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4-Aryl-1,4-Dihydropyridines as Potential Enoyl-Acyl Carrier Protein Reductase Inhibitors: Antitubercular Activity and
Katharigatta N Venugopala1, Pran Kishore Deb2, Melendhran Pillay3
1Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia.
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).
Aims:
Currently, available drugs are getting resistant and toxic. Hence, there is an urgent need for the development of potent molecules to treat tuberculosis.
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 paratrifluoromethyl 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. A 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 an attractive lead molecule for further exploration and development of more potent anti-TB agents as InhA inhibitors.
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