Discovery of novel 1,2,3-Triazole hybrids derivatives as vasorelaxant agents: Molecular structure, Hirshfeld surface, in-vivo and in-silico investigation by molecular docking simulation.

In this study, we have developed a new category of antihypertensive agents using copper-catalysed "click chemistry". This series of six hybrid compounds (HRa-f) consists of quinazoline-(3H)-one-1,2,3-triazole-acetamide derivatives. In order to confirm their structures, they were characterised by a number of techniques including infrared spectroscopy, proton and carbon nuclear magnetic resonance, heteronuclear multiple bond correlation, heteronuclear single quantum coherence and correlation spectroscopy. X-ray diffraction analysis and interactions, including hydrogen bonding which stabilises the crystal lattice, have been studied. Analyses of the Hirshfeld surface mapped to di, de, dnorm and shape index were used to detect intermolecular interactions. The histogram of the fingerprints shows that the H⋯H (48.2 %) and O⋯H (12.6 %) contacts are the dominant interactions in the crystal stacking. The vasorelaxant activity of the synthesised compounds was evaluated using aortic rings from precontracted rats exposed to epinephrine (10 μM). Dose-response studies indicated that the vasorelaxant efficacy varied depending on the structural modifications of the drugs. Molecular docking studies were also performed to predict binding affinity and identify the most likely binding interactions between the hybrid molecules and the calcium channel. Cav 1.2, the alpha-subunit containing key binding sites (EEE locus: GLU 363, GLU 706, GLU 1135, GLU 1464), was compared with the drug verapamil. Docking results confirmed that verapamil (-8.22 kcal/mol) was the most potent compound, followed by the HRa-f compounds.