RESUMEN
We synthesized a family of 3,5-dichloropyrazin-2(1H)-one derivatives and assessed their in vitro fungicidal activity against Candida albicans. Compounds 11 and 20 were most active against C. albicans and induced accumulation of reactive oxygen species in this pathogen. Using a genome-wide approach in the yeast Saccharomyces cerevisiae, we demonstrated that genes involved in vacuolar functionality and DNA-related functions play an important role in cellular mechanisms underlying the fungicidal activity of these compounds.
Asunto(s)
Antifúngicos/farmacología , Pirazinas/química , Pirazinas/farmacología , Candida albicans/metabolismo , ADN/química , Farmacorresistencia Fúngica/efectos de los fármacos , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Eliminación de Gen , Genoma Fúngico , Pruebas de Sensibilidad Microbiana , Modelos Químicos , Mutación , Pirazinas/síntesis química , Saccharomyces cerevisiae/metabolismo , Vacuolas/químicaRESUMEN
A series of novel pyrazinones designed as non-nucleoside reverse transcriptase inhibitors (NNRTIs) was synthesized and their anti-HIV structure-activity relationship (SAR) was studied.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Transcriptasa Inversa del VIH/metabolismo , Pirazinas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Diseño de Fármacos , VIH-1/efectos de los fármacos , VIH-1/genética , Modelos Moleculares , Mutación , Pirazinas/química , Pirazinas/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
Ajuga remota is the most frequently used medicinal herb for malaria treatment in Kenya. Its two known isolates ajugarin-1 (1) and ergosterol-5,8-endoperoxide (3) and a new isolate 8-O-acetylharpagide (2) were evaluated for their in vitro antiplasmodial activity. Ajugarin-1 was moderately active, with an IC(50) of 23.0 +/- 3.0 microM, as compared to chloroquine (IC(50) = 0.041 +/- 0.003 microM) against the chloroquine-sensitive (FCA 20/GHA) strain of Plasmodium falciparum. Ergosterol-5,8-endoperoxide was about 3x as potent (IC(50) = 8.2 +/- 1.1 microM), while 8-O-acetylharpagide, whose structure was established by spectroscopic evidence, was inactive. Both ajugarin-1 and ergosterol-5,8-endoperoxide did not exhibit cytotoxicity against A431 (skin carcinoma) cell line, but 8-O-acetylharpagide was significantly cytotoxic. This iridoid glucoside, which has been formerly isolated from Ajuga decumbens, was identified in A. remota for the first time.