Abstract

A series of diversely polyfunctionalized pyrazolo[3,4-b]pyridines were synthesized by the multicomponent reaction of phenyl/benzothiazolylhydrazine and 3-oxo-3-arylpropanenitrile with 1,3-diketones under solvent-free and solvent-mediated conditions. Nineteen pyrazolo[3,4-b]pyridine derivatives were screened for their anti-cancer activity against three human cancer cell lines namely NALM-6, SB-ALL and MCF-7. Non-fluorinated 1-(benzothiazolyl)pyrazolo[3,4-b]pyridines (6a–d) displayed better cytotoxicity results as compared to other tested derivatives. The compound 1-(benzothiazolyl)-4,6-dimethyl-3-(4-chlorophenyl)pyrazolo[3,4-b]pyridine, 6b, was identified as the most active derivative with 53% cell growth inhibition nearly equal to the standard drug doxorubicin (58%), in close agreement to drug-likeness and drug score predictions. Among the fluorinated derivatives, compound 2-(3-(4-chlorophenyl)-4-methyl-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)benzo[d]thiazole, 12c, was identified as hit compound with 46-39% cell growth inhibition against all the tested cell lines. Compound 6b was found to display suitable binding when docked inside the active site of Aurora-A kinase enzyme.

摘要

在无溶剂和溶剂介导的条件下，通过苯基/苯并噻唑基肼和 3-氧代-3-芳基丙腈与 1,3-二酮的多组分反应合成了一系列多样化的多官能化吡唑并[3,4- b ]吡啶。筛选了19 种吡唑并[3,4- b ]吡啶衍生物对三种人类癌细胞系即 NALM-6、SB-ALL 和 MCF-7 的抗癌活性。与其他测试衍生物相比，非氟化 1-(苯并噻唑基)吡唑并[3,4- b ]吡啶 ( 6a – d ) 显示出更好的细胞毒性结果。化合物1-(苯并噻唑基)-4,6-二甲基-3-(4-氯苯基)吡唑并[3,4- b ]吡啶，6b, 被确定为最活跃的衍生物，具有 53% 的细胞生长抑制，几乎等于标准药物阿霉素 (58%)，与药物相似性和药物评分预测非常一致。在氟化衍生物中，化合物2-(3-(4-氯苯基)-4-甲基-6-(三氟甲基) -1H-吡唑并[3,4- b ]吡啶-1-基)苯并[ d ]噻唑，图12c被鉴定为对所有测试细胞系具有46-39%细胞生长抑制的命中化合物。发现化合物6b在停靠在 Aurora-A 激酶的活性位点内时表现出合适的结合。