We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Design and development of novel inhibitors for the treatment of latent tuberculosis.
- Authors
Reshma, Rudraraju Srilakshmi; Yogeeswari, Perumal; Sriram, Dharmarajan
- Abstract
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. Methods Using 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. Results Among the derivatives, N -(pyridin-2-yl methyl)-2-(4-(quinolin-4-yl) piperazin-1-yl) acetamide was identified as a potent molecule, with an IC 50 for LAT of 1.04 μM. In nutrient-starved and zebra fish models, this molecule exhibited logarithmic reductions of 2.1- and 2.2-fold, respectively, at a concentration of 10 μg/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 50 μM. Conclusion Our 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.
- Publication
International Journal of Mycobacteriology, 2016, Vol 5, pS121
- ISSN
2212-5531
- Publication type
Article
- DOI
10.1016/j.ijmyco.2016.09.006