4-Aryl-1,4-Dihydropyridines as Potential Enoyl-Acyl Carrier Protein Reductase Inhibitors: Antitubercular Activity and Molecular Docking Study

Abstract

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.

1,4-Dihydropyridine as a Promising Scaffold for Novel Antimicrobials Against Helicobacter pylori

“…Fiszer-Maliszewska and co-workers in 1985 observed that some DHPs inhibited the in vitro growth of antibiotic-resistant Mycobacterium tuberculosis strains at 3.1 mg/L ( Fiszer-Maliszewska et al, 1985 ). Since then, the antitubercular properties of other DHP derivatives have been reported by many other researchers ( Trivedi et al, 2011 ; Desai et al, 2015 ; Zandhaghighi et al, 2017 ; Venugopala et al, 2021 ). DHPs have been also evaluated as antimicrobials against other pathogenic bacteria including S. aureus ( Ceviz et al, 1997 ; Olejnikova et al, 2014 ; Mahmoodi et al, 2015 ; Nkosi et al, 2016 ; Nosrati et al, 2021 ), E. coli ( Murthy et al, 2012 ; Olejnikova et al, 2014 ; Mahmoodi et al, 2015 ; Nkosi et al, 2016 ; Ahamed et al, 2018 ), Pseudomonas aeruginosa ( Mahmoodi et al, 2015 ; Nkosi et al, 2016 ; Ahamed et al, 2018 ), Vibrio cholerae ( Lavanya et al, 2021 ) and Klebsiella pneumoniae ( Murthy et al, 2012 ); but also against parasites ( Núñez-Vergara et al, 1997 ; Palit and Ali, 2008 ; Reimao et al, 2010 ; Pollo et al, 2017 ; Jeddi et al, 2021 ) and fungi ( Chhillar et al, 2006 ; Jezikova et al, 2017 ; Ahamed et al, 2018 ).…”

Comprehensive Coverage on Anti‐mycobacterial Endeavour Reported in 2021

“…Venugopala and co‐workers have reported 1,4‐dihydropyridine with MIC of 16 μg/mL and 128 μg/mL against H 37 Rv and MDR Mtb respectively (Figure 13). [60] Docking studies of this compound 30 against InhA (PDB IDs: 5G0S and 5G0 U) have shown good binding to InhA. Compound 30 was found safe without any toxicity up to 380 μg/mL through in vitro safety studies against the normal peripheral blood mononuclear cells.…”

A Facile One‐Pot Solvent‐Free Synthesis, in Vitro and in Silico Studies of a Series of Tetrahydropyridine Derivatives as Breast Cancer Inhibitors

“…[7] Compound E. TPMPA, is a selective antagonist of GABAC receptors, [8] and Compound F. GTS-21, is a nACh receptor agonist that is both orally active and selective for alpha-7 nicotinic acetylcholine (nACh). [9] THPs have also been comprehensively studied for their prospective pharmacological actions such as anticancer, [10][11] antidiabetic, [12] anti-neurotropic, [13] anti-tubercular, [14] bronchodilations, [15] larvicidal, [16] neuropeptide YY1 receptor antagonists, [17] neuroprotective, [18] platelet anti-aggregation, [19] anti-inflammatory, [20] mGluR1 antagonists, [21] antihypertensives, [22] antimicrobial, [23][24][25] antimycobacterial, [26] antifungal, [27] antimalarial [28] and anti-HIV [29] activities. Substituted tetrahydropyridines have been synthesized employing various catalysts like iodine, [30] bromodimethylsulfonium bromide, [31] glycolic acid, [32] vitamin B1, [33] lactic acid, [34] lanthanum nitrate, [35] nickel chloride hexahydrate, [36] sulfamic acid, [37] cyanuric chloride, [38] sodium dioctyl sulfosuccinate, [39] acetic acid, [40] tetrabutylammonium tribromide, [41] picric acid, [42] and thiourea dioxide.…”