Confronting Tuberculosis: A Synthetic Quinoline-Isonicotinic Acid Hydrazide Hybrid Compound as a Potent Lead Molecule Against Mycobacterium tuberculosis

• DOI: 10.1021/acsinfecdis.4c00277
• Publication Date: 2024-05-08T14:24:01Z
• Authors: Govinda Raju Vada...; Vipul V. Nilkanth; Arshad Rizvi; Sriram Yandrapally; Anushka Agarwal; Hepshibha Chirra; Rashmita Biswas; Mohammed Arifuddin; Vijay Nema; Alvala Mallika; Shekhar C. Mande; Sharmistha Banerjee
• Keywords: Antimycobacterial; Lead compound; Quinoline; Isonicotinic acid; Extensively drug-resistant tuberculosis

The current tuberculosis (TB) treatment is challenged by a complex first-line for drug-sensitive (DS) TB. Additionally, the prevalence of multidrug (MDR)- and extensively drug (XDR)-resistant TB necessitates search new prototypes. We synthesized screened 30 hybrid compounds containing aminopyridine 2-chloro-3-formyl quinoline to arrive at compound with potent antimycobacterial activity, UH-NIP-16. Subsequently, activity against DS MDR Mycobacterium (M.tb) strains were performed. It demonstrated an MIC50 value 1.86 ± 0.21 μM laboratory pathogenic M.tb strain H37Rv 3.045 0.813 clinical CDC1551. UH-NIP-16 also decreased values streptomycin, isoniazid, ethambutol, bedaquiline about 45, 55, 68, 76%, respectively, when used in combination, potentiating their activities. molecule was active strain. Cytotoxicity on PBMCs from healthy donors human cell lines found be negligible. Further, blind docking using Auto Dock Vina MGL tools onto diverse proteins showed high binding affinities multiple proteins, top five targets being metabolically critical CelA1, DevS, MmaA4, lysine acetyltransferase, immunity factor necrotizing toxin. These bindings confirmed fluorescence spectroscopy representative protein, MmaA4. Envisaging that pathogen will have lower probability developing resistance targets, we propose can further developed as lead bacteriostatic potential M.tb, both alone combination drugs.