Innovative Thiophene Schiff Bases: Synthesis and Evaluation as Antitubercular Agents

Background: Tuberculosis (TB) is a leading airborne disease, impacting millions annually and ranking among the top ten causes of global mortality. Post-COVID-19, TB incidence has increased due to its pulmonary nature, which facilitates infection spread. Current TB treatments primarily control rather than prevent infection and are associated with mycobacterial resistance and significant side effects. Purpose: This study aims to design and evaluate thiophene based Schiff bases as potential antitubercular agents targeting polyketide synthase 13 (Pks 13), crucial for mycolic acid production and less prone to resistance. Materials and Methods: Thiophene-based Schiff bases were designed based on Structure-Activity Relationship (SAR) analysis and subjected to in silico approaches, including molecular docking against Pks 13. Compounds with the best docking scores underwent further in silico analysis (ADME, drug-likeness, toxicity). These compounds were synthesized, recrystallized, characterized and evaluated for in vitro antitubercular activity using the Microplate Alamar Blue Assay (MABA). Results: Compounds Ca3 and Ca5 had the best docking scores (-8.6 and -8.4 kcal/mol) and showed significant antitubercular activity in vitro at 25 μg/mL and 12 μg/mL, respectively. In silico and in vitro results correlated well, indicating strong binding affinity and potency against Pks 13. Conclusion: Compounds Ca3 and Ca5 show promise as potent antitubercular agents targeting polyketide synthase 13, supporting further development and optimization of thiophene-based Schiff bases for TB treatment.