Design, Synthesis, and Evaluation of Thiophene-Based Pyrido2,3-D Pyrimidines and Alkyl-Substituted Thiophene Based Pyrido2,3-D Pyrimidines as Antibacterial Agents

Introduction: The rise in antibiotic resistance and the high prevalence of bacterial infections, particularly urinary tract infections (UTIs), have created an urgent need for new antibacterial agents. In response, thiophene-based pyrido2,3-dpyrimidines and alkyl-substituted thiophene- based pyrido2,3-dpyrimidines were designed in this study. Materials and Methods: Thiophene-based pyrido2,3-dpyrimidines and their alkyl-substituted analogues were designed using in silico tools and synthesized using standard procedures. Molecular docking studies were performed with the Maestro 12.9 module of Schrödinger software. In silico ADME profiles of the synthesized compounds were evaluated using the QikProp module of the Schrödinger suite. Antibacterial activity was assessed using the serial dilution method. Results: Molecular docking studies were conducted to predict the binding affinities of the synthesized compounds, while ADME properties were evaluated in silico. Antibacterial activity testing revealed that among the derivatives, MA 1.8 and MA 2.2 exhibited the most potent effects. The minimum inhibitory concentration (MIC) values for MA 1.8 were 1.56 μg/mL against B. subtilis, 3.125 μg/mL against S. aureus, 1.56 μg/mL against P. putida, and 3.125 μg/mL against E. coli. For MA 2.2, the MIC values were 3.125 μg/mL against B. subtilis, S. aureus, and E. coli, and 6.25 μg/mL against P. putida. Discussion: Both MA 1.8 and MA 2.2 demonstrated favorable docking scores compared to reference standards and exhibited acceptable in silico ADME profiles, supporting their potential druglikeness. The consistency between computational predictions and in vitro antibacterial assays underscores the reliability of integrating molecular docking, ADME screening, and biological evaluation for lead optimization. Conclusion: Thiophene-based pyrido2,3-dpyrimidine derivatives, particularly MA 1.8 and MA 2.2, emerged as promising antibacterial agents with potent activity against both Gram-positive and Gram-negative strains. Their strong binding affinities, favorable pharmacokinetic properties, and broad-spectrum antibacterial efficacy indicate that these compounds could serve as valuable lead molecules for the development of novel antibacterial agents.