Design, Synthesis, and Biological Evaluation of Novel Schiff Base Derivatives of 2‐Amino‐ N ‐(2‐((2,4‐dimethylphenyl)thio)phenyl)‐4‐methylthiazole‐5‐carboxamide with Docking Insights

ABSTRACT The 2‐amino‐4‐methylthiazole‐5‐carboxamide nucleus is regarded as a valuable structural framework in medicinal chemistry. Its chemical flexibility and ability to accommodate diverse substitutions make it a promising starting point for the design and development of pharmacologically active compounds. Herein, we designed and synthesized a series of Schiff base derivatives of the 2‐amino‐N‐(2‐((2,4‐dimethylphenyl)thio)phenyl)‐4‐methylthiazole‐5‐carboxamide ( 1 ) by condensing it with various aldehydes. The newly synthesized 2‐amino‐4‐methylthiazole‐5‐carboxamide‐based Schiff base derivatives were screened for their antimicrobial activity. The structures of the newly synthesized compounds were confirmed using multiple analytical tools, including mass spectrometry, 1 H NMR, 1 3 C NMR, and IR spectroscopy. The biological evaluation revealed moderate antibacterial activity among the synthesized compounds. Notably, compounds 1c , 1f , and 1i demonstrated considerable activity against gram‐negative Escherichia coli (MIC: 62.5 µg/mL) strain. The ortho‐hydroxy substituted imine derivative 1d and unsubstituted analog 1g demonstrated comparable antibacterial effects against Pseudomonas aeruginosa and Staphylococcus aureus , respectively, each exhibiting an MIC value of 62.5 µg/mL. A molecular docking study against the DNA gyrase enzyme revealed a good correlation between the predicted binding energy (−9.1 kcal/mol) and the observed antibacterial activity of analog 1c . These findings suggest that Schiff base derivatives possessing diverse functional groups represent promising scaffolds for further structural optimization and biological investigations in the search for new antibacterial agents.