Synthesis of Functionalized Pyrroles, Thiazoles, Thiazolones, and Pyrrolothiazoles via α-Oxoketene-N,S-acetal Intermediates: Characterization, Antitubercular Evaluation, and ADMET Prediction

Introduction: The discovery of new antitubercular agents remains a significant challenge due to the increasing emergence of multidrug-resistant strains of Mycobacterium tuberculosis. Functionalized pyrroles, thiazoles, thiazolones, and pyrrolothiazoles are important heterocyclic scaffolds known for their diverse biological activities. The present study aimed to develop an efficient synthetic strategy for the preparation of these heterocyclic derivatives and evaluate their potential as antitubercular agents.

Methods: A series of functionalized pyrrole-, thiazole-, thiazolone-, and pyrrolothiazole-based derivatives were synthesized from readily available enolizable ketones through β-oxodithioester, β-oxothioamide, and α-oxoketene-N,S-acetal intermediates using appropriate cyclization reactions. The synthesized compounds were characterized by Fourier Transform Infrared (FT-IR) spectroscopy, ¹H and ¹³C Nuclear Magnetic Resonance (NMR) spectroscopy, Mass Spectrometry (MS), and elemental (CHN) analysis. All compounds were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis. In addition, in silico ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) prediction was performed to assess their pharmacokinetic and drug-likeness properties.

Results: The developed synthetic protocol afforded the target heterocyclic derivatives in good to excellent yields with high purity. Spectral and analytical data confirmed the proposed structures of all synthesized compounds. Several derivatives demonstrated promising in vitro antitubercular activity, while ADMET prediction indicated favorable pharmacokinetic characteristics and acceptable drug-likeness profiles for selected compounds.

Conclusions: The developed methodology provides an efficient route for the synthesis of structurally diverse heterocyclic compounds with potential antitubercular activity. The combined synthetic, biological, and computational investigations identify these scaffolds as promising candidates for further optimization and development of novel antitubercular agents.