Facile Synthesis of 5-Bromo-N-Alkylthiophene-2-Sulfonamides and Its Activities Against Clinically Isolated New Delhi Metallo-ß-Lactamase Producing Klebsiella pneumoniae ST147.

ABSTRACT

Introduction: New Delhi Metallo-ß-lactamase producing Klebsiella pneumoniae (NDM-1-KP) sequence type (ST) 147 poses a significant threat in clinical settings due to its evolution into two distinct directions hypervirulence and carbapenem resistance. Hypervirulence results from a range of virulence factors, while carbapenem resistance stems from complex biological mechanisms. The NDM-1-KP ST147 clone has emerged as a recent addition to the family of successful clones within the species. Methods: In this study, we successfully synthesized 5-bromo-N-alkylthiophene-2-sulfonamides (3a-c) by reacting 5-bromothiophene-2-sulfonamide (1) with various alkyl bromides (2) using LiH. We also synthesized a series of compounds (4a-g) from compound (3b) using the Suzuki-Miyaura cross-coupling reaction with fair to good yields (56-72%). Further, we screened the synthesized molecules against clinically isolated New Delhi Metallo-ß-lactamase producing Klebsiella pneumoniae ST147. Subsequently, we conducted in-silico tests on compound 3b against a protein extracted from NDM-KP ST147 with PDB ID 5N5I. Results: The compound (3b) with favourable drug candidate status, MIC of 0.39 µg/mL, and MBC of 0.78 µg/mL. This low molecular weight compound exhibited the highest potency against the resistant bacterial strains. The in-silico tests revealed that the compound 3b against a protein extracted from NDM-KP ST147 with PDB ID 5N5I demonstrated H-bond and hydrophobic interactions. Conclusion: The 5-bromo-N-alkylthiophene-2-sulfonamides displayed antibacterial efficacy against New Delhi Metallo-ß-lactamase producing Klebsiella pneumoniae ST147. After the in-vivo trial, this substance might offer an alternative therapeutic option.