In vitro evaluation, in silico studies and toxicological assay of some xanthones as potential Leishmania donovani inhibitors

Xanthones are naturally occurring compounds that exist in some higher plants, fungi and lichen. Natural and synthetic xanthones have shown diverse biological and pharmacological properties. Thus, the present study was designed to examine the antileishmanial activity of five xanthone analogues, their cytotoxicity assay, and in silico studies to predict their physicochemical properties, ADME profile, and QSAR. Among these compounds, 3, 6-bis (4-bromobutoxy)-9H-xanthen-9one (XN 1) has shown the highest inhibitory effect with IC50 value 0.075 ± 1.88 μg/ml. Moreover, the pharmacokinetics prediction revealed its good solubility and oral bioavailability. The quantitative structure-property relationships (QSPR) were also studied which depicted the electronic parameter, EHOMO, the physical chemistry parameter that influences CLTOT. Furthermore, the assessment of cytotoxicity demonstrated that XN 1 exhibited the lowest cytotoxicity against brine shrimp, so it is considered the safest xanthone analogue with LD50 115.204 × 103μg/ml. Moreover, molecular docking was performed to investigate the molecular mechanism of action of the synthesized compounds which were found to have good binding affinities with different enzymes of leishmania that are involved in its essential pathways. These findings suggest that xanthones compounds can be a promising, and effective class of products for the treatment of visceral leishmaniasis.