Design of 1-(furan-2-yl)-N-(5-substituted phenyl-1, 3, 4-thiadiazol-2-yl) methanimine derivatives as Enoyl-ACP reductase inhibitors: Synthesis, molecular docking studies and anti-tubercular activity

Abstract

A series of 5-phenylsubstiuted 1, 3, 4 thiadiazoles clubbed with furan moiety (Fa-Fe) by means of azomethine linkage have been synthesized. All the newly synthesized compounds were characterized by IR, 1 HNMR and Mass analyses. All the synthesized molecules have been predicted as anti-tubercular in nature by PASS in silico approach. In vitro anti-tubercular screening was performed by alamar blue assay method on Mycobacterium tuberculosis H37Rv strain. Among the synthesized derivatives Fb and Fe were active at 3.125 µg/mL against Mycobacterium tuberculosis H37Rv strain. The mechanism of action of the active compounds was carried out by docking of receptor enoyl-ACP reductase. It has been concluded that both Fb and Fe posses a significant interaction of hydrogen bonding and electrostatic attraction with Tyr 158 and Met103 in the active site of enzyme.

Predictive Power of In Silico Approach to Evaluate Chemicals against M. tuberculosis: A Systematic Review

“…However, mutations in KatG/EthA have been reported and correlated with the development of Mtb resistance to INH and ETH [31,32], thus leading to the need for new molecules that can either directly inhibit the InhA enzyme or find novel molecular paths that can ultimately promote bacterium eradication. Within the 46 manuscripts, the Enoyl-[acyl-carrier-protein] reductase (NADH) (EC 1.3.1.9) was evaluated nine times [10,15,33,34,35,36,37,38,39]. All analyzed articles were able to correctly dock their postulated inhibitors on different sites of the enzyme and studied the obtained results with in vitro assays.…”

“…Also, to systematize the outcome, we found the ratio between the best MIC obtained and the controls analyzed, such as isoniazid, rifampicin, ethambutol, etc. For all those manuscripts that did not apply a reference compound [9,22,35,49,50,53,56,57,65,69,70], we calculated the mean MIC value (0.78 µM) of Isoniazid (the most potent M. tuberculosis inhibitor), using the values found in our chosen manuscripts, after outlier exclusion (z-score higher than 3). The molecules were considered excellent if they had a MIC ratio value below or close to 1, meaning that the compound found was equally effective to the control, or more so.…”

“…Validation of the virtual screening procedures or in silico methodologies is not mandatory, but it is often seen. Despite this, of the 46 papers, only 19 did any kind of assay to validate their results [6,11,12,13,14,15,16,23,33,35,38,39,44,46,47,55,56,58,61]. Validation trials were considered if they performed a redocking experiment with the targeted protein and its original ligand, compared the binding conformations of the found molecules and the original ligands on the targeted protein, and performed a molecular dynamics simulation.…”

Design, development, drug-likeness, and molecular docking studies of novel piperidin-4-imine derivatives as antitubercular agents

“…The docking studies 28 , 29 of the title compounds were carried out with EACP reductase enzyme (1ZID.pdb) by using Schrödinger software. The interaction of molecule with EACP reductase enzyme is shown in Figure 5 .…”

“…Schrödinger’s proprietary GlideScore was used to carry out the final scoring and rescoring of the energy-minimized poses from its scoring function. 28 , 29 Linux OS (Red Hat Enterprise WS 5.0) was used to carry out all docking computations.…”