RESUMO
To search for new cruzain inhibitors, the synthesis of a series of novel 2-(N'-benzylidenehydrazino)-4-trifluoromethyl-pyrimidines in a convergent manner is presented. The cruzain inhibitory activity of some of these compounds was evaluated and a binding model was proposed. All derivatives tested were active and the most significant inhibitory effect (80% at 100 microM) and IC(50) value (85 microM) were obtained from the 2-(N'-4-chloro-benzylidenehydrazino)-4-trifluoromethyl-pyrimidine. Although further structural optimization to improve solubility is necessary, the molecular docking studies suggest that these inhibitors occupy the S2 pocket without irreversible enzyme inactivation, through hydrophobic interactions, thus, indicating a desirable mode of interaction for the design of novel inhibitors.
Assuntos
Inibidores Enzimáticos/síntese química , Hidrazinas/farmacologia , Proteínas de Protozoários/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Tripanossomicidas/síntese química , Cisteína Endopeptidases/química , Cisteína Endopeptidases/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Hidrazinas/síntese química , Hidrazinas/química , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Proteínas de Protozoários/química , Proteínas de Protozoários/farmacologia , Pirimidinas/química , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/farmacologiaRESUMO
The synthesis and characterization of a new series of furan-3-carboxamides, from the aromatization of 4-trichloroacetyl-2,3-dihydrofuran to 3-trichloroacetyl furan followed by nucleophilic displacement of the trichloromethyl group or the corresponding carboxylic acid chloride by nitrogen-containing compounds, is presented. Preliminary in vitro antimicrobial activity of the title compounds was assessed against a panel of microorganisms including yeast, filamentous fungi, bacteria, and alga. Some of the furan-3-carboxamides exhibited significant in vitro antimicrobial activity. QSAR investigation was applied to find a correlation between the different physicochemical parameters of the compounds studied and their biological activity.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Antifúngicos/síntese química , Antifúngicos/farmacologia , Furanos/química , Amidas/química , Antifúngicos/química , Fungos/classificação , Fungos/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
This work presents a three-step synthesis of a new series of 4-substituted 2-oxo-6-trihalomethyl-[1,3]oxazinane-3-carboxylic acid ethyl esters, from beta-alkoxyvinyl trihalomethyl ketones of general formula X3C-C(O)-CH=C(R)-OR(1), where R = H, Me, Ph, and 4-Me-Ph; R(1) = Me and Et; and X = F and Cl. The Michael addition-substitution of the ethyl carbamate on beta-alkoxyvinyl trihalomethyl ketones furnished the corresponding (4,4,4-trihalo-3-oxo-but-1-enyl)-carbamic acid ethyl esters. These compounds underwent reduction with NaBH4 leading to the respective (4,4,4-trihalo-3-hydroxy-butyl)-carbamic acid ethyl esters. The 3-hydroxy-butyl carbamates were submitted to cyclization reaction with triphosgene to give a series of 4-substituted 2-oxo-6-trihalomethyl-[1,3]oxazinane-3-carboxylic acid ethyl esters. The in vitro antimicrobial activity, of some of the three new series of the title compounds, was assessed against a panel of microorganisms including yeast like fungi, bacteria, and algae, and their minimal inhibitory concentration and minimal fungicidal, bactericidal, and algacidal concentrations were determined. Some of the analyzed carbamates exhibited significant in vitro antimicrobial activity.
