Design and development of novel inhibitors for the treatment of latent tuberculosis

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Objective/background“The captain of all these men of death”, is the apt sobriquet for the age-old disease tuberculosis (TB). Despite the availability of many drugs, cases of increasing resistance in the forms of multi-drug and extensively drug-resistant TB and persistence [characteristic of Mycobacterium tuberculosis (MTB)] make the eradication of TB a nightmare. Approval of bedaquiline by the Food and Drug Administration focused attention on quinoline scaffolds for development of new anti-TB agents. Lysine ε-aminotransferase (LAT) in MTB plays a pivotal role in regulating amino acid synthesis, which in turn affects mycobacterial persistence. Here, developed quinoline inhibitors that targeted LAT with an objective to eliminate dormant forms of mycobacterium. MethodsUsing e-pharmacophore approaches, quinolone (PBD: 2CJD) leads were found to inhibit lysine binding to LAT. To investigate structural activity relationships, 21 analogues were synthesized and characterized based on the identified lead molecules. ResultsAmong the derivatives, N-(pyridin-2-yl methyl)-2-(4-(quinolin-4-yl) piperazin-1-yl) acetamide was identified as a potent molecule, with an IC50 for LAT of 1.04μM. In nutrient-starved and zebra fish models, this molecule exhibited logarithmic reductions of 2.1- and 2.2-fold, respectively, at a concentration of 10μg/mL. The compound also exhibited good activity against persistent forms of mycobacteria (biofilm model), showing logarithmic reduction of 2.8-fold. Additionally, the hit molecule showed concentration-dependent kill kinetics against dormant forms of mycobacteria, and were devoid of cytotoxicity against RAW cell lines 264.7 at concentrations of 50μM. ConclusionOur results indicated that the hit molecule showed activity against both active and persistent forms of infection, which is ideal for new anti-TB agents. This molecule requires further pharmacokinetic and dynamic screening for development as new drug candidate.