Attenuation of Mycobacterium species through direct and macrophage mediated pathway by unsymmetrical diaryl urea

VELAPPAN, ANAND BABU; TSAI, YI TING; KREMER, LAURENT; KAR MAHAPATRA, SANTANU; DATTA, DHRUBAJYOTI; WAN, BAOJIE; FRANZBLAU, SCOTT G.; CHARAN RAJA, MAMILLA R.; HALLOUM, IMAN; GRAMAJO, HUGO; DEBNATH, JOY

EUROPEAN JOURNAL OF MEDICAL CHEMISTRY

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

Año: 2016 vol. 125 p. 825 - 841

0223-5234

Abstract: Tuberculosis is a major threat for mankind and the emergence of resistance strain ofMycobacterium tuberculosis (Mtb) against first line antibiotics makes it lethal for humancivilization. In this study, we have synthesized different diaryl urea derivatives targeting theinhibition of mycolic acid biosynthesis. Among the 39 synthesized molecules, compounds 46,57, 58 and 86 showed MIC values £ 10 mg/ml against H37Rv and mc26030 strains. The bestmolecule with a methyl at ortho position of the first aromatic ring and prenyl group at the metaposition of the second aromatic ring showed the MIC value of 5.2 mg/ml and 1 mg/ml againstH37Rv and mc26030 respectively, with mammalian cytotoxicity of 163.4 mg/ml. The effectivecompounds showed selective inhibitory effect on mycolic acid (epoxy mycolate) biosynthesis in14C-radiolabelled assay. At the same time these molecules also executed their potentimmunomodulatory activity by up-regulation of IFN-g and IL-12 and down-regulation of IL-10.