Synthesis of potent vasodilating agents: in silico and in vitro evaluation of 6-(4-substitutedphenyl)-3-pyridazinone derivatives as potential hydralazine analogues

People of all age categories and lifestyles suffer to different extents from hypertension. Accordingly, this necessitates the rise of new ways to defeat this enemy. Vasodilators exert a principal portion of highly effectual antihypertensive agents; our research is focused on the design, synthesis and biological evaluation of a new series of 6-(4-substitutedphenyl)-3-pyridazinones as potential hydralazine vasodilator analogues implementing both in vitro and in silico approaches. All the synthesized compounds were assessed for their vitro vasorelaxant activity against multiple references. New members revealed potent vasorelaxant activity (EC50 = 0.02916–1.907 µM) compared to the conventional vasorelaxants hydralazine, diazoxide, isosorbitole mononitrate and nitroglycerin (EC50 = 18.21, 19.5, 30.1 and 0.1824 µM, respectively). Compounds 2e, 2h and 2j exerted superior activities compared to others with EC50 = 0.1162, 0.07154 and 0.02916 µM, respectively. The physiochemical properties and drug-likeliness behavior of the new derivatives were investigated by conducting ADMET studies. Highlights 1. Vasodilators as one of the most important anti-hypertensive classes. 2. A new series of 6-(4-substitutedphenyl)-3-pyridazinones were designed and synthesized. 3. 3DQSAR pharmacophore model generation was conducted and used in activity prediction. 4. Compounds 2e , 2h and 2j exerted superior in vitro vasorelaxant activities compared to hydralazine. 5. Most of the synthesized compounds revealed promising results in the in silico ADMET studies in accordance with the rational design.