DESIGN AND SYNTHESIS OF NOVEL MYCOBACTERIUM TUBERCULOSIS DHFR INHIBITORSAbstract
A series of 2,4-diaminotriazines were synthesized as Mycobacterium tuberculosis(Mtb) dihydrofolatereductase (DHFR) inhibitors. These derivatives were evaluated in whole cells by employing resazurinmicrotitre plate assay (REMA) against MtbH37Rv. Further, these were tested against other gram positive and gram negative bacterial strains to check specificity for Mtb. Cytotoxicity assessment was performed using HepG2 cell line and the compounds were found to be non-cytotoxic. The results indicated that some of the derivatives exhibited promising activity. The most active compound in the REMA assay was selected for DHFR enzyme assay against both the Mtb and human enzymes. The enzyme assay results indicated that this derivative exhibited selectivity towards the pathogenic enzyme. The most active compound in the whole cell assay against MtbH37Rv showed low cytotoxicity, was specific towards Mtb and displayed selectivity in the DHFR enzyme assay. Thus this study provides promising insight for design of potent and selective Mtb DHFR inhibitors.
Arundhati C. Lele , Mihir P. Khambete , A. Raju , Muktikanta Ray , M. G. R. Rajan , M. S. Degani *
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga (E), Mumbai, Maharashtra, India
19 November, 2015
12 January, 2016
07 February, 2016
01 June 2016