title: Attenuation of Mycobacterium species through direct and macrophage mediated pathway by unsymmetrical diaryl urea.
abstract: 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 μg/ml against H37Rv and mc26030 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 μg/ml and 1 μg/ml against H37Rv and mc26030 respectively, with mammalian cytotoxicity of 163.4 μg/ml. The effective compounds showed selective inhibitory effect on mycolic acid (epoxy mycolate) biosynthesis in14C-radiolabelled assay. At the same time these molecules also executed their potent immunomodulatory activity by up-regulation of IFN-γ and IL-12 and down-regulation of IL-10.
authors.affiliation: Department of Chemistry, School of Chemical and Biotechnology, SASTRA University, Tamilnadu 613401, India.
authors.forename: Anand Babu
authors.initials: AB
authors.lastname: Velappan
authors.affiliation: Department of Biotechnology, School of Chemical and Biotechnology, SASTRA University, Tamilnadu 613401, India.
authors.forename: Mamilla R
authors.initials: MR
authors.lastname: Charan Raja
authors.affiliation: Department of Chemistry, Indian Institute of Science Education and Research Pune, Maharashtra 411008, India.
authors.forename: Dhrubajyoti
authors.initials: D
authors.lastname: Datta
authors.affiliation: Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.
authors.forename: Yi Ting
authors.initials: YT
authors.lastname: Tsai
authors.affiliation: Centre d'étude des Pathogènes pour la Biotechnologie et la Santé CNRS FRE3689, Université de Montpellier, 34293 Montpellier cedex 5, France.
authors.forename: Iman
authors.initials: I
authors.lastname: Halloum
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St. Chicago, IL 60612, USA.
authors.forename: Baojie
authors.initials: B
authors.lastname: Wan
authors.affiliation: Centre d'étude des Pathogènes pour la Biotechnologie et la Santé CNRS FRE3689, Université de Montpellier, 34293 Montpellier cedex 5, France; INSERM, CPBS, 34293 Montpellier Cedex 05, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Kremer
authors.affiliation: Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.
authors.forename: Hugo
authors.initials: H
authors.lastname: Gramajo
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St. Chicago, IL 60612, USA.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.affiliation: Department of Biotechnology, School of Chemical and Biotechnology, SASTRA University, Tamilnadu 613401, India.
authors.forename: Santanu
authors.initials: S
authors.lastname: Kar Mahapatra
authors.affiliation: Department of Chemistry, School of Chemical and Biotechnology, SASTRA University, Tamilnadu 613401, India. Electronic address: joydebnath@scbt.sastra.edu.
authors.forename: Joy
authors.initials: J
authors.lastname: Debnath
mesh_terms: D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology*; D008826:Microbial Sensitivity Tests; D009161:Mycobacterium / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D009171:Mycolic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: C508609:IL10 protein, human; D009171:Mycolic Acids; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D014508:Urea
keywords: Antimycobacterial activity; Cytokines; Cytotoxicity; Diaryl urea; Mycolic acid; Structure-activity relationship; Tuberculosis