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 IC₅₀ 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.

Keywords::

• Ebselen
• benzisoselenazol-3(2H)-ones
• antifungal activity
• Saccharomyces cerevisiae
• Pma1p

Acknowledgments

Contributors: Author Billack designed all of the studies presented in this manuscript. Authors Billack, Santoro and Lau-Cam carried out the literature searches and summaries of previous work. Authors Billack, Santoro, and Nicholson carried out all experiments, collected the data, and performed statistical analyses of the collected data. Authors Piętka-Ottlik and Młochowski synthesized compound 2. Authors Billack and Santoro wrote the first draft of the manuscript, and authors Lau-Cam, Młochowski, and Piętka-Ottlik contributed to correcting, revising, and rewriting the manuscript. Authors Santoro and Billack prepared the graphs and figures. All authors contributed to and have approved the final manuscript.

Decleration of interest: This work was funded by the Department of Pharmaceutical Sciences (St. John’s University).