ABSTRACT
A series of urea/thiourea substituted benzoxaboroles was investigated for the inhibition of the three carbonic anhydrases encoded by Vibrio cholerae (VchCAα, VchCAß, and VchCAγ). In particular, benzoxaborole derivatives were here first assayed for the inhibition of a γ-class CA, extending the panel of CA classes that benzoxaboroles efficiently target beyond α and ß. Inhibition profiles demonstrated that VchCAα was significantly more inhibited compared to VchCAγ and, in turn, more efficiently modulated than VchCAß. Among the many selective benzoxaborole ligands detected against VchCAα over the off-target hCA II, compound 18, a p-NO2-phenylthiourea derivative, even exhibited a fully selective inhibition profile against the three VchCAs over hCA II. A comprehensive ligand/target interaction study was performed in silico for all three VchCA isoforms providing the first molecular modeling investigation with inhibitors of a γ-class CA to the best of our knowledge. The present study reinforces the rationale behind the use of benzoxaboroles as innovative antibacterial agents with a new mechanism of action, furnishing suggestions for the rational design of new potent and selective inhibitors targeting V. cholerae CAs over human off-target ones.
ABSTRACT
Recent studies identified the benzoxaborole moiety as a new zinc-binding group able to interact with carbonic anhydrase (CA) active site. Here, we report a structural analysis of benzoxaboroles containing urea/thiourea groups, showing that these molecules are very versatile since they can bind the enzyme assuming different binding conformations and coordination geometries of the catalytic zinc ion. In addition, theoretical calculations of binding free energy were performed highlighting the key role of specific residues for protein-inhibitor recognition. Overall, these data are very useful for the development of new inhibitors with higher selectivity and efficacy for various CAs.
Subject(s)
Boron Compounds/pharmacology , Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/metabolism , Boron Compounds/chemical synthesis , Boron Compounds/chemistry , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Conformation , Structure-Activity RelationshipABSTRACT
A series of 6-substituted ureido- and thioureido-benzoxaboroles were investigated as inhibitors of carbonic anhydrases from Trypanosoma cruzi (TcCA), and Leishmania donovani chagasi (LdcCA). Both enzymes were inhibited by benzoxaboroles in the micromolar range. Preferential inhibitory potency against the ß-CA LdcCA versus the α-CA TcCA was observed with submicromolar inhibitory activities. Some derivatives displayed excellent inhibitory and selectivity profile over the ubiquitous and physiological relevant human off-target hCA II. This study provides a convincing opportunity to study benzoxaborole scaffold for the design of antiprotozoan potential drugs targeting the pathogen's carbonic anhydrases.
Subject(s)
Antiprotozoal Agents/pharmacology , Boron Compounds/pharmacology , Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/metabolism , Heterocyclic Compounds, 2-Ring/pharmacology , Leishmania donovani/drug effects , Trypanosoma cruzi/drug effects , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Boron Compounds/chemical synthesis , Boron Compounds/chemistry , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Dose-Response Relationship, Drug , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemistry , Leishmania donovani/enzymology , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Trypanosoma cruzi/enzymologyABSTRACT
A series of 6-substituted benzoxaboroles were investigated as inhibitors of the ß-class carbonic anhydrase from three pathogenic fungi (Cryptococcus neoformans, Candida glabrata, and Malassezia globosa). Independently from the nature of the substituents on the phenyl of the urea/thiourea group, all reported derivatives showed nanomolar inhibitory activities against Can2 and CgNce103 vs micromolar inhibition against MgCA. Selectivity over human CA I and CA II was noticed. The observed structure-activity relationship trends have been rationalized by modeling study of selected compounds into the active site of Can2 and MgCA. The present letter demonstrates that benzoxaborole chemotype may offer interesting opportunities for the inhibition of ß-CA from pathogenic fungi and for the development of antifungal agents with a new mechanism of action.
ABSTRACT
We report the synthesis, biological evaluation, and structural study of a series of substituted heteroaryl-pyrazole carboxylic acid derivatives. These compounds have been developed as inhibitors of specific isoforms of carbonic anhydrase (CA), with potential as prototypes of a new class of chemotherapeutics. Both X-ray crystallography and computational modeling provide insights into the CA inhibition mechanism. Results indicate that this chemotype produces an indirect interference with the zinc ion, thus behaving differently from other related nonclassical inhibitors. Among the tested compounds, 2c with Ki = 0.21 µM toward hCA XII demonstrated significant antiproliferative activity against hypoxic tumor cell lines. Taken together, the results thus provide the basis of structural determinants for the development of novel anticancer agents.
ABSTRACT
In this paper we report the synthesis of a series of benzoxaborole derivatives, their inhibition properties against some carbonic anhydrases (CAs), recognized as important drug targets, and the characterization of the binding mode of these molecules to the CA active site. Our data provide the first experimental evidence that benzoxaboroles can be efficiently used as CA inhibitors.
Subject(s)
Carbonic Anhydrase Inhibitors/metabolism , Carbonic Anhydrases/metabolism , Binding Sites , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrases/chemistry , Catalytic Domain , Crystallography, X-Ray , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Molecular Dynamics Simulation , Protein Binding , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/metabolismABSTRACT
A one-pot synthesis of amides from aldheydes with N-chloroamines, prepared in situ from amines, has been developed. Both aliphatic and aromatic aldehydes and many types of mono- and disubstituted amines are tolerant in this transformation. This cross-coupling reaction appears simple and convenient, has a wide substrate scope and makes use of cheap, abundant, and easily available reagents.
Subject(s)
Aldehydes/chemistry , Amides/chemical synthesis , Amines/chemistry , Carbon/chemistry , Free Radicals/chemistry , Hydrogen/chemistry , Molecular Structure , Oxidation-ReductionABSTRACT
A one-pot two-step microwave assisted synthesis of variously disubstituted 1,2,4-oxadiazoles from carboxylic acids and amidoximes is reported. This methodology is characterized by short reaction times, is versatile, robust and high-yielding and allows for the preparation of heterocycles with a stereocenter with 100% enantiomeric purity.