Background: A small library of quinazolin-4-one clubbed thiazole acetates/acetamides lacking toxicity-producing functionalities was designed, synthesized, and evaluated for antidiabetic potential as glucokinase activators (GKA). Molecular docking studies were done in the allosteric site of the human glucokinase (PDB ID: 1V4S) enzyme to assess the binding mode and interactions of synthesized hits for best-fit conformations. All the compounds were evaluated by in vitro enzymatic assay for GK activation. Results: Data showed that compounds 3 (EC 50 = 632 nM) and 4 (EC 50 = 516 nM) showed maximum GK activation compared to the standards RO-281675 and piragliatin. Based on the results of the in vitro enzyme assay, docking studies, and substitution pattern, selected compounds were tested for their glucose-lowering effect in vivo by oral glucose tolerance test (OGTT) in normal rats. Compounds 3 (133 mg/dL) and 4 (135 mg/dL) exhibited prominent activity by lowering the glucose level to almost normal, eliciting the results in parallel to enzyme assay and docking studies. Binding free energy, hydrogen bonding, and π-π interactions of most active quinazolin-4-one derivatives 3 and 4 with key amino acid residues of the 1V4S enzyme were studied precisely. Preliminary in-silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction was carried out using SwissADME and PreADMET online software which revealed that all the compounds have the potential to become orally active antidiabetic agents as they obeyed Lipinski's rule of five. Conclusion: The results revealed that the designed lead could be significant for the strategic design of safe, effective, and orally bioavailable quinazolinone derivatives as glucokinase activators.
A simple and robust analytical reversed-phase high-performance liquid chromatography method was developed and validated for simultaneous chromatographic elution of three cardiovascular drugs, namely clopidogrel, aspirin (ASP) and atorvastatin. The method was developed in rat plasma and dosage formulation with high-quality chromatographic separation between the drug peaks by using a stainless steel analytical column thermo beta-basic, C18 (25 × 0.46 cm, 5 µm). The system was operated at 25°C using a mobile phase consisting of acetonitrile and phosphate buffer (pH 3.0) in the gradient ratio at a flow rate of 1 mL min(-1) with ultraviolet detection monitored at 232 nm. The parametric statistics, i.e., correlation coefficient of 0.999, was assessed for all the drugs having linearity over the tested concentration range (10-10,000 ng mL(-1)) in rat plasma using an unweighted calibration curve. The accuracy of samples for six replicate measurements at lower limit of quantitation level was within limit. The method was applicable for the quality control of the mentioned drugs in raw material, bulk drug and pharmaceutical formulations as well as in pharmacokinetic studies.
A stability-indicating liquid chromatographic method has been developed and validated for the determination of Diltiazem Hydrochloride (DTZ) together with its six related substances (Diltiazem sulphoxide, Imp-A, Imp-B, Imp-D, Imp-E, and Imp-F) in a laboratory mixture as well as in a novel tablet formulation developed in-house. Efficient chromatographic separation was achieved on a Hypersil BDS C18 (150 mm×4.6 mm, 5.0 μm) with mobile phase containing 0.2% Triethylamine (TEA) in gradient combination with acetonitrile (ACN) at a flow rate of 1.0 mL/min and the eluent was monitored at 240 nm. In the developed method, the resolution of DTZ from any pair of impurities was found to be greater than 2.0. The test solution and related substances were found to be stable in the diluent for 24 h. The developed method resolved the drug from its known impurities, stated above, and also from additional impurities generated when the formulation was subjected to forced degradation; the mass balance was found close to 99.9%.Regression analyses indicate correlation coefficient value greater than 0.997 for DTZ and its six known impurities. The LOD for DTZ and the known impurities was at a level below 0.02%. The method has shown good, consistent recoveries for DTZ (99.8–101.2%) and also for its six known impurities (97.2–101.3%). The method was found to be accurate, precise, linear, specific, sensitive, rugged, robust, and stability-indicating.
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