Novel oral anticoagulants are frequently used for the pharmacotherapy of thromboembolic disorders but still have drawbacks and side effects. While numerous synthetic and semisynthetic derivatives of nontoxic isosteviol possess potential therapeutic properties, including anticoagulant activity. Besides, thiourea is recognized in medicinal chemistry research as a component of a common framework of many drugs or bioactive compounds. The present work combines molecular modeling and docking approach for searching and designing novel thiourea isosteviol-based compounds as potential FXa inhibitors. Elaborated regression model well reflects the relationships between experimentally determined anticoagulant activity and molecular descriptors and may be used for the prediction of FXa inhibitory activity of novel thiourea isosteviol compounds. Among 20 descriptors incorporated into the ANN model, 60% are 2D topological descriptors, 25% describe three-dimensional molecular structure, and remaining 15% belong to constitutional descriptors. Additionally, docking simulation confirms the prominent binding of the newly in silico designed molecules with the active sites of the protein, which may be the lead molecules and can be further optimized for the efficient pharmacodynamic and pharmacokinetic profiles. Based on the results obtained, thiourea derivatives of isosteviol with 3-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl or 4-(oxazol-5-yl)phenyl substituent may be promising FXa inhibitors. Findings reported in the present work can be used as valuable information for the development of anticoagulants.

Direct oral anticoagulants are an important and relatively new class of synthetic anticoagulant drugs commonly used for the pharmacotherapy of thromboembolic disorders. However, they still have some limitations and serious side effects, which continuously encourage medicinal chemists to search for new active compounds acting as human-activated coagulation factor X (FXa) inhibitors. Isosteviol is a nontoxic hydrolysis product of naturally occurring stevioside and possesses a wide range of therapeutic properties, including anticoagulant activity. The present contribution describes the in silico design of novel oxime ether isosteviol derivatives as well as a molecular modeling approach based on QSAR analysis and a docking simulation for searching for novel isosteviol-based compounds as potential FXa inhibitors. The elaborated ANN model, encompassing topological and geometrical information, exhibited a significant correlation with FXa-inhibitory activity. Moreover, the docking simulation indicated six of the most promising isosteviol-like compounds for further investigation. Analysis showed that the most promising derivatives contain heterocyclic, aromatic, five-membered moieties, with substituents containing chlorine or fluorine atoms. It is anticipated that the findings reported in the present work may provide useful information for designing effective FXa inhibitors as anticoagulant agents.

Objective: The present work discusses developing a novel method for estimation of residual solvents in Gliclazide using Gas chromatography and determining its consistency, reliability and reproducibility by performing its validation. Methods: A Gas chromatograph equipped with aflame ionization detector, column DB-624 (60 m x 0.32 mm x 1.8 µm) with Nitrogen as carrier gas was used and the column temperature was 40 °C (hold for 15 min) and increased to 240 °C at 20 °C per min. The solutions were prepared using-Methyl-2-Pyrrolidone (NMP) diluent as per the procedure given in protocol and appropriately injected as per the sequence. The validation parameters checked were System suitability, Specificity, Linearity and Range, Accuracy, Precision, Limit of detection, Limit of quantitation, Ruggedness and Robustness. Results: The data for each validation parameter tested is compiled and documented. It was found that the results obtained for each parameter compiled with their given acceptance criteria. Hence, the developed method was considered reproducible, reliable and consistent. Conclusion: The method of analysis complies with all the parameters tested and it was found to be reliable, consistent and reproducible.

Objective: The present study discusses molecular docking of some novel coumarin–benzothiazole Schiff bases and the prediction of pharmacokinetic properties of potent molecules by the computational method. Methods: Five protein targets were selected for the study and their structures were taken from RCSB Protein Data Bank in PDB format. Preparation of proteins was done using Discovery Studio 2021 Client. A total of twenty derivatives were drawn using ChemDraw 20.0 and saved in Mol format. Molecular docking was performed using PyRx software. Docking results were visualized by Discovery Studio 2021 Client. The pharmacokinetic properties of the best compounds were determined using the pkCSM tool. Results: All twenty derivatives were docked against the five proteins, namely DNA Ligase (PDB ID: 3PN1), Topoisomerase (PDB ID: 3TTZ), Sterol demethylase (PDB ID: 5FSA), Enoyl-acyl-carrier protein (PDB ID: 1BVR) and Glutamate racemase (PDB ID: 5HJ7). The compound JJB18 has shown the best binding score against DNA ligase (-10.7 kcal/mol), Glutamate racemase (-8.4 kcal/mol), and Enoyl-acyl-carrier protein (-10.8 kcal/mol). Further, compound JJB19 has shown the best score for fungal sterol demethylase (-10.6 kcal/mol) and compound JJB20 towards topoisomerase (-9.4 kcal/mol) than the standard drugs. The physicochemical properties of potent derivatives were also reported. Conclusion: Molecular Docking study indicates that coumarin–benzothiazole Schiff bases may be effective inhibitors for the different microbial proteins. Additionally, in silico ADMET studies predicts drug-like features. Hence, these compounds may be considered lead molecules and further investigation of their analogues may help in the development of novel drugs for the treatment of microbial diseases.

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