Benzylaminoethyureido-Tailed Benzenesulfonamides: Design, Synthesis, Kinetic and X-ray Investigations on Human Carbonic Anhydrases

Abstract

A drug design strategy of carbonic anhydrase inhibitors (CAIs) belonging to sulfonamides incorporating ureidoethylaminobenzyl tails is presented. A variety of substitution patterns on the ring and the tails, located on paraor metapositions with respect to the sulfonamide warheads were incorporated in the new compounds. Inhibition of human carbonic anhydrases (hCA) isoforms I, II, IX and XII, involving various pathologies, was assessed with the new compounds. Selective inhibitory profile towards hCA II was observed, the most active compounds being low nM inhibitors (K I s of 2.8-9.2 nM, respectively). Extensive X-ray crystallographic analysis of several sulfonamides in an adduct with hCA I allowed an in-depth understanding of their binding mode and to lay a detailed structure-activity relationship.

Benzylaminoethylureido‐Tailed Benzenesulfonamides Show Potent Inhibitory Activity against Bacterial Carbonic Anhydrases

“…Compounds 1-20 were synthesized according to our previous reported procedures. [15] Briefly, the commercially available sulfanilamide (SA) and metanilamide (MA) were reacted with phenylchloroformate under mild conditions. The isolated phenylcarbamates (A, B) were subjected to addition with mono-N-Boc-ethylene diamine to afford the Boc-aminoethylureidobenzene sulfonamide C and D. Removal of the N-Boc protection (E, F) exposed the primary terminal amine, which was reacted according to a standard reductive amination protocol with a series of commercially available benzaldehydes to afford the final compounds 1-20 as outlined in Scheme 1.…”

“…The isolated phenylcarbamates (A, B) were subjected to addition with mono-N-Boc-ethylene diamine to afford the Boc-aminoethylureidobenzene sulfonamide C and D. Removal of the N-Boc protection (E, F) exposed the primary terminal amine, which was reacted according to a standard reductive amination protocol with a series of commercially available benzaldehydes to afford the final compounds 1-20 as outlined in Scheme 1. [15] The potential inhibitory activity of the compounds 1-20 against the α-, β-, γ-CA from V. cholerae, and β-, γ-CA from B. pseudomallei was explored using the stopped-flow CO 2 hydrase assay. [16] The inhibition values (K i ) obtained were referred to the standard sulfonamide drug Acetazolamide (AAZ) and are all reported in Table 1.…”

Identification of Novel and Potent Indole-Based Benzenesulfonamides as Selective Human Carbonic Anhydrase II Inhibitors: Design, Synthesis, In Vitro, and In Silico Studies

“…hCA I (PDB code: 6Y00, resolution 1.37 Å) [ 35 ], hCA II (PDB code: 4BF1, resolution 1.35 Å) and hCA IX (PDB code: 4ZWX, resolution 1.70 Å) [ 36 ] crystal structures were retrieved from the Protein Data Bank ( , accessed on 19 February 2022). The downloaded crystal structures were prepared employing the preparation wizard of the Schrodinger 2021 suite package under the default settings with the pH value set at a value of 7.4.…”

Synthesis, Molecular Docking Analysis and Biological Evaluations of Saccharide-Modified Thiadiazole Sulfonamide Derivatives

“…h CAs are a class of zinc metalloenzymes with 15 subtypes. In the human body, their main physiological roles are as catalysts for the reversible interconversion of carbon dioxide and bicarbonate [ 5 , 6 , 7 ]. CA IX is a special isoform of the h CAs family.…”