In Vitro Antimycobacterial Activity and Physicochemical Characterization of Diaryl Ether Triclosan Analogues as Potential InhA Reductase Inhibitors

Abstract

<jats:p>Two sets of diphenyl ether derivatives incorporating five-membered 1,3,4-oxadiazoles, and their open-chain aryl hydrazone analogs were synthesized in good yields. Most of the synthesized compounds showed promising in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv. Three diphenyl ether derivatives, namely hydrazide 3, oxadiazole 4 and naphthylarylidene 8g exhibited pronounced activity with minimum inhibitory concentrations (MICs) of 0.61, 0.86 and 0.99 μg/mL, respectively compared to triclosan (10 μg/mL) and isoniazid (INH) (0.2 μg/mL). Compounds 3, 4, and 8g showed the InhA reductase enzyme inhibition with higher IC50 values (3.28–4.23 µM) in comparison to triclosan (1.10 µM). Correlation between calculated physicochemical parameters and biological activity has been discussed which justifies a strong correlation with respect to the inhibition of InhA reductase enzyme. Molecular modeling and drug-likeness studies showed good agreement with the obtained biological evaluation. The structural and experimental information concerning these three InhA inhibitors will likely contribute to the lead optimization of new antibiotics for M. tuberculosis.</jats:p>

Exploiting thiol-functionalized benzosiloxaboroles for achieving diverse substitution patterns – synthesis, characterization and biological evaluation of promising antibacterial agents

“…Moreover, based on available IC 50 and MIC (for standard and clinical S. aureus MRSA strains) values, the selectivity index (SI) was calculated for several compounds as the IC 50 /MIC ratio (Table 5). 60 Within the group of most active compounds ( 6 , 12 , 20 , 22–24 ), SI values were generally higher than 10, indicating their potential as antibacterial agents with respect to S. aureus MRSA.…”

“…The selectivity index (SI) was calculated as , in accordance with previously described protocols. 60 …”

Novel Inhibitors of Acetyl- and Butyrylcholinesterase Derived from Benzohydrazides: Synthesis, Evaluation and Docking Study

“…We previously reported on the preparation of 4-iodobenzohydrazide [ 15 ], and we also used the procedure for 2-phenylacetohydrazide [ 16 ], [1,1’-biphenyl]-4-carbohydrazide [ 17 ], 4-phenoxybenzohydrazide [ 18 ], 4-(trifluoromethoxy)benzohydrazide [ 19 ], 3-(trifluoromethyl)benzohydrazide [ 20 ], 2-(trifluoromethyl)benzohydrazide [ 21 ], 4-(hydrazinecarbonyl)benzenesulfonamide [ 22 ], 4-cyanobenzohydrazide [ 23 ] and 4-(trifluoromethyl)benzenesulfonylhydrazide [ 24 ].…”

The key players in the arsenal of combating TB; reviewing the lead InhA inhibitors

“…The InhA active site involves the substrate binding loop (SBL: residues 197-226) as well as the NAD cofactor that interacts with the protein and the acyl substrate (or inhibitors) (26,27) . The InhA inhibitors include prodrugs such as INH which irreversibly interact with NAD forming an adduct (28) , direct inhibitors like triazoles, diphenyl ethers, and triclosan involved in reversible binding to the NAD (29)(30)(31) , or bulky inhibitors displacing the NAD like pyridomycin (32) . Literature reports revealed that Tyr158 and Phe149 are the two key amino acids involved in the binding interactions (33) .…”