TY - JOUR

T1 - Series of Trifluoromethylisoxazolyl- and Trifluoromethylpyrazolyl-Substituted (Hetero)aromatic Sulfonamide Carbonic Anhydrase Inhibitors: Synthesis and Convenient Prioritization Workflow for Further In Vivo studies

AU - Сибинчич, Николина

AU - Калинин, Станислав Алексеевич

AU - Шаройко, Владимир Владимирович

AU - Ефимова, Джулия

AU - Гасилина , Ольга

AU - Корсаков, Михаил Константинович

AU - Гуреев, Максим

AU - Красавин, Михаил Юрьевич

PY - 2023/2/1

Y1 - 2023/2/1

N2 - Aims: To synthesize novel sulfonamide inhibitors of carbonic anhydrase and develop in vitro prioritization workflow to select compounds for in vivo evaluation. Background: Carbonic anhydrase (CA) inhibitors gain significant attention in the context of drug discovery research for glaucoma, hypoxic malignancies, and bacterial infections. In previous works, we have successfully used direct sulfochlorination approach to develop diverse heterocyclic primary sulfonamides with remarkable activity and selectivity against therapeutically relevant CA isoforms. Objective: Synthesis and investigation of the CA inhibitory properties of novel trifluoromethylisoxa-zolyl-and trifluoromethylpyrazolyl-substituted (hetero)aromatic sulfonamides. Methods: Thirteen trifluoromethylisoxazolyl-and thirteen trifluoromethylpyrazolyl-substituted (het-ero)aromatic sulfonamides were synthesized by direct sulfochlorination of hydroxyisoxazolines and pyrazoles followed by reaction with ammonia. The compound structures were confirmed by1 H and13 C NMR as well as element analysis. The obtained compounds were evaluated, using the CA esterase activity assay, for their potential to block the catalytic activity of bovine CA (bCA). Results: Eight most potent compounds selected based on the esterase activity assay data were tested for direct affinity to the enzyme using the thermal shift assay (TSA). These compounds displayed Kd values (measured by TSA) in the double-digit nanomolar range, thus showing comparable activity to the reference drug acetazolamide. Conclusion: Coupling the bCA esterase activity assay with thermal shift assay represents a stream-lined and economical strategy for the prioritization of sulfonamide CA inhibitors for subsequent evaluation in vivo.

AB - Aims: To synthesize novel sulfonamide inhibitors of carbonic anhydrase and develop in vitro prioritization workflow to select compounds for in vivo evaluation. Background: Carbonic anhydrase (CA) inhibitors gain significant attention in the context of drug discovery research for glaucoma, hypoxic malignancies, and bacterial infections. In previous works, we have successfully used direct sulfochlorination approach to develop diverse heterocyclic primary sulfonamides with remarkable activity and selectivity against therapeutically relevant CA isoforms. Objective: Synthesis and investigation of the CA inhibitory properties of novel trifluoromethylisoxa-zolyl-and trifluoromethylpyrazolyl-substituted (hetero)aromatic sulfonamides. Methods: Thirteen trifluoromethylisoxazolyl-and thirteen trifluoromethylpyrazolyl-substituted (het-ero)aromatic sulfonamides were synthesized by direct sulfochlorination of hydroxyisoxazolines and pyrazoles followed by reaction with ammonia. The compound structures were confirmed by1 H and13 C NMR as well as element analysis. The obtained compounds were evaluated, using the CA esterase activity assay, for their potential to block the catalytic activity of bovine CA (bCA). Results: Eight most potent compounds selected based on the esterase activity assay data were tested for direct affinity to the enzyme using the thermal shift assay (TSA). These compounds displayed Kd values (measured by TSA) in the double-digit nanomolar range, thus showing comparable activity to the reference drug acetazolamide. Conclusion: Coupling the bCA esterase activity assay with thermal shift assay represents a stream-lined and economical strategy for the prioritization of sulfonamide CA inhibitors for subsequent evaluation in vivo.

UR - https://www.mendeley.com/catalogue/4f1f6f8b-a1db-3e3c-a18c-cb8edb328892/

U2 - 10.2174/1573406418666220831112049

DO - 10.2174/1573406418666220831112049

M3 - Article

VL - 19

SP - 193

EP - 210

JO - Future Medicinal Chemistry

JF - Future Medicinal Chemistry

SN - 1756-8919

IS - 2

ER -