Six series based on barbituric acid 5a-e, 10a-d; thiobarbituric acid 6a-e, 11a-d and 1,3-dimethylbarbituric acid 7a-e, 12a-d were prepared and screened for their in vitro PARP1 inhibition. They revealed promising inhibition at nanomolar level especially compounds 5c, 7b, 7d and 7e (IC₅₀ = 30.51, 41.60, 41.53 and 36.33 nM) with higher potency than olaparib (IC₅₀ = 43.59 nM). Moreover, compounds 5b, 5d, 7a, 12a and 12c exhibited good comparable activity (IC₅₀ = 65.93, 58.90, 66.57, 45.40 and 50.62 nM, respectively). Furthermore, the most active compounds 5c, 7b, 7d, 7e, 12a and 12c against PARP1 in vitro were evaluated in the BRCA1 mutated triple negative breast cancer cell line MDA-MB-436 where 5c and 12c showed higher potency compared to olaparib and result in cell cycle arrest at G2/M phase. 5c and 12c showed apoptotic effects in MDA-MB-436 and potentiated the cytotoxicity of temozolomide in A549 human lung epithelial cancer cell line. Compounds 5c and 12c represent interesting starting points towards PARP1 inhibitors.

基于巴比妥酸5a-e，10a-d的六个系列; 制备了硫代巴比妥酸6a-e，11a-d和1，3-二甲基巴比妥酸7a-e，12a-d，并对其体外PARP1抑制作用进行了筛选。他们显示出在纳摩尔水平上有希望的抑制作用，尤其是化合物5c，7b，7d和7e（IC ₅₀  = 30.51、41.60、41.53和36.33 nM），其效力高于奥拉帕尼（IC ₅₀  = 43.59 nM）。此外，化合物5b，5d，7a，12a和12c表现出良好的可比活性（IC ₅₀ 分别为65.93、58.90、66.57、45.40和50.62 nM）。此外，在BRCA1突变的三阴性乳腺癌细胞系MDA-MB-436中评估了体外对PARP1活性最高的化合物5c，7b，7d，7e，12a和12c，其中5c和12c与olaparib相比显示出更高的效能，并且结果在细胞周期停滞在G2 / M期。5c和12c在MDA-MB-436中显示出凋亡作用，并增强了替莫唑胺在A549人肺上皮癌细胞系中的细胞毒性。化合物5c和12c代表了针对PARP1抑制剂的有趣起点。