Abstract
Two new series of pyridazin-3-one tethered 4-substituted thiosemicarbazide side chains (4a-l) and their cyclized versions (5a-h) were designed. The vasorelaxant activities of the newly synthesized compounds were screened using both in vitro and in silico evaluation approaches. The target compounds were synthesized starting from their corresponding 4-substitutedacetophenones and were unambiguously characterized using various spectroscopic techniques. Then, 3D QSAR pharmacophore and molecular docking studies were performed to evaluate the potential activity of the target compounds as well as their binding affinities toward various binding sites of the hypothesized biological receptor (IP3). Subsequently, the synthesized derivatives were assessed for their in vitro vasorelaxant activities over isolated pre-contracted rat thoracic aorta. All synthesized compounds exhibited a potent range of activity, with EC(50) of 0.0117-2.2680 μM for series 4a-l and 0.0025-2.9480 μM for series 5a-l compared with those of the reference standards (EC(50) of hydralazine, isosorbide mononitrile, diazoxide and nitroglycerin = 18.2100, 30.1, 19.5 and 0.1824, respectively). Compounds 4f, 4h, 5d and 5e showed superior activity with EC(50) of 0.0136, 0.0117, 0.0053 and 0.0025 μM, respectively. These compounds demonstrated a remarkable increase in eNOS mRNA expression by approximately 25%, 54.9%, 83.6% and 140.3%, respectively. Moreover, these compounds exhibited a considerable uplevelling of the aortic content of NO by approximately 35.7%, 84%, 135.7% and 186.5%, respectively, compared with the corresponding value in nitroglycerin (P < 0.0001). The computer-based ADMET studies of the new derivatives demonstrated promising physicochemical properties and drug-likeliness behavior, including optimal aqueous solubility, good oral bioavailability, excellent intestinal absorption and no cytochrome P450 enzyme inhibition.