Abstract：
Two novel series of hydrazinyl-based benzenesulfonamides 9a-j and 10a-j were designed and synthesized using SLC-0111 as the lead molecule. The newly synthesized compounds were evaluated for their inhibitory activity against four different human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. Both the series reported here were practically inactive against the off-target isozyme hCA I. Notably, derivative 10a exhibited superior potency (Ki of 10.2 nM) than acetazolamide (AAZ) against the cytosolic isoform hCA II. The hCA IX and XII isoforms implicated in tumor progression were effectively inhibited with Kis in the low nanomolar range of 20.5-176.6 nM and 6.0-127.5 nM, respectively. Compound 9g emerged as the most potent and selective hCA IX and XII inhibitor with Ki of 20.5 nM and SI of 200.1, and Ki of 6.0 nM and SI of 683.7, respectively, over hCA I. Furthermore, six compounds (9a, 9h, 10a, 10g, 10i, and 10j) exhibited significant inhibition toward hCA IX (Kis = 27.0, 41.1, 27.4, 25.9, 40.7, and 30.8 nM) relative to AAZ and SLC-0111 (Kis = 25.0 and 45.0 nM, respectively). These findings underscore the potential of these derivatives as potent and selective inhibitors of hCA IX and XII over the off-target hCA I and II.
摘要：
以SLC-0111为先导分子，设计并合成了两个新型系列的基于肼基苯磺酰胺9a-j和10a-j。评估了新合成的化合物对四种不同的人碳酸酐酶（hCA）亚型I的抑制活性，II,IX,和XII。此处报道的两个系列实际上都对脱靶同工酶hCAI无活性。值得注意的是，衍生物10a对胞质同工型hCAII表现出比乙酰唑胺（AAZ）更高的效力（Ki为10.2nM）。在20.5-176.6nM和6.0-127.5nM的低纳摩尔范围内，Kis有效抑制了与肿瘤进展有关的hCAIX和XII亚型。分别。化合物9g是最有效和选择性的hCAIX和XII抑制剂，Ki为20.5nM，SI为200.1，Ki为6.0nM，SI为683.7。超过hCAI。此外，六个化合物(9a,9h,10a,10g,10i,和10j）相对于AAZ和SLC-0111（Kis=25.0和45.0nM，对hCAIX（Kis=27.0、41.1、27.4、25.9、40.7和30.8nM）表现出明显的抑制作用，分别)。这些发现强调了这些衍生物作为hCAIX和XII相对于脱靶hCAI和II的有效和选择性抑制剂的潜力。
