Design, Synthesis, Characterization, Molecular Modeling, and ADMET Analysis of Novel Quinazolin‐4(3 <i>H</i> )‐One‐Triazole Hybrids as Vasorelaxant Agent

Abstract

In this study, a new series of quinazoline-4(3H)-one-triazole hybrid derivatives 4a-e was synthesized via one pot click chemistry protocol, starting from N-alkyl bromo quinazolin-4(3H)-one 2a-b and terminal alkynes 3a-e, achieving excellent yields and short reaction times. To confirm their structures, the compounds were characterized using several techniques, including proton and carbon nuclear magnetic resonance (NMR) spectroscopy, as well as high-resolution mass spectrometry (HRMS). In vitro evaluations of vasorelaxant activity on isolated rat aortic rings precontracted by epinephrine (EP, 10 µM) revealed that all compounds exhibited a significant vasorelaxant activity compared with the reference drug, verapamil. absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties prediction indicated a generally favorable pharmacokinetic profile, although some compounds showed potential risks of mutagenicity. Molecular docking analysis revealed high binding affinities with the protein target linked to vasorelaxant activity, with compound 3-(10-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)decyl)quinazolin-4(3H)-one (4d) showing greater stability in the active site than verapamil. In addition, molecular dynamics simulations confirmed that compound 4d enhances Cav1.1 protein stability, as evidenced by lower root mean square deviation (RMSD) values and reduced fluctuations, underlining its promise as an innovative therapeutic candidate for hypertension management.