhibited that twelve of the compounds were exhibited higher effective responsesthan digoxin while eight of the compounds were less active than digoxin [78,79]. The triazole included 4, 5-dihydro-pyridazinones can be further modified to exhibit improved activity than the references drugs.…”

Diverse chemical and biological potentials of various pyridazine and pyridazinone derivatives

“…The synthesis of pyridazinone derivatives and investigation of their chemical and biological activities have gained more importance in recent years. Pyridazines and pyridazinones show wide spectrum of biological activities in the literature as potent inodilators (Kumar et al, 2010;Lee et al, 2010), vasorelaxants (Abouzid et al, 2010;Costas et al, 2010;Guerrero et al, 2008) and potent cardiotonic agents (Amin et al, 2008;Wang et al, 2009;. They showed also anticonvulsant (Edith et al, 2009;Sivakumar et al, 2009;Siddiqui et al, 2006), vasodilatory (Demirayak et al, 2009;Bansal et al, 2009), antihypertensive (Siddiqui et al, 2002;Ogretir et al, 2002;Vergelli et al, 2007), antimicrobial (Sotelo et al, 2002;Sayed et al, 2002), anti-inflammatory (Gokce et al, 2001;Dogruer et al, 2003;Frolov et al, 2004;Banoglu et al, 2004), anti feedant (Cao et al, 2003), herbicidal (Han et al, 2002), anti-nocieceptiv (Barbaro et al, 2002) activities.…”