title: Design, synthesis and characterization of novel inhibitors against mycobacterial β-ketoacyl CoA reductase FabG4.
abstract: We report the design and synthesis of triazole-polyphenol hybrid compounds 1 and 2 as inhibitors of the FabG4 (Rv0242c) enzyme of Mycobacterium tuberculosis for the first time. A major advance in this field occurred only a couple of years ago with the X-ray crystal structure of FabG4, which has helped us to design these inhibitors by the computational fragment-based drug design (FBDD) approach. Compound 1 has shown competitive inhibition with an inhibition constant (Ki) value of 3.97 ± 0.02 μM. On the other hand, compound 2 has been found to be a mixed type inhibitor with a Ki value of 0.88 ± 0.01 μM. Thermodynamic analysis using isothermal titration calorimetry (ITC) reveals that both inhibitors bind at the NADH co-factor binding domain. Their MIC values, as determined by resazurin assay against M. smegmatis, indicated their good anti-mycobacterial properties. A preliminary structure-activity relationship (SAR) study supports the design of these inhibitors. These compounds may be possible candidates as lead compounds for alternate anti-tubercular drugs. All of the reductase enzymes of the Mycobacterium family have a similar ketoacyl reductase (KAR) domain. Hence, this work may be extrapolated to find structure-based inhibitors of other reductase enzymes.
authors.affiliation: IIT Kharagpur, Chemistry, Kharagpur, West Bengal, India. absk@chem.iitkgp.ernet.in.
authors.forename: Deb Ranjan
authors.initials: DR
authors.lastname: Banerjee
authors.forename: Debajyoti
authors.initials: D
authors.lastname: Dutta
authors.forename: Baisakhee
authors.initials: B
authors.lastname: Saha
authors.forename: Sudipta
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Kalyan
authors.initials: K
authors.lastname: Senapati
authors.forename: Amit K
authors.initials: AK
authors.lastname: Das
authors.forename: Amit
authors.initials: A
authors.lastname: Basak
mesh_terms: D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D059808:Polyphenols / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D059808:Polyphenols; D014230:Triazoles; D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase