Unveiling the Potential of the Thiopyrimidinone Nucleus as a Vasoactive Scaffold: An Approach to Developing Novel Alpha‐1 Adrenoceptor Antagonists

Abstract This investigation into the potential of 2‐thiopyrimidinones derivatives as inhibitors of α‐adrenergic receptors demonstrated promising results for their use in antihypertensive therapy. The proposed compounds, 2‐thiopyrimidinones derivatives, were evaluated through ex vivo vascular reactivity assays in Wistar rat arteries, and the interaction modes of these compounds with α 1A ‐adrenergic receptors were analyzed through molecular docking simulations. Six of the 22 drug candidates inhibited phenylephrine‐induced contraction of isolated aorta, indicating the potential of these substances to act as α 1A adrenoceptor antagonists. Experimental results reveal that hydrophobic substituent groups attached to the sulfur atom of the heterocycle, such as ethyl and benzyl, are crucial for activity. Conversely, the absence of substituent groups attached to the sulfur atom or the presence of hydrogen‐bond‐accepting and ‐donating substituent groups, such as hydroxyls and carbonyls, does not favor vasoactive activity. The best prototypes were also evaluated via in silico studies using a strategy that combined molecular dynamics with molecular docking. The synthesized compounds interacted with key residues of the α 1A receptor, including highly conserved residues among adrenergic receptors. Theoretical pharmacokinetic and physicochemical parameters identified the most active 2‐thiopyrimidinones as promising oral drug candidates, suggesting the emergence of a new class of adrenergic antagonists.