Background:
Tuberculosis remains one of the most deadly infectious diseases worldwide due to the emergence
of multi-drug resistance (MDR) and extensively drug resistance (XDR) strains of Mycobacterium tuberculosis (MTB).
Materials and Methods:
Herein, the screening of a total of eight symmetrical 1,4-dihydropyridine (1,4-DHP) derivatives
(4a-4h) was carried out for whole-cell anti-TB activity against the susceptible H37Rv and MDR strains of MTB.
Results and Discussion:
Most of the compounds exhibited moderate to excellent activity against the susceptible H37Rv.
Moreover, the most promising compound 4f (against H37Rv) having para-trifluoromethyl phenyl group at 4-position and
bis para-methoxy benzyl ester group at 3- and 5-positions of 1,4-dihydropyridine pharmacophore, exhibited no toxicity, but
demonstrated weak activity against MTB strains resistant to isoniazid and rifampicin. In light of the inhibitory profile of the title compounds, enoyl-acyl carrier protein reductase (InhA) appeared to be the appropriate molecular target. Docking study
of these derivatives against InhA receptor revealed favorable binding interactions. Further, in silico predicted ADME properties of these compounds 4a-4h were found to be in the acceptable ranges including satisfactory Lipinski’s rule of five,
thereby indicating their potential as drug-like molecules.
Conclusion:
In particular, the 1,4-DHP derivative 4f can be considered as an attractive lead molecule for further exploration
and development of more potent anti-TB agents as InhA inhibitors.
Diastereocontrol in Radical Addition to β-Benzyloxy Hydrazones: Revised Approach to Tubuvaline and Synthesis of O-Benzyltubulysin V Benzyl Ester
