The natural product piperine, the major bioactive alkaloid present in black pepper fruits, has the ability to modulate the functional activity of several biological targets. In this study, we have utilized the natural piperine as a tail moiety to develop new SLC-0111 analogues (6a-d, 8 and 9) as potential carbonic anhydrase inhibitors. Thereafter, different functionalities, free carboxylic acid (11a-c), acetyl (13a) and ethyl ester (13b-c), were exploited as bioisosteres of the sulfamoyl functionality. All piperine-based derivatives were assessed for their inhibitory actions against four human (h) CA isoforms: hCA I, II, IX and XII. The best hCA inhibitory activity was observed for the synthesized primary piperine-sulfonamides (6a-d and 8). In particular, both para-regioisomers (6c and 8) emerged as the most potent hCA inhibitors in this study with two-digit nanomolar activity against hCA II (K_Is = 93.4 and 88.6 nM, respectively), hCA IX (K_Is = 38.7 and 68.2 nM, respectively), and hCA XII (K_Is = 57.5 and 45.6 nM, respectively). Moreover, piperine-sulfonamide 6c was examined for its anti-cancer and pro-apoptotic actions towards breast MCF-7 cancer cell line. Collectively, piperine-based sulfonamides could be considered as a promising scaffold for development of efficient anticancer candidates with potent CA inhibitory activities.

天然产物胡椒碱是黑胡椒果实中的主要生物活性生物碱，具有调节多种生物靶点功能活性的能力。在这项研究中，我们利用天然胡椒碱作为尾部分来开发新的 SLC-0111 类似物（6a-d、8和9）作为潜在的碳酸酐酶抑制剂。此后，不同的官能团，游离羧酸 ( 11a-c )、乙酰基 ( 13a ) 和乙酯 ( 13b-c )，被用作氨磺酰基官能团的生物等排体。评估了所有基于胡椒碱的衍生物对四种人类 ( h ) CA 亚型的抑制作用： hCA I、II、IX 和 XII。对于合成的初级胡椒碱磺酰胺（6a-d和8） ，观察到最好的h CA抑制活性。特别是，两种对位异构体（6c和8）在本研究中成为最有效的h CA 抑制剂，对h CA II（K _I s = 93.4 和 88.6 nM）、h CA IX（K _I s = 38.7 和 68.2 nM，分别）和h CA XII（K _I s = 57.5 和 45.6 nM，分别）。此外，胡椒碱磺胺检查了6c对乳腺癌 MCF-7 癌细胞系的抗癌和促凋亡作用。总的来说，基于胡椒碱的磺胺类药物可以被认为是一种有前途的支架，用于开发具有有效 CA 抑制活性的有效抗癌候选药物。