RESUMO
Emerging yeasts are among the most prevalent causes of systemic infections with high mortality rates and there is an urgent need to develop specific, effective and non-toxic antifungal agents to respond to this issue. In this study 35 aldehydes, hydrazones and hydrazines were obtained and their antifungal activity was evaluated against Candida species (C. parapsilosis, C. tropicalis, C. krusei, C. albicans, C. glabrata and C. lusitaneae) and Trichosporon asahii, in an in vitro screening. The minimum inhibitory concentrations (MICs) of the active compounds in the screening was determined against 10 clinical isolates of C. parapsilosis and 10 of T. asahii. The compounds 4-pyridin-2-ylbenzaldehyde] (13a) and tert-butyl-(2Z)-2-(3,4,5-trihydroxybenzylidine)hydrazine carboxylate (7b) showed the most promising MIC values in the range of 16-32 µg/mL and 8-16 µg/mL, respectively. The compounds' action on the stability of the cell membrane and cell wall was evaluated, which suggested the action of the compounds on the fungal cell membrane. Cell viability of leukocytes and an alkaline comet assay were performed to evaluate the cytotoxicity. Compound 13a was not cytotoxic at the active concentrations. These results support the discovery of promising candidates for the development of new antifungal agents.
Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Hidrazonas/farmacologia , Trichosporon/efeitos dos fármacos , Antifúngicos/síntese química , Antifúngicos/química , Benzaldeídos/farmacologia , Candida/patogenicidade , Candidíase/tratamento farmacológico , Ácidos Carboxílicos/farmacologia , Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Parede Celular/efeitos dos fármacos , Hidrazinas/farmacologia , Hidrazonas/síntese química , Hidrazonas/química , Leucócitos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Piridinas/farmacologia , Trichosporon/patogenicidade , Tricosporonose/tratamento farmacológicoRESUMO
Dermatomycosis causes highly frequent dermal lesions, and volatile oils have been proven to be promising as antifungal agents. The antifungal activity of geraniol, nerol, citral, neral and geranial (monoterpenes), and terbinafine and anidulafungin (control drugs) against seven opportunistic pathogenic yeasts and four dermatophyte species was evaluated by the Clinical and Laboratory Standards Institute microdilution tests. Monoterpenes were more active against dermatophytes than yeasts (geometric mean of minimal inhibitory concentration (GMIC) of 34.5 and 100.4 µg.ml-1, respectively). Trichophyton rubrum was the fungal species most sensitive to monoterpenes (GMIC of 22.9 µg.ml-1). The trans isomers showed higher antifungal activity than the cis. The mechanism of action was investigated evaluating damage in the fungal cell wall (Sorbitol Protection Assay) and in the cell membrane (Ergosterol Affinity Assay). No changes were observed in the MIC of monoterpenes in the sorbitol protection assay.The MIC of citral and geraniol was increased from 32 to 160 µg.ml-1 when the exogenous ergosterol concentrations was zero and 250 µg.ml-1, respectively. The monoterpenes showed an affinity for ergosterol relating their mechanism of action to cell membrane destabilization.
RESUMO
Trichomonas vaginalis is a flagellated parasite that causes trichomonosis, the most common non-viral sexually transmitted disease (STD) in the world. Worryingly, trichomonosis is associated to increased transmission of HIV. Due to high frequency of the infection during pregnancy and the development of metronidazole-resistant isolates, therapeutic alternatives to 5-nitroimidazole are being searched. Triterpenes are natural products presenting several biological activities such as anti-protozoal activity. The aim of this study was to evaluate the in vitro anti-T. vaginalis activity from betulinic and ursolic acids, as well as semisynthetic derivatives obtained. Compounds obtained from betulinic acid presented better activity than those from ursolic acid. Piperazine derivatived from betulinic acid presented minimum inhibitory concentration (MIC) value of 91.2 µM, and the kinetic growth curve performed with parasites treated with this most active compound revealed complete inhibition of trophozoite proliferation at 2 h of incubation and total abolition of trophozoite growth in 24 h, revealing that the piperazine derivative is an efficient trichomonacidal molecule. The same compound promoted total erythrocyte lysis and lactate dehydrogenase (LDH) liberation of 83 and 100% (at 45.6 and 91.2 µM, respectively), indicating parasite membrane damage. The piperazine derivative demonstrated cytotoxic effect against the HMVII and HeLa cell lineages at the MIC value. This is the first report of semisynthetic triterpenoid derivatives with anti-T. vaginalis activity, revealing the high potential of these compounds as trichomonacidal agents.
Assuntos
Antitricômonas/farmacologia , Trichomonas vaginalis/efeitos dos fármacos , Triterpenos/farmacologia , Resistência a Medicamentos , Eritrócitos/efeitos dos fármacos , Feminino , Células HeLa , Hemólise , Humanos , Masculino , Metronidazol/farmacologia , Testes de Sensibilidade Microbiana , Triterpenos Pentacíclicos , Piperazina , Piperazinas/farmacologia , Trichomonas vaginalis/crescimento & desenvolvimento , Ácido Betulínico , Ácido UrsólicoRESUMO
Dermatomycoses are among the most widespread and common superficial and cutaneous fungal infections in humans. There is an urgent need to develop efficient and non-toxic antimycotic agents with a specific spectrum of activity. Triterpenes have been demonstrated to exhibit a wide range of biological activities, including antifungal activities. In this study, through hemisynthesis, we aimed to obtain triterpene-isosteric molecules from betulinic and ursolic acids to improve the antifungal activity and spectrum of action of these compounds. Six compounds were resynthesized and tested against eleven mucocutaneous and cutaneous mycotic agents. The results of the susceptibility assays were expressed as the minimal inhibitory concentration (MIC). The MIC values of the piperazinyl derivatives of ursolic and betulinic acids that were active against pathogenic yeasts were in the range of 16-32 µg/mL and 4-16 µg/mL, respectively, whereas fungicidal effects were observed at concentrations ranging from 16 to 128 µg/mL and 8 to 128 µg/mL, respectively. The piperazinyl derivative of betulinic acid exhibited an antifungal profile similar to that of terbinafine and was the most effective derivative against dermatophytes. This strategy led to a promising candidate for the development of a new antifungal agent.