Abstract

Cyclin dependent kinases (CDKs) are a group of enzymes involved in different phases of the cell cycle. In addition, it has been reported that CDK9 could be used as a crucial target for the development of antiviral drugs such as purine analogues; roscovitine and dinaciclib. A new series of benzothiazolyl pyrazolopyrimidine carboxamide derivatives were synthesized and evaluated for their antiviral activity against avian influenza "bird flu" (H5N1). The novel compounds were synthesized via the reaction of pyrazolo carboxamide derivatives with different derivatives of ylidine benzothiazole. The reaction proceeded via a Michael addition pathway. Antiviral activity was determined using a plaque reduction assay against the H5N1 virus. Five compounds showed the highest inhibitory activity in the range of 61.6 to 71.6% at 0.1 μmol/mL. Based on a molecular docking study, an enzyme assay was carried out against CDK9 for the previously mentioned top-ranked compounds. It was found that compound 11f was the most potent inhibitor of CDK9 with an IC₅₀ of 0.062 μmol/mL. A QSAR model was built to determine the hidden feature responsible for the biological activity of the novel compounds. It was found that two sets of descriptors, 3 D Potential energy descriptors and 2 D Atom Counts and Bond Counts descriptors, were correlated to a linear model with RMSE and r2 coefficient values of 0.75 and 0.80, respectively. A molecular dynamic simulations study of 11f over 10 ns against dinaciclib showed that both 11f and dinaciclib achieved equilibrium at 2 Å.

Supplemental data for this article is available online at https://doi.org/10.1080/15257770.2022.2059674 .

摘要

细胞周期蛋白依赖性激酶 (CDK) 是一组参与细胞周期不同阶段的酶。此外，据报道，CDK9 可用作开发嘌呤类似物等抗病毒药物的关键靶点；roscovitine 和 dinaciclib。合成了一系列新的苯并噻唑基吡唑并嘧啶甲酰胺衍生物，并评估了它们对禽流感“禽流感”（H5N1）的抗病毒活性。这些新化合物是通过吡唑并羧酰胺衍生物与不同的二亚甲基苯并噻唑衍生物反应合成的。反应通过迈克尔加成途径进行。使用针对 H5N1 病毒的噬斑减少测定来确定抗病毒活性。五种化合物在 0.1 μmol/mL 的浓度范围内显示出最高的抑制活性，范围为 61.6% 至 71.6%。基于分子对接研究，针对 CDK9 对前面提到的排名靠前的化合物进行了酶测定。发现化合物11f是最有效的 CDK9 抑制剂，IC ₅₀为 0.062 μmol/mL。建立了一个 QSAR 模型来确定负责新化合物生物活性的隐藏特征。发现两组描述符，3D 势能描述符和 2D 原子数和键数描述符，与 RMSE 和 r2 系数值分别为 0.75 和 0.80 的线性模型相关。11f对dinaciclib超过 10 ns的分子动力学模拟研究表明，11f和dinaciclib在 2 Å 处达到平衡。

本文的补充数据可在 https://doi.org/10.1080/15257770.2022.2059674 在线获取。