RESUMO
The synthesis, in vitro antifungal evaluation and structure-activity relationship studies of 14 compounds of the N-phenyl-, N-aryl-, N-phenylalkyl- maleimide and 3,4-dichloromaleimide series are reported. The compounds were evaluated against a panel of standardized yeasts and filamentous fungi as well as clinical isolates of Candida albicans. The activities of N-phenylalkyl-3,4-dichloromaleimide derivatives but not those of N-phenylalkyl-maleimide derivatives showed to be dependent on the length of the alkyl chain. N-Phenylpropyl-3,4-dichloromaleimide showed the broadest spectrum of action and lower minimal inhibitory concentrations (MIC) in all of the fungi tested. The nitrogen-carbon distance between the two rings seems to play an important role in the antifungal behavior of these compounds. The most active structure showed inhibited (1,3)beta-D-glucan and chitin synthases, enzymes that catalyze the synthesis of the major fungal cell-wall polymers.
Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Maleimidas/síntese química , Maleimidas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Quitina Sintase/antagonistas & inibidores , Fungos/efeitos dos fármacos , Glucosiltransferases/antagonistas & inibidores , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
The synthesis and antifungal properties of a series of new N-aryl alpha,beta-substituted succinimides against a panel of dermatophytes of clinical relevance are reported. Among those compounds possessing a N-phenyl substituent, 7-thia-2-azabicyclo[2,2,1]hept-2-en-3-amine[5,6-c]succinimide was the better inhibitor of Trichophyton rubrum, the major ethiological agent of all infections produced by dermatophytes. In contrast, succinimides containing a N-(p-sulfonylphenyl) substituent, only inhibited Epidermophyton floccosum, all active compounds possessing an oxabicyclo group in positions alpha,beta of the imide. Substituents on the oxabicyclo group were important for the activity. Regarding the mechanism of action, N-(p-N'-4-methoxyphenylsulfamoylphenyl)-8-oxabicyclo[2,2,1]hept-4-en-3- methyl[5,6-c]succinimide produced a mottled inhibition halo in the Neurospora crassa assay, showing that it would act by inhibiting the synthesis or assembly of the fungal cell wall.
Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Arthrodermataceae/efeitos dos fármacos , Succinimidas/síntese química , Succinimidas/farmacologia , Arthrodermataceae/ultraestrutura , Testes de Sensibilidade Microbiana , Neurospora crassa/efeitos dos fármacos , Neurospora crassa/ultraestruturaRESUMO
This work describes the phytochemical analysis and analgesic activity of a non polar fraction obtained from Adiantum cuneatum grown in Brazil. The results showed that the hexane fraction as well as two pure compounds, identified as filicene (1) and filicenal (2), given intraperitoneally, exhibited potent analgesic activity when evaluated in two models of pain in mice, writhing test and formalin-induced pain. Compound 1 presented a calculated ID50 value of 19.5 micromol/kg body weight, when evaluated in writhing test, being about 7-fold more active than some reference drugs, like as acetyl salicylic acid and acetaminophen. It also inhibited both phases (neurogenic and inflammatory) of the formalin test at 10 mg/kg (24 micromol/kg). The chemical composition of the plant grown in Brazil is similar to that grown in other countries. The results confirm and justify the popular use of this plant for the treatment of dolorous processes.
Assuntos
Adiantum/química , Analgésicos/química , Analgésicos/farmacologia , Plantas Medicinais/química , Adiantum/crescimento & desenvolvimento , Analgésicos/isolamento & purificação , Animais , Brasil , Feminino , Formaldeído , Masculino , Medicina Tradicional , Camundongos , Dor/induzido quimicamente , Dor/tratamento farmacológico , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Folhas de Planta/química , Plantas Medicinais/crescimento & desenvolvimentoRESUMO
This paper describes the synthesis of new cyclic imides obtained by reaction with aminophenazone (CAS 58-15-1, 4-aminoantipyrine) and different anhydrides with further cyclization with acetic acid under reflux. Their structures were confirmed by spectral data (IR and NMR) and elemental analysis. The analgesic activity of the synthesized compounds was investigated initially with the writhing test in mice and the most promising compound, a 3,4-dichloromaleimide derivative (3), was analyzed using other models of nociception. The results indicated that compound 3 exerts potent analgesic activity in mice, being more active than some reference drugs. The analgesia caused by this compound was not reversed by naloxone in the writhing test. In the hotplate test, compound 3 did not increase the latency period of pain induced by thermal stimuli, confirming that it does not interact with opioid systems.