Design, synthesis and evaluation of diphenyl ether analogues as antitubercular agents

Abstract

We herein report the investigation of new diphenyl ethers as Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA) inhibitors by structure-based drug design approach.

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.…”

“…The three most used in vitro assays were minimum inhibitory concentration (MIC), applied 30 times; enzymatic inhibition (measuring IC 50 ), which was used 25 times; and cytotoxicity assay, employed 20 times. All other in vitro assays were specific to the hypothesis the researchers were trying to prove (such as tuberculosis-infected macrophage assay [39] or intracellular killing of M. tuberculosis [63]) and were all described at least one time each within 19 manuscripts [9,12,13,15,21,22,33,39,44,48,49,50,53,54,57,58,62,63,67,70].…”

“…Nevertheless, it is important that approved drugs have few or nontoxic effects in human cellular lines, so it was an interesting feature to study. We found that only 19 of the analyzed manuscripts did cytotoxicity assays of their most promising molecules [10,12,13,15,16,21,23,33,34,39,44,47,48,54,56,57,63,65,70]. The other 26 documents did not test their best molecules for toxic effects.…”

“…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.…”

“…Through our screening process, we retrieved 46 documents, ranging from 2005 to 2018, which are described in Figure 4. Two manuscripts were from 2005 [9,53]; one each was from 2007 [60], 2008 [64], and 2009 [65]; two each were from 2011 [34,55] and 2012 [36,63]; five were from 2013 [10,26,35,38,70]; 10 were from 2014 [14,16,23,44,45,46,49,58,66]; nine were from 2015 [6,11,12,15,47,48,50,56,67]; six were from 2016 [13,33,54,57,61,69]; five were from 2017 [21,22,39,59,68]; and finally, only two were from 2018 [37,62].…”