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Withania somnifera is a traditional Indian herb described under the ‘Rasayana’ class in Ayurveda, which gained immense popularity as a dietary supplement in the USA, Europe, Asia, and the Indian domestic market. Despite enormous research on the pharmacological effect of withanosides and withanolides, bioanalytical method development and pharmacokinetics remained challenging and unexplored for these constituents due to isomeric and isobaric characteristics. In current research work, molecular descriptors, pharmacokinetic, and toxicity prediction (ADMET) of these constituents were performed using Molinspiration and admetSAR tools. A rapid, selective, and reproducible bioanalytical method was developed and validated for seven withanosides and withanolides as per USFDA/EMA guidelines, further applied to determine pharmacokinetic parameters of Withania somnifera root extract (WSE) constituents in male Sprague Dawley rats at a dose of 500 mg/kg. Additionally, an ex vivo permeability study was carried out to explore the absorption pattern of withanosides and withanolides from the intestinal lumen. In silico, ADMET revealed oral bioavailability of withanosides and withanolides following Lipinski’s rules of five with significant absorption from the gastrointestinal tract and the ability to cross the blood-brain barrier. Upon oral administration of WSE, Cmax was found to be 13.833 ± 3.727, 124.415 ± 64.932, 57.536 ± 7.523, and 7.283 ± 3.341 ng/mL for withanoside IV, withaferin A, 12-Deoxy-withastramonolide, and withanolide A, respectively, with Tmax of 0.750 ± 0.000, 0.250 ± 0.000, 0.291 ± 0.102, and 0.333 ± 0.129 h. Moreover, at a given dose, withanoside V, withanolide B, and withanone were detected in plasma; however, the concentration of these constituents was found below LLOQ. Thus, these four major withanoside and withanolides were quantified in plasma supported by ex vivo permeation data exhibiting a time-dependent absorption of withanosides and withanolides across the intestinal barrier. These composite findings provide insights to design a clinical trial of WSE as a potent nutraceutical.

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Objective: The study was aimed to investigate the cytotoxic effect of S-5H-[1,2,4]-triazino (5,6-b) indol-3-yl-3,4-phenylethane-thioate derivatives as epidermal growth factor Receptor (EGFR) inhibitors. Methods: In the present study 14 novel triazine analogues were synthesized and characterized using different spectroscopic techniques such as FT-IR, NMR and Mass Spectroscopy. The anticancer activity was performed using MCF-7 (breast cancer) and K-562 (leukaemia) cell lines. Further, molecular docking was carried out using Vlife Molecular Docking Software (MDS) on crystal structure of epidermal growth factor receptor (EGFR) to identify the binding mode of interaction with an active site. Results: Compounds MA-7, MA-8, MA-12, MA-13 and MA-14 show potent activity against cancer cell lines in the range of<10 to 84.4 µg/ml. Further molecular docking on EGFR also supports that there is a strong correlation between in silico and in vitro biological activity. The results of this study may be further useful for lead optimization process. Conclusion: The results of this study indicates that the synthesized triazine analogues can give a potential lead as an anticancer agent.