Abstract
Introduction:In efforts to develop new antitubercular (anti-TB) compounds, herein we describe cytotoxic evaluation of 15 newly synthesized pyrrolyl pyrazoline carbaldehydes.Method & Materials:Surflex-Docking method was used to study binding modes of the compounds at the active site of the enzyme enoyl ACP reductase from Mycobacterium tuberculosis (M. tuberculosis), which plays an important role in FAS-II biosynthetic pathway of M. tuberculosis and also it is an important target for designing novel anti-TB agents.Results:Among the synthesized compounds, compounds 4g and 4i showed H-bonding interactions with MET98, TYR158 and co-factor NAD+, all of which fitted well within the binding pocket of InhA. Also, these compounds have shown the same type of interaction as that of 4TZK ligand. The compounds were further evaluated for preliminary anti-TB activities against M. tuberculosis H37Rv strain.Conclusion:Some compounds were also screened for their mammalian cell toxicity using human lung cancer cell-line (A549) that was found to be nontoxic.
Highlights
In efforts to develop new antitubercular compounds, we describe cytotoxic evaluation of 15 newly synthesized pyrrolyl pyrazoline carbaldehydes
To examine the mechanism of anti-TB activity and to understand the comprehensive intermolecular interactions between the synthesized compounds and the enzyme, molecular docking studies were performed on the crystal structure of M. tuberculosis enoyl reductase (InhA) complexed with 1-cyclohexyl-N- (3,5-dichlorophenyl)-5-oxopyrrolidine-3carboxamide (PDB ID 4TZK, 1.62 Å X-ray resolution) using surflex-dock programme of sybyl-X 2.0 software
Based on the greater level of resistance associated with INH isolates against InhA, docking studies were performed on InhA complex with 1-cyclohexyl-N-(3,5-dichlorophenyl)-5-oxopyrrolidine-3-carboxamide, which indicates the presence of drug-receptor interactions
Summary
In efforts to develop new antitubercular (anti-TB) compounds, we describe cytotoxic evaluation of 15 newly synthesized pyrrolyl pyrazoline carbaldehydes. Of the striking antimicrobial drug targets, FAS-II pathway has gained much attention in the modern era for developing INH based new chemical entities [4 - 7]. NADH-dependent enoyl acyl carrier protein (ENR) reductase encoded by Mycobacterium gene InhA is the key catalyst involved in mycolic acid biosynthesis in FAS-II patway. Earlier reports have recognized that InhA is the primary target for INH [8], a leading drug used for the treatment of TB for over 40 years. Reports have suggested that the formed INH-NADH adduct by the action of KatG (catalase-peroxide enzyme) on INH to form an acyl radical, which in turn covalently binds to NADH, acts as an effective inhibitor of InhA and other InhA inhibitors such as triclosan, pyrazole derivatives, diazaborines and indole-5-amides [9 - 13]
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