N-Substituted Phenylhydrazones Kill the Ring Stage of Plasmodium falciparum.

Antimalarial resistance has hampered the effective treatment of malaria, a parasitic disease caused by Plasmodium species. As part of our campaign on phenotypic screening of phenylhydrazones, a library of six phenylhydrazones was reconstructed and evaluated for their in vitro antimalarial and in silico receptor binding and pharmacokinetic properties. The structures of the phenylhydrazone hybrids were largely confirmed using nuclear magnetic resonance techniques. We identified two compounds which exhibited significant antimalarial potential against the ring stage (trophozoite) of 3D7 chloroquine-sensitive (CS) strain and DD2 chloroquine-resistant (CR) strains of Plasmodium falciparum with monosubstituted analogs bearing meta or para electron-donating groups showing significant activity in the single-digit micromolar range. Structure activity relationship is presented showing that electron-donating groups on the substituent hydrophobic pharmacophore are required for antimalarial activity. Compounds PHN6 and PHN3 were found to be the most potent with pIC50s (calculated form in vitro IC50s) of 5.37 and 5.18 against 3D7 CS and DD2 CR strains, respectively. Our selected ligands (PHN3 and PHN6) performed better when compared to chloroquine regarding binding affinity and molecular stability with the regulatory proteins of Plasmodium falciparum, hence predicted to be largely responsible for their in vitro activity. Pharmacokinetic prediction demonstrated that the phenylhydrazones may not cross the blood-brain barrier and are not P-glycoprotein (P-gp) substrates, a good absorption of 62% to 69%, and classified as a category IV compound based on toxicity grading.

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.

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.