title: Synthesis of various 3-nitropropionamides as Mycobacterium tuberculosis isocitrate lyase inhibitor.
abstract: Various 3-nitropropionamides were synthesized and evaluated for in vitro activities against log and starved phase culture of two mycobacterial species and Mycobacterium tuberculosis (MTB) isocitrate lyase (ICL) enzyme inhibition studies. Among 22 compounds, 1-cyclopropyl-7-(3,5-dimethyl-4-(3-nitropropanoyl)piperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (22) was found to be the most active compound in vitro with MICs of 0.16 and 0.04 μM against log- and starved-phase culture of MTB. Compound 22 also showed good enzyme inhibition of MTB ICL with IC(50) of 0.10 ± 0.01 μM. The docking studies also confirmed the binding potential of the compounds at the ICL active site.
authors.affiliation: Antitubercular Drug Discovery Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, India. dsriram@bits-hyderabad.ac.in
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.forename: Swetha
authors.initials: S
authors.lastname: Methuku
authors.forename: Devambatla Ravi Kumar
authors.initials: DR
authors.lastname: Vyas
authors.forename: Palaniappan
authors.initials: P
authors.lastname: Senthilkumar
authors.forename: Mallika
authors.initials: M
authors.lastname: Alvala
authors.forename: Variam Ullas
authors.initials: VU
authors.lastname: Jeankumar
mesh_terms: D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007522:Isocitrate Lyase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009574:Nitro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000813:Anilides; D004791:Enzyme Inhibitors; D009574:Nitro Compounds; D007522:Isocitrate Lyase