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. Data showed that compounds 3 (EC50 = 632 nM) and 4 (EC50 = 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. 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.

中文翻译：

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喹唑啉-4-酮衍生物缺乏作为葡萄糖激酶激活剂的产生毒性的特性：设计，合成，分子对接和硅内ADMET预测

设计，合成并合成了一个小型的喹唑啉-4-酮棍状噻唑乙酸酯/乙酰胺类小库，该库没有产生毒性的功能，并评估了其作为糖激酶激活剂（GKA）的抗糖尿病潜力。在人葡萄糖激酶（PDB ID：1V4S）的变构位点进行了分子对接研究，以评估结合模式和合成命中物的最佳匹配构象。通过体外酶促测定评估所有化合物的GK活化。数据显示，与标准RO-281675和吡拉格列汀相比，化合物3（EC50 = 632 nM）和4（EC50 = 516 nM）表现出最大的GK活化。根据体外酶分析，对接研究和取代模式的结果，通过口服葡萄糖耐量试验（OGTT）在正常大鼠中测试了所选化合物的体内降糖作用。化合物3（133 mg / dL）和化合物4（135 mg / dL）通过将葡萄糖水平降低至几乎正常水平而表现出突出的活性，并与酶法测定和对接研究相平行。精确研究了最活跃的喹唑啉-4-酮衍生物3和4与1V4S酶的关键氨基酸残基的结合自由能，氢键和π-π相互作用。使用SwissADME和PreADMET在线软件对硅的吸收，分布，代谢，排泄和毒性（ADMET）进行了初步的预测，结果表明，所有化合物均符合Lipinski的5条规则，因此有可能成为口服抗糖尿病药。