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

作者：Velappan Anand Babu; Raja Mamilla R Charan; Datta Dhrubajyoti; Tsai Yi Ting; Halloum Iman; Wan Baojie; Kremer Laurent; Gramajo Hugo; Franzblau Scott G; Mahapatra Santanu Kar; Debnath Joy

来源：European Journal of Medicinal Chemistry, 2017, 125: 825-841.

DOI：10.1016/j.ejmech.2016.09.083

• Tuberculosis
• Diaryl urea
• Structure-activity relationship
• Antimycobacterial activity
• Cytotoxicity
• Mycolic acid
• Cytokines

Tuberculosis is a major threat for mankind and the emergence of resistance strain of Mycobacterium tuberculosis (Mtb) against first line antibiotics makes it lethal for human civilization. In this study, we have synthesized different diaryl urea derivatives targeting the inhibition of mycolic acid biosynthesis. Among the 39 synthesized molecules, compounds 46, 57, 58 and 86 showed MIC values <= 10 mu g/ml against H37Rv and mc(2)6030 strains. The best molecule with a methyl at ortho position of the first aromatic ring and prenyl group at the meta position of the second aromatic ring showed the MIC value of 5.2 mu g/ml and mu g/ml against H37Rv and mc(2)6030 respectively, with mammalian cytotoxicity of 163.4 mu g/ml. The effective compounds showed selective inhibitory effect on mycolic acid (epoxy mycolate) biosynthesis in C-14-radiolabelled assay. At the same time these molecules also executed their potent immunomodulatory activity by up-regulation of IFN-gamma and IL-12 and down-regulation of IL-10.

• 出版日期2017-1-5