Hybridization of reported weakly active antiproliferative hit 5-amino-4-pyrimidinol derivative with 2-anilino-4-phenoxypyrimidines suggests a series of 2,5-diamino-4-pyrimidinol derivatives as potential antiproliferative agents. Few compounds belonging to the proposed series were reported as CSF1R/DAPK1 inhibitors as anti-tauopathies. However, the correlation between CSF1R/DAPK1 signalling pathways and cancer progression provides motives to reprofile them against cancer therapy. The compounds were synthesised, characterized, and evaluated against M-NFS-60 cells and a kinase panel which bolstered predictions of their antiproliferative activity and suggested the involvement of diverse molecular targets. Compound 6e, the most potent in the series, showed prominent broad-spectrum antiproliferative activity inhibiting the growth of hematological, NSCLC, colon, CNS, melanoma, ovarian, renal, prostate and breast cancers by 84.1, 52.79, 72.15, 66.34, 66.48, 51.55, 55.95, 61.85, and 60.87%, respectively. Additionally, it elicited an IC50 value of 1.97 µM against M-NFS-60 cells and good GIT absorption with Pe value of 19.0 ± 1.1 × 10-6 cm/s (PAMPA-GIT). Molecular docking study for 6e with CSF1R and DAPK1 was done to help to understand the binding mode with both kinases. Collectively, compound 6e could be a potential lead compound for further development of anticancer therapies.

中文翻译：

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基于嘧啶的DAPK1 / CSF1R双重抑制剂的概况分析：2,5-二氨基-4-嘧啶醇衍生物的鉴定为新型潜在的抗癌先导化合物。

已报道的弱活性抗增殖命中5-氨基-4-嘧啶衍生物与2-苯胺基-4-苯氧基嘧啶的杂交表明，一系列2,5-二氨基-4-嘧啶衍生物是潜在的抗增殖剂。属于拟议系列的化合物中，很少有报道将其作为CSF1R / DAPK1抑制剂作为抗Tauopathies抑制剂。然而，CSF1R / DAPK1信号通路与癌症进展之间的相关性提供了重新调整其抵抗癌症治疗的动机。合成，表征和针对M-NFS-60细胞和激酶面板进行了评估，这些化合物增强了其抗增殖活性的预测并暗示了多种分子靶标的参与。化合物6e（该系列中最有效的化合物）显示出显着的广谱抗增殖活性，可抑制血液，NSCLC，结肠癌，中枢神经系统，黑色素瘤，卵巢癌，肾癌，前列腺癌和乳腺癌的比例分别为84.1、52.79、72.15、66.34、66.48、51.55、55.95、61.85和60.87％。此外，它对M-NFS-60细胞的IC50值为1.97 µM，对GIT的吸收良好，Pe值为19.0±1.1×10-6 cm / s（PAMPA-GIT）。进行了6e与CSF1R和DAPK1的分子对接研究，以帮助了解这两种激酶的结合方式。总体而言，化合物6e可能是抗癌疗法进一步发展的潜在先导化合物。进行了6e与CSF1R和DAPK1的分子对接研究，以帮助了解这两种激酶的结合方式。总体而言，化合物6e可能是抗癌疗法进一步发展的潜在先导化合物。进行了6e与CSF1R和DAPK1的分子对接研究，以帮助了解这两种激酶的结合方式。总体而言，化合物6e可能是抗癌疗法进一步发展的潜在先导化合物。