Paoletti Niccolò, Giovannuzzi Simone, Bonardi Alessandro, De Luca Viviana, Capasso Clemente, Nocentini Alessio, Gratteri Paola, Supuran Claudiu T
NEUROFARBA Department, Laboratory of Molecular Modelling, Cheminformatics & QSAR, University of Florence, Firenze, Italy.
NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, Firenze, Italy.
Arch Pharm (Weinheim). 2025 Jan;358(1):e2400814. doi: 10.1002/ardp.202400814.
This study investigates aliphatic sulfonamide derivatives as inhibitors of the α-, β-, and γ-class carbonic anhydrase (CA) isoforms from Vibrio cholerae (VchCAs). A series of 26 compounds bearing a triazole linker and urea- or ether-based tails were described and evaluated for their inhibitory action using a stopped-flow CO hydrase technique. These inhibitors demonstrated a preferential efficacy against VchCAβ. Specifically, the ureido derivatives showed the highest inhibitory potency with inhibition constants (Ks) in the submicromolar range (0.67-0.93 µM). Selectivity indices were calculated to assess the selective inhibition of VchCAβ over human CA I and II, as well as other VchCA isozymes. Urea-linked compounds demonstrated a significant 25- to 125-fold selectivity for VchCAβ over hCAs and 14- to 26-fold over other VchCAs. Molecular modeling elucidated the interactions contributing to the efficacy and selectivity of aliphatic sulfonamides as VchCA inhibitors, aligning with and reinforcing the experimental results. The latter suggests that aliphatic sulfonamides could serve as valid targeted therapeutics to treat V. cholerae infections.
本研究考察了脂肪族磺酰胺衍生物作为霍乱弧菌（VchCAs）α、β和γ类碳酸酐酶（CA）同工酶抑制剂的情况。描述了一系列带有三唑连接基以及基于脲或醚的尾部的26种化合物，并使用停流CO水合酶技术评估了它们的抑制作用。这些抑制剂对VchCAβ表现出优先效力。具体而言，脲基衍生物显示出最高的抑制活性，抑制常数（Ks）在亚微摩尔范围内（0.67 - 0.93 μM）。计算了选择性指数，以评估VchCAβ对人CA I和II以及其他VchCA同工酶的选择性抑制。与hCAs相比，脲连接的化合物对VchCAβ表现出显著的25至125倍的选择性，对其他VchCAs表现出14至26倍的选择性。分子建模阐明了有助于脂肪族磺酰胺作为VchCA抑制剂的效力和选择性的相互作用，与实验结果一致并强化了该结果。后者表明脂肪族磺酰胺可用作治疗霍乱弧菌感染的有效靶向治疗药物。
