Synthesis and characterization of Thieno[3,2-d]pyrimidine Derivatives for Antimicrobials activity

Abstract

Abstract: Objectives: To synthesize and characterize novel thieno[3,2-d]pyrimidine derivatives as potential antimicrobial agents targeting DNA gyrase to address the critical clinical challenge of multidrug-resistant bacterial infections.

Methods: Ten thieno[3,2-d]pyrimidine derivatives (S1-S10) were synthesized through nucleophilic substitution at the 2-position using N-benzylamine with diverse acyl and sulfonyl substituents. Compounds were characterized by FTIR, ¹H NMR, ¹³C NMR, and mass spectrometry. Molecular docking was performed using GeinDock Suite v1.0 against DNA gyrase B subunit (PDB ID: 1AJ6). Drug-likeness, ADME properties, and toxicity profiles were evaluated using ForceADME and Geintox-II platforms.

Results: All compounds were successfully synthesized with yields ranging 63.4-72.8%. Three compounds demonstrated exceptional binding affinities: S5 (-8.2 kcal/mol), S8 (-8.2 kcal/mol), and S9 (-8.1 kcal/mol), significantly higher than other derivatives (range: -6.8 to -7.9 kcal/mol). Key binding interactions involved THR165, ASN46, and hydrophobic residues ILE78/PRO79. All compounds violated Lipinski's Rule with molecular weights 382-458 g/mol and showed low gastrointestinal absorption. Toxicity analysis revealed LD50 values of 1001-2018 mg/kg (class 4-5).

Conclusion: The study identifies three potent DNA gyrase inhibitors with strong clinical potential for treating resistant bacterial infections. Despite ADME limitations requiring optimization, these novel scaffolds represent promising lead compounds for antimicrobial drug development, warranting immediate in vivo efficacy studies and structural modifications for future clinical translation.