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Title: Development of Novel Mycobacterium tuberculosis Enoyl Acyl Carrier Protein Reductase Inhibitors
Guide(s): SRIRAM
Keywords: Development of Novel,Mycobacterium tuberculosis,Carrier Protein Reductase, Inhibitors
University: Birla Institute of Technology and Science
Completed Date: 1/8/2014
Abstract: In the present study we focused on achieving promising antimycobacterial cellular potency through developing potential Mycobacterium tuberculosis InhA (2-trans-enoyl-acyl carrier protein reductase) direct inhibitors. newlineUtilizing the moderately active hits identified by our research group earlier via virtual screening efforts, four different chemo-types of inhibitors were selected as initial InhA leads. The obtained leads were taken up for hit expansion by chemical synthesis and library of a total 123 molecules from 4 different series/leads as InhA inhibitors was synthesized that displayed considerable in vitro enzyme efficacy and bactericidality against Mycobacterium tuberculosis H37Rv strain. Compound PR_15 (1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-3-(4-methoxyphenyl)urea) emerged as the most potent molecule displaying 93.12 % inhibition of Mycobacterium tuberculosis InhA at 10 and#956;M with an IC50 of 2.96 and#956;M, inhibited drug sensitive Mycobacterium tuberculosis with MIC of 8.86 and#956;M and was non-cytotoxic at 50 and#956;M. Compounds RD_21 (2-(5-(4-(Benzyloxy)benzylidene)-4-oxo-2-thioxothiazolidin-3-yl)-N-(3,4-dichlorophenyl)acetamide) and RD_37 (3-(5-(Benzo[d] [1,3]dioxol-5-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl)-N-(2-chloro-5-(trifluoromethyl) phenyl)propanamide) were considered to be most potent antimycobacterial compounds with Mycobacterium tuberculosis MIC of 0.37 and 0.38 and#956;M respectively in the presence of efflux pump inhibitor piperine. The ability of potent ligands to stabilize the catalytic domain of the InhA protein was re-ascertained biophysically through differential scanning fluorimetry experiments wherein the thermal stability of the catalytic domain of InhA native protein and of the protein bound with the ligand was measured. The safety profile of synthesized compounds was evaluated by checking their in vitro cytotoxicity against RAW 264.7 cell line (mouse leukemic monocyte macrophage) by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Also, all the synthesized.
Pagination: 5.95 MB
Appears in Departments:Pharmacy

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