2-Aminothiophene and 2-aminothiazole scaffolds as potent antimicrobial agents: Design, synthesis, biological evaluation, and computational insights.

The development of new antitubercular drugs is critically hindered by the persistent and adaptive nature of Mycobacterium tuberculosis (Mtb), underscoring an urgent need for innovative therapeutic strategies. In this work, a series of structurally varied 2-aminothiophene and 2-aminothiazole derivatives was designed, synthesized, and characterized using FT-IR, NMR, HRMS, and single-crystal X-ray techniques. The thiophene analogues were prepared via the Gewald reaction, while thiazole derivatives were obtained through Hantzsch synthesis, with structural diversity achieved by modifying alkyl, ester, and fused ring groups. Several compounds exhibited potent antitubercular activity against Mtb H37Rv, with 4h, 4k, and 4l showing MIC values of 0.78 μg/mL, comparable to the standard drug Ethambutol. SAR studies revealed that linear alkyl chains enhanced activity, whereas aryl and fused rings were less favourable. Additionally, compounds 4q, 4s, 7g, 7o, and 9e emerged as moderate antibacterial leads against both Gram-positive and Gram-negative bacteria. Cytotoxicity assays for the potent compounds were performed in Vero cells and THP-1 cells, supporting a favourable safety profile and selective activity against Mtb. Furthermore, target prediction, molecular docking, along with DFT and ADMET analyses, provided valuable insights into their putative molecular targets, binding modes, and the drug-like and electronic properties that influence bioactivity. Collectively, these results identify compound 4k as a promising lead candidate against Mtb, underscoring the potential of the 2-aminothiophene scaffold as a valuable framework for antitubercular drug discovery. These findings encourage further exploration of 2-aminothiophene and 2-aminothiazole scaffolds by medicinal chemists for the development of novel, potent, and selective antitubercular and antibacterial drug candidates.