title: Design, synthesis and characterization of dual inhibitors against new targets FabG4 and HtdX of Mycobacterium tuberculosis.
abstract: Herein, we present dual inhibitors of new targets FabG4 and HtdX for the first time. In this work, eight compounds have been designed, synthesized, characterized and evaluated for bio-activities. Amongst them, six compounds have shown inhibitory activities. Three of them (12-14) demonstrate dual inhibition of both FabG4 and HtdX at low micromolar concentration. In addition, the dual inhibitors show good anti-mycobacterial properties against both planktonic growth and biofilm culture of Mycobacterium species. This study is an important addition to tuberculosis drug discovery because it explores two new enzymes as drug targets and presents their dual inhibitors as good candidates for pre-clinical trials.
authors.affiliation: Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India.
authors.forename: Deb Ranjan
authors.initials: DR
authors.lastname: Banerjee
authors.affiliation: Department of Biotechnology, Indian Institute of Technology, Kharagpur 721302, India.
authors.forename: Rupam
authors.initials: R
authors.lastname: Biswas
authors.affiliation: Department of Biotechnology, Indian Institute of Technology, Kharagpur 721302, India. Electronic address: amitk@hijli.iitkgp.ernet.in.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Das
authors.affiliation: Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India; School of Bioscience, Indian Institute of Technology, Kharagpur 721302, India. Electronic address: absk@chem.iitkgp.ernet.in.
authors.forename: Amit
authors.initials: A
authors.lastname: Basak
mesh_terms: D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000595:Amino Acid Sequence; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D055162:Biocatalysis; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D000429:Alcohol Oxidoreductases; C023744:acetoacetyl-CoA reductase; D006836:Hydro-Lyases
keywords: Biofilm; FabG4; HtdX; MIC; Polypharmacology; Tuberculosis