Abstract
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.
Highlights
The prepared target compounds were characterized by spectral reaction of hydrazide 3 with variant aromatic aldehydes 7a–k resulted in the formation of anticipated arylidenes 8a–k (Scheme 2)
Ar = zero > naphthyl > thienyl > p-Cl-phenyl > 3 pyridinyl ~ 4-pyridinyl > p-NO2 -phenyl. All these data suggested that the diaryl ether scaffold is very important for the antitubercular activity, removal of the o-chloro group in triclosan, as well as the introduction of oxadiazole or its open-chain analog hydrazide, increased activity than the parent triclosan
The minimum inhibitory concentrations (MICs) of Compounds 3, 4, 6a–l, and 8a–k for M. tuberculosis H37Rv were determined by the microplate Alamar blue assay (MABA) (Table 1) [31,32]
Summary
(MTB), remains remains the the world’s world’s deadliest infection, having recently surpassed. MTB infection infectionisisstrenuous, strenuous,requires requires long-term treatment of combination chemotherapy ofor two or drugs, like pyrazinamide, isoniazid (INH), rifampicin, streptomycin and/or ethambutol Being of critical in the formation of the stable of the stable ternary InhA-triclosan-NAD+ complex Replacement of this group by a sulfur atom inflammatory and analgesic [19], antimicrobial [20] and antitumor [21,22], In the search of more effective anti-tuberculosis, oxadiazole is one of the most versatile scaffolds against MTB strain. Despite the promising in vitro activity of the currently pharmacodynamic properties thereby improving the druggability of triclosan These compounds existing diphenyl ethers have poor bioavailability [28] and limited aqueous solubility [28], which is showed good antitubercular potency against MTB strain H37Rv (Figure 2) [16].
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