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.

• Klíčová slova
• Bacterial carbonic anhydrases, Drug Discovery, Enzymes Inhibitors, Sulfonamides, Vibrio cholerae,
• MeSH
• benzensulfonamidy MeSH
• inhibitory karboanhydras chemická syntéza   chemie   farmakologie   MeSH
• karboanhydrasy genetika   metabolismus   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• sulfonamidy chemická syntéza   chemie   farmakologie   MeSH
• Vibrio cholerae účinky léků   genetika   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory karboanhydras MeSH
• karboanhydrasy MeSH
• sulfonamidy MeSH

Human carbonic anhydrase IX (CA IX), a protein specifically expressed on the surface of solid tumour cells, represents a validated target both for anticancer therapy and diagnostics. We recently identified sulfonamide dicarbaboranes as promising inhibitors of CA IX with favourable activities both in vitro and in vivo. To explain their selectivity and potency, we performed detailed X-ray structural analysis of their interactions within the active sites of CA IX and CA II. Series of compounds bearing various aliphatic linkers between the dicarbaborane cluster and sulfonamide group were examined. Preferential binding towards the hydrophobic part of the active site cavity was observed. Selectivity towards CA IX lies in the shape complementarity of the dicarbaborane cluster with a specific CA IX hydrophobic patch containing V131 residue. The bulky side chain of F131 residue in CA II alters the shape of the catalytic cavity, disrupting favourable interactions of the spherical dicarbaborane cluster.

• Klíčová slova
• Carbonic anhydrase IX, carborane, enzyme inhibitors, structure-activity relationship,
• MeSH
• antigeny nádorové genetika   MeSH
• HEK293 buňky MeSH
• hydrofobní a hydrofilní interakce MeSH
• inhibitory karboanhydras chemie   farmakologie   MeSH
• karboanhydrasa IX antagonisté a inhibitory   genetika   MeSH
• katalytická doména MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• protinádorové látky chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• sekvence aminokyselin MeSH
• sloučeniny boru chemie   MeSH
• sulfonamidy chemie   farmakologie   MeSH
• vazba proteinů MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny nádorové MeSH
• CA9 protein, human MeSH Prohlížeč
• decaborane MeSH Prohlížeč
• inhibitory karboanhydras MeSH
• karboanhydrasa IX MeSH
• protinádorové látky MeSH
• sloučeniny boru MeSH
• sulfonamidy MeSH

Carborane-based compounds are promising lead structures for development of inhibitors of carbonic anhydrases (CAs). Here, we report structural and computational analysis applicable to structure-based design of carborane compounds with selectivity toward the cancer-specific CAIX isoenzyme. We determined the crystal structure of CAII in complex with 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane at 1.0 Å resolution and used this structure to model the 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane interactions with CAIX. A virtual glycine scan revealed the contributions of individual residues to the energy of binding of 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane to CAII and CAIX, respectively.

• MeSH
• glycin chemie   MeSH
• inhibitory karboanhydras chemie   farmakologie   MeSH
• karboanhydrasy chemie   MeSH
• katalytická doména MeSH
• krystalografie rentgenová MeSH
• kvantová teorie * MeSH
• lidé MeSH
• molekulární modely * MeSH
• sloučeniny boru chemie   farmakologie   MeSH
• substrátová specifita účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dodecaborate MeSH Prohlížeč
• glycin MeSH
• inhibitory karboanhydras MeSH
• karboanhydrasy MeSH
• sloučeniny boru MeSH