Rational drug design, synthesis and biological evaluation of dihydrofolate reductase inhibitors as antituberculosis agents

TitleRational drug design, synthesis and biological evaluation of dihydrofolate reductase inhibitors as antituberculosis agents
Publication TypeJournal Article
Year of Publication2015
AuthorsTawari, NR, Bag, S, Raju, A, Lele, AC, Bairwa, R, Ray, MKanta, Rajan, MGR, Nawale, LU, Sarkar, D, Degani, MS
JournalFuture Medicinal Chemistry
Volume7
Issue8
Pagination979-988
Date PublishedJUN
ISSN1756-8919
Abstract

Background: A series of 2,4-diamino-s-triazines was designed, with potential for activity against Mycobacterium tuberculosis (Mtb) dihydrofolate reductase enzyme, on the basis of virtual screening results and structure-based drug design. Results: The compounds were evaluated against Mtb (H(37)Rv) and their cytotoxicity was assessed using VERO cell lines. Of particular note, two compounds were found to have the most promising antituberculosis activity (6b minimum inhibitory concentration: 1.76 mu M and 6i minimum inhibitory concentration: 1.57 mu M) along with low cytotoxicity (CC50 : > 300 mu M). The enzyme assay results of these two indicated significant inhibition of Mtb dihydrofolate reductase along with selectivity. Selected derivatives were tested against dormant tubercle bacilli in vivo and ex vivo indicating potential inhibition. Conclusion: This study provides promising antituberculosis dihydrofolate reductase inhibitors that can act as potential leads for further development.

DOI10.4155/FMC.15.48
Type of Journal (Indian or Foreign)

Foreign

Impact Factor (IF)

3.345

Divison category: 
Organic Chemistry