Design, Synthesis and Evaluation of Substituted Benzimidazoles as Potent Polyketide Synthase 13 Inhibitors for Tuberculosis

Background: Tuberculosis remains a major global health concern, affecting millions of lives annually due to its high morbidity and mortality rates. The urgent need for effective treatments has driven research into novel therapeutic strategies. This study focuses on the development of anti-tubercular compounds targeting polyketide synthase 13, a crucial enzyme in the production of mycolic acids, which are essential for the integrity and drug resistance of the Mycobacterium tuberculosis cell wall. Materials and Methods: Substituted benzimidazole derivatives were designed through Structure-Activity Relationship investigations and molecular docking studies. The compounds were synthesized and tested for their antimicrobial activity using the Microplate Alamar Blue Assay. This assay was employed to determine the Minimum Inhibitory Concentration against Mycobacterium tuberculosis H37RV. Additionally, the well plate method was used to evaluate the effectiveness of these compounds against Klebsiella pneumoniae and Staphylococcus aureus. Results: Among the synthesized benzimidazole derivatives, compounds Ga2 and Ga3 demonstrated the highest potency against tuberculosis. These compounds exhibited superior binding affinity to polyketide synthase 13, exhibiting favourable amino acid interactions in diverse, effectively inhibiting mycobacterial growth, in turn justified by the in silico analysis The findings highlight the effectiveness of the designed derivatives in disrupting mycolic acid synthesis, thereby enhancing drug permeability and efficacy against Mycobacterium tuberculosis. Conclusion: This study demonstrates the potential of computational chemistry and structure-based drug design in identifying and optimizing novel anti-tubercular agents. The promising results of benzimidazole derivatives, particularly Ga2 and Ga3, against tuberculosis emphasize their potential as effective therapeutic candidates targeting specific enzymes critical to the bacterium’s survival and pathogenicity.