ABSTRACT
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.
Subject(s)
Antifungal Agents/pharmacology , Pyrazines/chemistry , Pyrazines/pharmacology , Candida albicans/metabolism , DNA/chemistry , Drug Resistance, Fungal/drug effects , Fungal Proteins/genetics , Fungal Proteins/metabolism , Gene Deletion , Genome, Fungal , Microbial Sensitivity Tests , Models, Chemical , Mutation , Pyrazines/chemical synthesis , Saccharomyces cerevisiae/metabolism , Vacuoles/chemistryABSTRACT
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.
Subject(s)
Anti-HIV Agents/chemical synthesis , HIV Reverse Transcriptase/metabolism , Pyrazines/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Drug Design , HIV-1/drug effects , HIV-1/genetics , Models, Molecular , Mutation , Pyrazines/chemistry , Pyrazines/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
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.
