Herein, the mono and dialkylation of pyridazino[4,5-b]indole were achieved with a set of alkylating agents, including amyl bromide, allyl bromide, benzyl bromide and ethyl chloroacetate in the presence of K₂CO₃/acetone or KOH/DMSO. The hydrazinolysis of mono and di-esters 10 and 11 gave the target hydrazides 12 and 13, which displayed promising, potent, and significant cytotoxic activity against the MCF-7 cell line with IC₅₀ values of 4.25 and 5.35 μm compared to that of the standard drug 5-FU (IC₅₀ 6.98 μm), respectively. RT-PCR analysis of the most active compound 12 was performed to determine its mode of action through the up-regulation of pro-apoptotic genes and inhibition of anti-apoptotic and PI3K/AKT/mTOR genes. The findings were consistent with the proposed mechanism illustrated in the in silico study. Further, the in vivo analysis exhibited its potent anti-cancer activity through the prolongation of survival parameters, and inhibition of ascetic fluid parameters in EAC-bearing mice.

中文翻译：

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发现基于酰肼的哒嗪并[4,5-b]吲哚支架作为一种新的磷酸肌醇3-激酶（PI3K）抑制剂用于乳腺癌治疗

在此，哒嗪并[4,5- b ]吲哚的单烷基化和二烷基化是在K ₂ CO ₃ /丙酮或KOH/存在下用一组烷基化剂实现的，包括溴甲烷、烯丙基溴、苄基溴和氯乙酸乙酯。亚甲基亚砜。单酯和二酯10和11的肼解得到目标酰肼12和13，它们对 MCF-7 细胞系显示出有希望的、有效的和显着的细胞毒活性，IC ₅₀值分别为 4.25 和 5.35 μm。标准药物 5-FU (IC ₅₀ 6.98 μm)。最活跃的化合物12的 RT-PCR 分析通过上调促凋亡基因和抑制抗凋亡基因和 PI3K/AKT/mTOR 基因来确定其作用方式。该发现与计算机研究中说明的拟议机制一致。此外，体内分析通过延长 EAC 小鼠的存活参数和抑制腹水参数显示出其有效的抗癌活性。