title: Benzimidazole-based compounds kill Mycobacterium tuberculosis.
abstract: Tuberculosis remains one of the deadliest infectious diseases, killing 1.4 million people annually and showing a rapid increase in cases resistant to multiple drugs. New antibiotics against tuberculosis are urgently needed. Here we describe the design, synthesis and structure-activity relationships of a series of benzimidazole-based compounds with activity against Mycobacterium tuberculosis (Mtb) in a replicating state, a physiologically-induced non-replicating state, or both. Compounds 49, 67, 68, 69, 70, and 72, which shared a 5-nitrofuranyl moiety, exhibited high potency and acceptable selectivity indices (SI). As illustrated by compound 70 (MIC90 < 0.049 μg/mL, SI > 512), the 5-nitrofuranyl group was compatible with minimal cytotoxicity and good intra-macrophage killing, although it lacked non-replicating activity when assessed by CFU assays. Compound 70 had low mutagenic potential by SOS Chromotest assay, making this class of compounds good candidates for further evaluation and target identification.
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nanwei Road, Xuanwu District, Beijing 100050, PR China.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA; Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Selin
authors.initials: S
authors.lastname: Somersan Karakaya
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nanwei Road, Xuanwu District, Beijing 100050, PR China.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Guo
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nanwei Road, Xuanwu District, Beijing 100050, PR China.
authors.forename: Purong
authors.initials: P
authors.lastname: Zheng
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Gold
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nanwei Road, Xuanwu District, Beijing 100050, PR China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: David
authors.initials: D
authors.lastname: Little
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Roberts
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Thulasi
authors.initials: T
authors.lastname: Warrier
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Xiuju
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Maneesh
authors.initials: M
authors.lastname: Pingle
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: cnathan@med.cornell.edu.
authors.forename: Carl F
authors.initials: CF
authors.lastname: Nathan
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nanwei Road, Xuanwu District, Beijing 100050, PR China; Tsinghua-Peking Center for Life Sciences and School of Medicine, Tsinghua University, Haidian Dist., Beijing 100084, PR China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Haidian Dist., Beijing 100084, PR China. Electronic address: gliu@imm.ac.cn.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002478:Cells, Cultured; D015195:Drug Design; D006801:Humans; D008264:Macrophages / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D001562:Benzimidazoles; C031000:benzimidazole
keywords: Benzimidazole; Drug; Mycobacterium tuberculosis; Nitrofuran; Tuberculosis