title: Development of gallic acid formazans as novel enoyl acyl carrier protein reductase inhibitors for the treatment of tuberculosis.
abstract: The enoyl acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (MTB) is an attractive target for developing novel antitubercular agents. A series of gallic acid formazans, were computationally designed and docked into the active site of InhA to understand their binding mode and potential to inhibit InhA. Nine compounds from the designed series were identified as potential InhA inhibitors, on the basis of good Glide score. These compounds were synthesized in the laboratory and evaluated for in vitro antitubercular activity against drug-sensitive and multi-drug resistant strains of MTB. Out of nine compounds, three compounds exhibited the most promising MIC of <2μM against the sensitive strain of MTB, H37Rv. The compounds were evaluated against five resistant strains of MTB. Most of the compounds exhibited activity superior to the standard, linezolid, against all these resistant strains. The mechanism of action of these compounds was concluded to be InhA inhibition, through InhA enzyme inhibition study. Insignificant cytotoxicity of these compounds was observed on RAW 264.7 cell line. Inactivity of all these compounds against gram positive and gram negative bacteria indicated their specificity against MTB. The compounds were further analyzed for ADME properties and showed potential as good oral drug candidates. The results clearly identified some novel, selective and specific InhA inhibitors against sensitive and resistant strains of MTB.
authors.affiliation: Department of Pharmaceutical Chemistry, C.U. Shah College of Pharmacy, S.N.D.T. Women's University, Sir Vithaldas Vidyavihar, Juhu Tara Road, Santacruz (West), Mumbai 400049, India. Electronic address: vanitasaharan@yahoo.co.in.
authors.forename: Vanita D
authors.initials: VD
authors.lastname: Saharan
authors.affiliation: Department of Pharmaceutical Chemistry, C.U. Shah College of Pharmacy, S.N.D.T. Women's University, Sir Vithaldas Vidyavihar, Juhu Tara Road, Santacruz (West), Mumbai 400049, India.
authors.forename: Supriya S
authors.initials: SS
authors.lastname: Mahajan
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D005562:Formazans / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D005707:Gallic Acid / Q000737:chemistry*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000067996:RAW 264.7 Cells; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D005562:Formazans; D005707:Gallic Acid; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium
keywords: Cytotoxicity; Enoyl acyl carrier protein reductase; Formazans; Glide; Tuberculosis