Antimelanogenic Activity of Novel 2-thiohydantion Derivatives

Abstract

The main purpose of this study was to synthesize novel bioactive molecules based on the 2-thiohydantoin moiety and address their antimelanogenic potency and potential for therapeutic application in the treatment of skin hyperpigmentation disorders in humans (freckles, chloasma, melasma, senile lentigines, ephelides and melanoderma). A series of 2-thiohydantoin derivatives has been tested in the zebrafish model, a powerful and highly predictive biotechnological animal platform used for toxicity assessment and biological activity evaluation of novel bioactive molecules, simplifying thus the path to clinical trials and reducing the failure at later stages of testing. The zebrafish embryos were exposed to six different concentrations of newly synthesized 2-thiohydantoins at developmental stage of 6 hpf (hours post fertilization), and analysed for toxicity (survival, cardiotoxicity, hepatotoxicity and teratogeniciy) and antimelanogenic activity by 120 hpf. Their antimelanogenic activity and toxicty were compared to those of Kojic acid and hydroquinone, well-known depigmenting agents used for the treatment of skin hyperpigmentation disorders. Out of 11 tested 2-thiohydantoin derivatives, 9 compounds reduced body pigmentation of the tretaed zebrafish embryos with different efficacy. Among them, three derivatives exhibited the best melanogenesis inhibitory activity, decreasing the body pigmentation at a dose of 5 μM, while did not cause any adverse effect at the 10-fold higher dose. Moreover, each of these compounds exerted much better therapeutic profile than Kojic acid and hydroquinone, the former of which was non-toxic and poorly effective and the latter highly effective but extremely toxic. These data indicated that 2-thiohydantoins present novel effective and safe depigmenting agents with a potential application for the treatment of skin hyperpigmentation disorders in humans. The presented results of biological activity evaluation in vivo clearly demonstrate that compounds with 2-thiohydantoin moiety could present a novel effective and safe antimelanogenic compounds with a large potential for further clinical evaluation and therapeutic application in humans.