Tackling Microbial Resistance with Isatin-Decorated Thiazole Derivatives: Design, Synthesis, and in vitro Evaluation of Antimicrobial and Antibiofilm Activity

INTRODUCTION: Antibiotic resistance is a global threat that has been increasing recently, especially with antibiotic overuse and misuse. The search for new antibiotics is becoming more and more indispensable. METHODS: Design and synthesis of isatin derivatives as surrogates of SB-239629, a bacterial tyrosine-tRNA synthetases (TyrRS) inhibitor. The newly synthesized compounds were screened for their antimicrobial and antibiofilm activities. Docking studies were used to investigate potential binding modes of these compounds with TyrRS. RESULTS AND DISCUSSION: Newly synthesized isatin-decorated thiazole derivatives (7b, 7d, and 14b) have shown potent antimicrobial activities against E. coli, a representative of gram-negative bacteria. Also, 7f showed the best activity against Methicillin Resistant Staphylococcus aureus (MRSA). In addition, 7h and 11f were found to have antifungal activities against Candida albicans equivalent to that of the reference Nystatin. All the new isatin derivatives with antimicrobial activities were found to exhibit strong biofilm distortion effects at half their minimum inhibitory concentrations (MIC). Moreover, thiazole derivatives 11a-f showed promising biofilm formation inhibition. Finally, molecular docking studies were used to investigate possible binding modes of target compounds with S. aureus and E. coli TyrRS. CONCLUSION: The novel isatin-decorated thiazole derivatives show strong antimicrobial and antifungal activities with potential action on TyrRS.