<p class="MDPI12titleori1" style="mso-line-height-alt: 14.0pt;">Convenient Synthesis, Molecular Docking and <em>In-Vitro</em> Antibacterial Activity Studies of 3-<em>N</em>-Substituted 5-aryl(hetaryl)thieno[2,3-D]pyrimidin-4(3<em>H</em>)-Ones

This study reports the convenient synthesis of a new series of sustainable heterocyclic compounds called 3-N-Substituted 5-aryl(hetaryl)-thieno[2,3-d]pyrimidin-4(3H)-ones, encompassing two biologically important pharmacophores namely thiophen and pyrimidine. A stepwise synthesis of 5-aryl(hetaryl)thieno[2,3-d]pyrimidine-4(3H)-ones with variable substituents at the N 3 position was proposed, which involves the synthesis of aromatic and heteroaromatic substituted 2-aminothiophenes, their condensation with N,N′-dimethylformamide dimethylacetal. Obtained 2-dimethylaminomethyleneamino-thiophenes condense with primary amines. This sequence of reactions leads to the production of new polyheteroconjugated systems with advantages like simple work up, easy separation of the products and chromatography-free purification. Structural elucidation was done by spectroscopic method and elemental analysis and have confirmed their molecular structure. The synthesized compounds were tested on their antibacteriial activity against Gram positive and Gram negative bacteria. Compound 6k showed notable antibacterial activity compared to the standard drug (Gentamicin) against S. aureus bacteria. Compounds 6e and 6k were evaluated for their antimicrobial potential via molecular docking against S. aureus Aminoglycoside Phosphotransferase and P. aeruginosa TrmD. Compound 6k exhibited superior binding affinity and an enhanced pharmacokinetic profile, positioning it as a promising lead for further optimization and development as an antimicrobial agent. However, as this study represents an initial screening, further in silico investigations are required for predicting antibacterial activity of target derivatives with calculated substituents. Overall, this work highlights the efficiency of a convenient approach for synthesizing 3-N-Substituted 5-aryl(hetaryl)-thieno[2,3-d]pyrimidin-4(3H)-ones and underscores their potential as promising scaffolds for the development of potent antibacterial agents.