Abstract

A small library of substituted cyclic guanidine incorporated benzothiazole-6-sulphonamides was synthesized. All obtained compounds were investigated for their inhibitory activity against the key brain-associated human carbonic anhydrase isoform hCA VII (a promising target for the treatment of neuropathic pain) and three isoforms expressed in brain and other tissues, hCA I, II, and IV. Sulphaguanidine derivatives 9a–d were inactive on the all investigated isoforms while the primary sulphonamide containing guanidines 6a–c and 7a–c were inactive towards hCA IV but displayed inhibiting properties on hCA I, II, and VII with K_Is values in the low nanomolar to micromolar ranges. The results indicated that isoforms hCA II and VII were potently and selectively inhibited by these compounds, whereas the cytosolic hCA I was less sensitive to inhibition. The derivatives reported in this study might be useful for design of more potent and selective inhibitors of hCA II and VII.

摘要

合成了一个小的取代环胍并入苯并噻唑-6-磺酰胺库。研究了所有获得的化合物对与大脑相关的关键人碳酸酐酶异构体 hCA VII（治疗神经性疼痛的一个有希望的靶标）以及在大脑和其他组织中表达的三种异构体 hCA I、II 和 IV 的抑制活性。磺胺胍衍生物9a–d对所有研究的亚型均无活性，而含有胍6a–c和7a–c 的伯磺酰胺对 hCA IV 没有活性，但对 hCA I、II 和 VII 表现出抑制特性，K _Is值处于低纳摩尔浓度至微摩尔范围。结果表明，同种型 hCA II 和 VII 被这些化合物有效且选择性地抑制，而胞质 hCA I 对抑制不太敏感。本研究中报道的衍生物可能有助于设计更有效和更具选择性的 hCA II 和 VII 抑制剂。