Mechanism of Antifungal Triazoles and Related Drugs: Electron Transfer, Reactive Oxygen Species and Oxidative Stress

Abstract

Open Access Review Article Scheme 1. Redox cycling in the presence of oxygen in vivo can lead to Oxidative Stress (OS) from the formation of Reactive Oxygen Species (ROS), such as hydrogen peroxide, hydroperoxides, alkyl peroxides, and diverse radicals (hydroxyl, alkoxyl, hydroperoxyl, and superoxide) shown in Scheme 2. Abstract Aromatic triazoles are known to be effective antifungal agents. The generally accepted mode of action entails inhibition of ergosterol in the membrane. A hypothesis is presented herein based on Electron Transfer (ET), Reactive Oxygen Species (ROS) and Oxidative Stress (OS) which may be a unifying mechanism. Many substances in vivo are known to operate in a multifaceted manner. A prior article provides evidence for involvement of ET-ROS-OS for a variety of antifungal agents. In the present case, the active entity appears to be a highly conjugated imine. For drugs containing alcohol substituents, dehydration would provide the requisite conjugation. A few related aromatic nitrogen heterocycles are also addressed. The unifying mechanism involving ET-ROS-OS, which has received substantial support, is applied to anti-fungul triazoles based on the ET imine-iminium portion, as part of a multifaceted scheme.