Abstract

Cyclin dependent kinases (CDKs) enzymes regulate cell proliferation and transcriptional processes and can be considered as important targets for the development of anticancer and antimicrobial drugs. In this work, novel benzothiazolyl pyrazolopyrimidine carboxamide and benzothiazolyl pyrazolopyrimidine carbonitrile derivatives were synthesized and characterized. The synthetic process was carried out via the reaction of ylidine benzothiazole derivatives with pyrazolocarboxamide and pyrazolocarbonitrile through a Michael addition pathway. Docking studies were done against CDK2 and CDK9 enzymes and revealed that compound 8a showed high free energy of binding against CDK2 (-8.10 kcal/mol) while compound 15a showed the highest free energy of binding against CDK2 (-8.16 kcal/mol) and CDK9 (-7.87 kcal/mol). Molecular dynamics simulations were conducted to compare the stability of binding of the most active compound 15a and the potent reference drugs roscovitine and dinaciclib. A CDK enzyme assay was done against CDK2 and CDK9 for the previously mentioned top-ranked compounds, 8a and 15a. It was found that compound 15a was the most potent inhibitor for both enzymes with IC₅₀ of 127 ± 1.01 nM and 65 ± 0.50 nM. The anticancer activity of the synthesized compounds was also determined by NCI against 60 cell lines. Compound 8a showed the highest cytotoxic activity against a large number of the tested cell lines. The antimicrobial activity of the synthesized compounds was determined against various gram positive and gram-negative bacteria as well as fungi. The results showed that compound 15a had the strongest antibacterial activity.

摘要

细胞周期蛋白依赖性激酶 (CDK) 调节细胞增殖和转录过程，可被视为开发抗癌和抗菌药物的重要靶标。在这项工作中，合成并表征了新型苯并噻唑基吡唑并嘧啶甲酰胺和苯并噻唑基吡唑并嘧啶腈衍生物。合成过程是通过嘧啶苯并噻唑衍生物与吡唑甲酰胺和吡唑甲腈通过迈克尔加成途径反应进行的。对接研究针对 CDK2 和 CDK9 酶进行，结果表明化合物8a显示出与 CDK2 结合的高自由能 (-8.10 kcal/mol)，而化合物15a显示出与 CDK2 (-8.16 kcal/mol) 和 CDK9 (-7.87 kcal/mol) 结合的最高自由能。进行了分子动力学模拟，以比较最具活性的化合物15a与强效参考药物 roscovitine 和 dinaciclib的结合稳定性。针对前面提到的排名靠前的化合物8a和15a，针对 CDK2 和 CDK9 进行了 CDK 酶测定。发现化合物15a是两种酶最有效的抑制剂，IC ₅₀分别为 127 ± 1.01 nM 和 65 ± 0.50 nM。合成化合物的抗癌活性也通过 NCI 针对 60 种细胞系进行了测定。化合物8a显示出对大量测试细胞系的最高细胞毒活性。确定了合成化合物对各种革兰氏阳性和革兰氏阴性细菌以及真菌的抗菌活性。结果表明，化合物15a具有最强的抗菌活性。