Hit, Lead & Candidate Discovery The thiazole ring system represents a significant building block that exists in many biologically active natural products and clinically successful anticancer drugs. Modifications of the thiazole core have been a proven and highly effective method in improving anticancer potency. We designed a novel thiazole‐based molecule, 4‐(dimethylamino)‐2‐(p‐tolylamino) thiazole‐5‐carbonitrile, which showed potent in vitro anticancer effect against targeted Bcl‐2 Jurkat cell‐line quantified using 3‐(4, 5‐dimethythiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) assay. Physicochemical parameters (pKa, LogP, LogD) of the molecule have also been evaluated as a part of the drug development process. Moreover, a rapid Reverse phase‐high performance liquid chromatography (RP‐HPLC) bioanalytical method has been developed to quantitate the molecule in human plasma. The method has been validated following the United States Food and Drug Administration bioanalytical method validation guideline. The stability studies showed no significant instability of the analyte in respective stability conditions (6 hr autosampler, 8 hr bench top, 30 days long‐term, and 3 freeze–thaw cycles). The molecule was found to be stable for 3 hr in human plasma. The molecule was shown to have high plasma protein binding affinity. It showed favorable pKa (11), Log P (3.01), Log D (2.96), and plasma protein binding (90%) values toward its further exploitation as a lead anticancer candidate molecule. The developed bioanalytical method can be used for quantifying the molecule in different pharmacokinetic, toxicokinetic, or other clinical trial samples involving human plasma during development process or in routine bioavailability and bioequivalence study after its regulatory approval.
Background Trend analysis, graphical representation, and summarization of pharmacological research trends were carried out to act as guidance for the future. The main objectives of the research are to find out the complete research trend on the national tree of India so far and to validate its traditional uses along with the pharmacological hepatoprotective activity of Ficus benghalensis L. by developing three in vitro experimental models. Methods The fruit of the said plant (F. benghalensis) was extracted with different solvent (petrochemical ether, chloroform, ethyl acetate, ethanol, water) system and the yield value was determined. Phytochemical screening was also done with a different solvent. In an in-vitro study, the liver of freshly slaughtered goat (Capra Capra) was used for various investigational tests, and the hepatotoxicity was induced by carbon tetrachloride (CCl4) at a dose of 2 ml/kg, Acetaminophen at a dose of 7 g/kg, and with Erythromycin at a dose of 1.4 g/kg. The ethanol extract of fruits of F. benghalensis at the doses of 100 mg/kg, 250 mg/kg, and 500 mg/kg were used to observe its hepatoprotective effect against drug/chemical-induced in vitro hepatotoxicity as the model developed here with against a standard molecule, Silymarin. Results Amongst all solvents, ethanol was considered to be a universal solvent and resulted in a yield of 2.96%, which is maximum. Phytochemical screening of ethanol extract of fruit also showed the presence of alkaloids, steroids, flavonoids, carbohydrates, and glycosides. The protein concentration of liver homogenate based on comparison with standard protein concentration was found to be 1.6 mg/mL as measured at λmax of 750 nm. About the protein concentration, catalase (enzymatic) activity was also measured using the standard curve of H2O2, to calculate the specific activity of different models to compare the study results. Conclusion The significant effect of the reduction of hepatotoxicity was found at a dose of 500 mg/kg of fruit extract against Silymarin. Evaluation of Hepatoprotective activity of fruit in terms of catalase activity with different models flourishing the new research scope to fulfill the shortage of availability of a new, efficient, safe hepatoprotective agent in upcoming days. Graphical abstract
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