Pyridine‐N‐Oxide Alkaloids from Allium stipitatum and Their Synthetic Disulfide Analogs as Potential Drug Candidates against Mycobacterium tuberculosis: A Molecular Docking, QSBAR, and ADMET Prediction Approach

Abstract

In this study, we consider pyridine-N-oxide alkaloids from Allium stipitatum and their synthetic disulfide analogs (PDAs) as candidates for next-generational antimycobacterial agents, in light of growing resistance to existing conventional therapies. In silico studies involving molecular docking simulations of 12 PDAs were carried out against 7 Mycobacterium tuberculosis target proteins (MTs) to determine their theoretical binding affinities. Compounds A3, A6, and B9 demonstrated stronger binding affinities on similar MTs. Molecular descriptors (MDs) describing structural and physicochemical properties of the compounds were also calculated using ChemDes, explored using Pearson’s correlation analysis, and principal component analysis (PCA) in comparison with MDs from conventional antitubercular medicines. The PDAs possessed similar scores as isoniazid and pyrazinamide. The MDs were also used to conduct a quantitative structure-binding affinity relationship (QSBAR) study by building good fit and significant models through principal component regression (PCR) and partial least squares regression (PLSR). Leave-one-out cross-validation was adopted in the PLSR, resulting in good predictive models on all MTs (range of R 2 = 0.7541 ‐ 0.8992 ; range of Q 2 = 0.6183 ‐ 0.8162 ). Both PCR and PLSR models predicted the significant effects of ndonr, Hy, Mol wt, nhev, nring, ndb, Log P, W, Pol, ISIZ, TIAC, Getov, and UI on the binding of ligands to the MTs. In silico prediction of PDAs’ ADMET profiles was conducted with QikProp utility. The ADMET profiles of the compounds were favorable. The outcome of the current study strengthens the significance of these compounds as promising lead candidates for the treatment of multidrug-resistant tuberculosis.

Discovery of some phenylhydrazones as potential antimalarials: An integrated computational approach on PfATP6 and PfDHFR mutant proteins

“…Furthermore, each of these drugs conforms to the Lipinski, Ghose, Verber, Egan and Muegge rules for orally active drugs and hence has the potential to be developed into oral medications. Apart from hepatotoxicity, druginduced cardiotoxicity is another often-reported adverse event that has resulted in drug withdrawal [41]; one source of drug-induced cardiotoxicity is inhibition of hERG (human ether-à-go-go-related gene) K + channels, which produces a type of fatal arrhythmia known as torsade de pointes or long QT syndrome [42]. Analysis of the optimal analogues suggested that they are neither cardiotoxic nor hepatotoxic (Table S4 and Table S5).…”

Potential of plant extracts against Mycobacterium tuberculosis: an integrative review

“…Alkaloids, present in most of the plants with activity against MTB, have a mechanism of action like isoniazid and pyrazinamide in MTB cell membrane, acting as efflux pump inhibitors, which hinders one of the main resistance mechanisms of MTB (AMENGOR et al, 2022). Some of these compounds have already gone to advanced stages of testing, such as thiliacorinin, nortiliacorinin and thiliacorin, which showed low MIC values such as 3.1 µg/mL, demonstrating that this class of compounds has great antimycobacterial potential (BOSE et al, 2021).…”

The association of dietary patterns with latent tuberculosis infection among young adults: A case-control study in Shanghai

“…It is necessary to use multiple methods to explore dietary patterns and their associations with Mtb infection among close contacts in boarding colleges and universities to obtain a complete picture. The most common techniques used for dietary pattern extraction are a posteriori analyses, mainly principal component analysis (PCA), which takes observed correlations as the basis among dietary variables [4,10,13,14].…”