University of Florence, Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia.
Bioorg Chem. 2019 May;86:183-186. doi: 10.1016/j.bioorg.2019.01.065. Epub 2019 Jan 29.
A series of 1,2,3-triazole-bearing benzenesulfonamides was assessed for the inhibition of carbonic anhydrases (CA, EC 4.2.1.1) from bacteria Vibrio cholerae (VchCAα and VchCAβ) and Mycobacterium tuberculosis (β-mtCA3). Growing resistance phenomena against existing antimicrobial drugs are globally spreading and highlight a urgent need of agents endowed with alternative mechanisms of action. Two global WHO strategies aim to reduce cholera deaths by 90% and eradicate the tuberculosis epidemic by 2030. The derivatives here reported represent interesting leads towards the optimization of new antibiotic agents showing excellent inhibitory efficiency and selectivity for the target CAs over the human (h) off-target isoform hCA I. In detail, the first subset of derivatives potently inhibits VchCAα in a low nanomolar range (Ks between 0.72 and 22.6 nM). Compounds of a second subset, differing from the first one for the position of the spacer between benzenesulfonamide and triazole, preferentially inhibit VchCAβ (Ks in the range 54.8-102.4 nM) and β-mtCA3 (Ks in the range 28.2-192.5 nM) even more than the clinically used AAZ, used as the standard.
一系列含有 1,2,3-三唑的苯磺酰胺类化合物被评估为抑制来自霍乱弧菌（VchCAα 和 VchCAβ）和结核分枝杆菌（β-mtCA3）的碳酸酐酶（CA，EC 4.2.1.1）。针对现有抗菌药物的耐药现象正在全球范围内蔓延，这凸显出急需具有替代作用机制的药物。世界卫生组织（WHO）有两项全球战略，旨在将霍乱死亡人数减少 90%，并在 2030 年前消除结核病流行。这里报道的衍生物是优化新抗生素药物的有前途的先导化合物，对目标 CA 具有优异的抑制效率和选择性，而对人源（h）非靶标 hCA I 的抑制作用较低。具体来说，第一组衍生物以低纳摩尔范围（Ks 为 0.72-22.6 nM）强力抑制 VchCAα。第二组化合物与第一组化合物的区别在于苯磺酰胺和三唑之间的间隔位置，它们优先抑制 VchCAβ（Ks 范围为 54.8-102.4 nM）和β-mtCA3（Ks 范围为 28.2-192.5 nM），甚至比作为标准的临床使用的 AAZ 更有效。
