4‐Sulfamoylphenylalkylamides as Inhibitors of Carbonic Anhydrases Expressed in Vibrio cholerae

Abstract

A current issue of antimicrobial therapy is the resistance to treatment with worldwide consequences. Thus, the identification of innovative targets is an intriguing challenge in the drug and development process aimed at newer antimicrobial agents. The state-of-art of anticholera therapy might comprise the reduction of the expression of cholera toxin, which could be reached through the inhibition of carbonic anhydrases expressed in Vibrio cholerae (VchCAα, VchCAβ, and VchCAγ). Therefore, we focused our interest on the exploitation of sulfonamides as VchCA inhibitors. We planned to design and synthesize new benzenesulfonamides based on our knowledge of the VchCA catalytic site. The synthesized compounds were tested thus collecting useful SAR information. From our investigation, we identified new potent VchCA inhibitors, some of them displayed high affinity toward VchCAγ class, for which few inhibitors are currently reported in literature. The best interesting VchCAγ inhibitor (S)-N-(1-oxo-1-((4-sulfamoylbenzyl) amino)propan-2-yl)furan-2-carboxamide (40) resulted more active and selective inhibitor when compared with acetazolamide (AAZ) as well as previously reported VchCA inhibitors.

Synthesis and biological evaluation of sulfonamide‐based compounds as inhibitors of carbonic anhydrase from Vibrio cholerae

“…[9,14,15] The abovementioned binding mode has been demonstrated by several co-crystal adducts of sulfonamides in complex with α-classes [16][17][18][19][20] ; moreover, docking simulations suggested the network of interactions for sulfonamides with VchCAα, VchCAβ, and VchCAγ. [21][22][23] Several benzoxaboroles [24] (e.g., compound 3, Figure 1) also proved to be potent inhibitors against VchCAγ over VchCAα, VchCAβ, and hCA I/II isozymes (3). Finally, dithiocarbamates, coumarins, and carboxylic acids inhibited bacterial CAs through a distinct mode of interaction.…”

Screening Campaign and Docking Investigations in Identifying New Hit Compounds as Inhibitors of Human Carbonic Anhydrases Expressed In Tumour Cells

“…These compounds belong to a series of molecules that we have already tested toward different druggable CA isoforms in our previous papers. [15,16] Assessment of CA Inhibitory assay toward hCA I, hCA II, hCA IX, and hCA XII isoforms Compounds 1-31 were in vitro tested using a stopped-flow carbon dioxide hydrase assay. Table 1 collects their K i values against hCA IX and hCA XII, in comparison with ubiquitous hCA I and hCA II and with well-known CA Inhibitors compounds acetazolamide (AAZ) and SLC-0111 that were previously tested in the same experimental conditions.…”

“…In details, all tested compounds possess the arylsulfonamide anchoring moiety linked with various hydrophobic rings or polar moieties; the linking group possesses various length and polarity on the basis of the number of hydrogen bond donor and acceptor functionalities. These compounds belong to a series of molecules that we have already tested toward different druggable CA isoforms in our previous papers [15,16] …”

“…For several selected and un‐characterized compounds retrieved from Specs database, the 1 H‐NMR data were collected and are reported in Supporting Information (Figures S1–S20). The compounds 29 – 31 were reported in our previous paper in which the synthetic route and structural characterization were carefully described [16] …”

“…The compounds 29-31 were reported in our previous paper in which the synthetic route and structural characterization were carefully described. [16]…”