Analogue-Based Design, Synthesis, and Antimicrobial Study of Aryl and Heteroaryl Sulfonamides as Multi-Targeted Antimicrobial Compounds

Objective: Antimicrobial resistance is a major global concern in the treatment of infectious diseases. The development of multi-targeted antimicrobial agents is the key objective of this study. Herein, we report the analogue-based design, synthesis, and biological evaluation of bioisosteres of sulfonamides for broad-spectrum antimicrobial activity. Methods: A ligand-based approach utilizing bioisosteric replacement was employed to design new antimicrobial sulfonamides. Accordingly, ten novel compounds were synthesized. Their in silico binding interactions with various virulent proteins were analyzed. Results and Discussion: The antimicrobial efficacy of these compounds was assessed against both Gram-positive (Streptococcus pyogenes) and Gram-negative (Shigella flexneri) bacteria by determining their zone of inhibition (ZOI) and minimum inhibitory concentration (MIC90) values. Among the synthesized compounds, 1-((4-methoxyphenyl)sulfonyl)piperazine (IVa) exhibited the highest activity, with MIC90 values of 3.9 and 7.8 μg/mL against S. pyogenes and S. flexneri, respectively. The cytotoxicity of the most active compounds (IIIg and IVa) was assessed using a Live/Dead BacLight fluorescence assay. Additionally, field emission scanning electron microscopy (FE-SEM) was performed to examine bacterial cell morphological changes upon treatment. The in silico cytotoxicity profile of the synthesized compounds was evaluated using the SwissADME and TOPKAT models in Accelrys Discovery Studio 4.1. Furthermore, molecular docking studies were conducted using the CDOCKER module to investigate the binding interactions of the most active compound (IVa) with dihydropteroate synthase and microbial DNA gyrase-IV, demonstrating its multi-targeted mechanism of action. Conclusions: The results revealed that (IVa) interacts with key amino acid residues of dihydropteroate synthase with a binding energy of −193.891 kcal/mol and DNA gyrase-IV with a binding energy of −75.982 kcal/mol.