Synthesis, biological evaluation and in silico molecular modeling of pyrrolyl benzohydrazide derivatives as enoyl ACP reductase inhibitors
In efforts to develop lead anti-TB compounds, a novel series of 19 pyrrolyl benzohydrazides were synthesized and screened to target enoyl-ACP reductase enzyme, which is one of the important enzymes involved in type II fatty acid biosynthetic pathway of M. tuberculosis. Pharmacophores were constructe...
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Published in: | European journal of medicinal chemistry Vol. 126; pp. 286 - 297 |
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Main Authors: | , , , , , |
Format: | Journal Article |
Language: | English |
Published: |
France
Elsevier Masson SAS
27-01-2017
Elsevier |
Subjects: | |
Online Access: | Get full text |
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Summary: | In efforts to develop lead anti-TB compounds, a novel series of 19 pyrrolyl benzohydrazides were synthesized and screened to target enoyl-ACP reductase enzyme, which is one of the important enzymes involved in type II fatty acid biosynthetic pathway of M. tuberculosis. Pharmacophores were constructed using GALAHAD to generate alignment of data sets and calculated by Pareto ranking. The pharmacophore features were then filtered by Surflex-dock study using enoyl ACP reductase from M. tuberculosis. Compounds 5b and 5d showed H-bonding interactions with Tyr158, Thr196 and co-factor NAD+ that fitted well within the binding pocket of InhA. All the synthesized compounds were screened for preliminary antibacterial activities against Gram-positive S. aureus and Gram-negative E. coli and M. tuberculosis H37Rv to evaluate their antitubercular activities. Some representative compounds were further tested for mammalian cell toxicity using human lung cancer cell-line (A549) that was found to be nontoxic. These compounds exhibited moderate inhibition activities against InhA.
Antitubercular activity of novel series of pyrrolyl benzamide derivatives was analyzed. Pharmacophore mapping constructed using GALAHAD and Molecular modeling studied using Surflex-Dock on enoyl ACP reductase from Mycobacterium tuberculosis. [Display omitted]
•Pharmacophore mapping was carried out using GALAHAD approach on a series of pyrrolyl benzohydrazide derivatives.•Synthesis of a range of pyrrolyl benzamide derivatives described.•Surflex docking studies was carried out to understand the binding affinity of the compounds.•Inhibitors were active against Mycobacterium tuberculosis, Staphylococcus aureus, Eschrichia coli, Cell-line (A549) and InhA. |
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ISSN: | 0223-5234 1768-3254 |
DOI: | 10.1016/j.ejmech.2016.11.032 |