European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2022-06-09 , DOI: 10.1016/j.ejmech.2022.114525 Usman Ghani 1
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 hyperpigmentation, 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.
中文翻译:
蘑菇和人类酪氨酸酶的唑类抑制剂:黑色素性皮肤病药物开发的当前进展和前景
唑类是一种著名且有前途的药物,可用于治疗一系列疾病,尤其是真菌感染。还已知多种唑类衍生物表现出酪氨酸酶抑制作用,其中一些具有很有前景的活性,具有治疗皮肤病的潜力,例如炎症后色素沉着过度、痣、斑点、黄褐斑和黑色素瘤。最近,噻唑基间苯二酚衍生物已显示出有效的人类酪氨酸酶抑制作用,具有安全有效的治疗人类皮肤色素沉着过度的治疗特征,目前正在进行临床试验。如果获得批准,这些衍生物将是第一个用于治疗皮肤色素沉着过度的唑类药物。尽管迄今为止,科学文献一直在见证对酪氨酸酶抑制剂的一般评论,没有一个具体全面的讨论唑类酪氨酸酶抑制剂。鉴于唑类的这种潜力,这篇重点综述强调了它们的广泛衍生物,它们具有良好的蘑菇和人类酪氨酸酶抑制活性以及治疗黑色素性皮肤病的临床潜力。目前,这些疾病已经用曲酸、对苯二酚和其他药物进行治疗,这些药物的设计和开发是基于它们抑制蘑菇酪氨酸酶的能力。蘑菇和人类酪氨酸酶的活性位点具有影响底物或抑制剂结合的结构差异。出于这个原因,曲酸和其他药物由于最初是使用蘑菇酪氨酸酶开发的,并已在临床上用于人体酪氨酸酶,因此存在疗效和安全性问题。酪氨酸酶抑制剂的设计和开发应以人类酪氨酸酶为基础,但在获取人类酶并了解其结构和功能方面存在挑战。该综述讨论了这些挑战,包括蘑菇和人类酪氨酸酶之间的结构和功能差异以及它们被抑制的方式。该评价还通过分析和比较它们对蘑菇和人类酪氨酸酶的酪氨酸酶抑制活性、计算数据和可用的临床概况,评估了具有开发皮肤色素沉着过度药物潜力的有前景的唑类衍生物。它旨在为开发用于治疗皮肤色素沉着过度、黑色素瘤和相关皮肤病的新型唑类药物奠定基础。