title: Evaluation of the antifungal and plasma membrane H+-ATPase inhibitory action of ebselen and two ebselen analogs in S. cerevisiae cultures.
abstract: The plasma membrane H(+)-ATPase pump (Pma1p) has been proposed as a viable target for antifungal drugs since this high capacity proton pump plays a critical role in the intracellular regulation of pH and in nutrient uptake of yeast and other fungi. In recent years, this and other laboratories have verified that the antifungal activity of 2-phenylbenzisoselenazol-3(2H)-one, an organoselenium compound commonly referred to as ebselen (1), stems, at least in part, from its inhibitory action on the fungal Pma1p. In the present study, the antifungal efficacy of 2-(3-pyridinyl)-benzisoselenazol-3(2H)-one (2) and 2-phenylbenzisoselenazol-3(2H)-one 1-oxide (3), two ebselen analogs, was evaluated using a strain of S. cerevisiae and compared against that of 1. In addition, the study also examined the inhibitory potential of these three compounds toward the Pma1p of S. cerevisiae. Based on mean IC(50) values, the antifungal potency was found to decrease in the order 3 > 1 > 2. However, in terms of inhibitory action on Pma1p, the potency decreased in the order 1 > 3 > 2. The magnitude of these activities appears to be correlated with the corresponding log P values, with compound 2 being the most hydrophilic and the least active of the three.
authors.affiliation: St. John's University, Jamaica, NY, USA. billackb@stjohns.edu
authors.forename: Blase
authors.initials: B
authors.lastname: Billack
authors.forename: Magdalena
authors.initials: M
authors.lastname: Pietka-Ottlik
authors.forename: Michelle
authors.initials: M
authors.lastname: Santoro
authors.forename: Stacia
authors.initials: S
authors.lastname: Nicholson
authors.forename: Jacek
authors.initials: J
authors.lastname: Młochowski
authors.forename: Cesar
authors.initials: C
authors.lastname: Lau-Cam
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000737:chemistry* / Q000494:pharmacology*; D054833:Isoindoles; D016566:Organoselenium Compounds / Q000737:chemistry* / Q000494:pharmacology*; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; D029701:Saccharomyces cerevisiae Proteins; C042986:ebselen; C092477:PMA1 protein, S cerevisiae; D006180:Proton-Translocating ATPases