ATP binding cassette transporter A1 (ABCA1) is a critical transporter that mediates cellular cholesterol efflux from macrophages to apolipoprotein A-I (ApoA-I). Therefore, increasing the expression level of ABCA1 is anti-atherogenic and ABCA1 expression upregulators have become novel choices for atherosclerosis treatment. In this study, a series of N-benzothiazolyl-2-benzenesulfonamides, based on the structure of WY06 discovered in our laboratory, were designed and synthesized as novel ABCA1 expression upregulators. Based on an in vitro ABCA1 upregulatory cell model, ABCA1 upregulation of target compounds was evaluated. Compounds 6c, 6d, and 6i have good upregulated ABCA1 expression activities, with EC₅₀ values of 0.97, 0.37, and 0.41 μM, respectively. A preliminary structure–activity relationship is summarized. Replacing the methoxy group on the benzothiazole moiety of WY06 with a fluorine or chlorine atom and exchanging the ester group with a cyano group resulted in more potent ABCA1 upregulating activity. Moreover, compound 6i increased ABCA1 mRNA and protein expression and significantly promoted cholesterol efflux in RAW264.7 cells. In conclusion, N-benzothiazolyl-2-benzenesulfonamides were identified as novel ABCA1 expression upregulators.

中文翻译：

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N-苯并噻唑基-2-苯磺酰胺作为新型 ABCA1 表达上调剂的鉴定

ATP 结合盒转运蛋白 A1 (ABCA1) 是一种重要的转运蛋白，可介导细胞胆固醇从巨噬细胞流出至载脂蛋白 AI (ApoA-I)。因此，提高 ABCA1 的表达水平是抗动脉粥样硬化的，ABCA1 表达上调剂已成为治疗动脉粥样硬化的新选择。本研究以本实验室发现的WY06结构为基础，设计合成了一系列N-苯并噻唑基-2-苯磺酰胺作为新型ABCA1表达上调剂。基于体外ABCA1上调细胞模型，评估目标化合物的ABCA1上调。化合物6c、6d和6i具有良好的上调 ABCA1 表达活性，与 EC_{50 个}值分别为 0.97、0.37 和 0.41 μM。总结了初步的构效关系。将 WY06 的苯并噻唑部分上的甲氧基替换为氟或氯原子并将酯基替换为氰基导致更有效的 ABCA1 上调活性。此外，化合物6i增加了 RAW264.7 细胞中 ABCA1 mRNA 和蛋白质的表达，并显着促进了胆固醇的流出。总之， N -benzothiazolyl-2-benzosulfonamides 被鉴定为新型 ABCA1 表达上调剂。