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

Abstract

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 Ca 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.

Facile access to 4′-(N-acylsulfonamide) modified nucleosides and evaluation of their inhibitory activity against SARS-CoV-2 RNA cap N7-guanine-methyltransferase nsp14

“…1A). 15,16 Interestingly, several potent antiviral agents carrying an N-acylsulfonamide group and targeting the NS3 or NS3-4A protease of hepatitis C virus have also been described. [17][18][19] Recently, our group reported the synthesis of 5′-N-sulfonamide adenosine derivatives that showed significant inhibition of SARS-CoV-2 (N7-guanine)-methyltransferase (N7-MTase) nsp14 by acting as a competitor of S-adenosyl-L-methionine (SAM), the methyl donor in the N7-cap RNA methylation.…”

“…1A). 15,16 Interestingly, several potent antiviral agents carrying an N -acylsulfonamide group and targeting the NS3 or NS3-4A protease of hepatitis C virus have also been described. 17–19…”

Sulfonamide derivatives with benzothiazole scaffold: Synthesis and carbonic anhydrase I–II inhibition properties

“…Primary sulfonamides are a broad class of specific inhibitors of CA enzymes. 39 Secondary sulfonamides are generally regarded as weak CAIs. However, they have historically been an important class.…”

“…34 Aromatic/heterocyclic sulfonamides, which are of great importance in the pharmaceutical industry, have been extensively used for many years to investigate the pathophysiology and treat diverse diseases such as epilepsy, antibacterial, glaucoma, antibacterial, anticancer, antifungal, anti-obesity, diuretic, antiglaucoma and anticonvulsant. [35][36][37] Furthermore, secondary sulfonamides and their N-substituted forms [38][39] have been identified as potent inhibitors of hCA I and hCA II in most studies, whereas some bis-sulfonamide compounds have been reported to be potent inhibitors against CA II isozyme and less inhibitory against CA I. 40 Recently, molecular hybridization design has emerged as a new approach by combining at least two pharmacophore-specific moieties to modulate multiple disease targets simultaneously, which will be the combined force in providing pharmacological activity and will also increase the capacity to interact with multiple biological targets.…”

“…Aromatic/heterocyclic sulfonamides, which are of great importance in the pharmaceutical industry, have been extensively used for many years to investigate the pathophysiology and treat diverse diseases such as epilepsy, antibacterial, glaucoma, antibacterial, anticancer, antifungal, anti‐obesity, diuretic, antiglaucoma and anticonvulsant 35–37 . Furthermore, secondary sulfonamides and their N‐substituted forms 38–39 have been identified as potent inhibitors of hCA I and hCA II in most studies, whereas some bis‐sulfonamide compounds have been reported to be potent inhibitors against CA II isozyme and less inhibitory against CA I 40 …”