Azole inhibitors of mushroom and human tyrosinases: Current advances and prospects of drug development for melanogenic dermatological disorders

Azoles are a famous and promising class of drugs for treatment of a range of ailments especially fungal infections. A wide variety of azole derivatives are also known to exhibit tyrosinase inhibition, some of which possess promising activity with potential for treatment of dermatological disorders such as post-inflammatory hy-perpigmentation, nevus, flecks, melasma, and melanoma. Recently, thiazolyl-resorcinol derivatives have demonstrated potent human tyrosinase inhibition with a safe and effective therapeutic profile for treatment of skin hyperpigmentation in humans, which are currently under clinical trials. If approved these derivatives would be the first azole drugs to be used for treatment of skin hyperpigmentation. Although the scientific literature has been witnessing general reviews on tyrosinase inhibitors to date, there is none that specifically and comprehensively discusses azole inhibitors of tyrosinase. Appreciating such potential of azoles, this focused review highlights a wide range of their derivatives with promising mushroom and human tyrosinase inhibitory activities and clinical potential for treatment of melanogenic dermatological disorders. Presently, these disorders have been treated with kojic acid, hydroquinone and other drugs, the design and development of which are based on their ability to inhibit mushroom tyrosinase. The active sites of mushroom and human tyrosinases carry structural differences which affect substrate or inhibitor binding. For this reason, kojic acid and other drugs pose efficacy and safety issues since they were originally developed using mushroom tyrosinase and have been clinically used on human tyrosinase. Design and development of tyrosinase inhibitors should be based on human tyrosinase, however, there are challenges in obtaining the human enzyme and understanding its structure and function. The review discusses these challenges that encompass structural and functional differences between mushroom and human tyrosinases and the manner in which they are inhibited. The review also gauges promising azole derivatives with potential for development of drugs against skin hyperpigmentation by analyzing and comparing their tyrosinase inhibitory activities against mushroom and human tyrosinases, computational data, and clinical profile where available. It aims to lay groundwork for development of new azole drugs for treatment of skin hyperpigmentation, melanoma, and related dermatological disorders.