Fibrate-based N-acylsulphonamides targeting carbonic anhydrases: synthesis, biochemical evaluation, and docking studies

Journal of Enzyme Inhibition and Medicinal Chemistry

Atilla Akdemir¹  Barbara De Filippis²  Rosa Amoroso²  Simone Carradori²  Cristina Maccallini²  Letizia Giampietro²  Alessandra Ammazzalorso²  Marialuigia Fantacuzzi²  Andrea Angeli³  Claudiu T. Supuran⁴ 

[1]Department of Pharmacology, Faculty of Pharmacy, Computer-Aided Drug Discovery Laboratory, Bezmialem Vakif University, Istanbul, Turkey

[2]Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy

[3]Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Florence, Italy

[4]Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Florence, Italy

[5]Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences, Università degli Studi di Firenze, Florence, Ital

关键词: N-acylsulphonamides;    carbonic anhydrase;    PPAR antagonist;    fibrate derivatives;    benzothiazole;    benzophenone;   

DOI  :  10.1080/14756366.2019.1611801

来源: publisher

【 摘 要 】

A large library of fibrate-based N-acylsulphonamides was designed, synthesised, and fully characterised in order to propose them as zinc binders for the inhibition of human carbonic anhydrase (hCA) enzymatic activity. Synthesised compounds were tested against four hCAs (I, II, IX, and XII) revealing a promising submicromolar inhibitory activity characterised by an isozyme selectivity pattern. Structural modifications explored within this scaffold are: presence of an aryl ring on the sulphonamide, p-substitution of this aryl ring, benzothiazole or benzophenone as core nuclei, and an n-propyl chain or a geminal dimethyl at Cα carbon. Biological results fitted well with molecular modelling analyses, revealing a putative direct interaction with the zinc ion in the active site of hCA I, II and IX. These findings supported the exploration of less investigated secondary sulphonamides as potential hCA inhibitors.

【 授权许可】

CC BY