ADME Study, Molecular Docking, Synthesis, Characterization, and Preliminary Antimicrobial Activity Evaluation of New Glycine Derivatives of Sulfonamide

Abstract

A novel glycine-based sulfonamide derivates were synthesized. This study presents the newly synthesized compounds (G1-G6) that exhibit promising DHPS inhibition activities, designed through a molecular docking analysis targeting the Yersinia pestis DHPS protein (PDB ID: 5JQ9). The docked compounds were subsequently subjected to ADME study to evaluate their pharmacokinetic properties. This work started with the synthesis of the glycine methyl ester HCL salt by esterification of the carbonyl group of the carboxylic acid functionality of glycine with thionyl chloride and methanol and the synthesis of 4-acetamidobenzene sulfonyl chloride from acetanilide, the reaction of the latter two intermediates using the TEA as base and neutralizing agent in DCM led to the synthesis of a sulfonamide-containing compound. This compound was then reacted with hydrazine hydrate to give the hydrazide, which was then reacted with various aldehydes using glacial acetic acid as a catalyst to give the final target compounds G1-6. The identification of these compounds was carried out using infrared spectroscopy (ATR-FTIR) and proton magnetic resonance. Using the well diffusion method, the antimicrobial activity of the final compounds was tested in vitro against two Gram-positive bacteria, two Gram-negative bacteria and one fungus in comparison with the standard drugs sulfamethoxazole, sulfadiazine and fluconazole. In general, all synthesized compounds have moderate to high antimicrobial activity, but compounds G5 and G6 with the highest activity had zone inhibition (ZI) ranging from 16 to 21 mm.