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Melanin, the main component of skin color, is synthesized in the melanosomes of melanocytes through a physiological process called melanogenesis and then transferred to neighboring keratinocytes. Melanin absorbs high-energy UV radiation and transforms it into the thermal energy. In this way, melanin plays a protective role against UV-induced DNA damage. However, abnormal skin pigmentation is a major dermatological concern. Abnormal production of melanin causes hypopigmentation or hyperpigmentation such as vitiligo, melasma, age spot, and freckle. In addition, it has been reported that alteration in melanin production is observed in melanoma and Parkinson’s disease. Although key factors including melanocortin 1 receptor (MC1R), Microphthalmia associated transcription factor (MITF) and tyrosinase have been found, the molecular mechanism of melanogenesis is not yet fully understood. Potent chemical regulators for melanogenesis could be a useful tool to elucidate the complex mechanisms. In particular, the regulation of dyschromias is of growing interest, and further options for the treatment of hyperpigmentation are in great demand across Asia. Such a demand has led to the discovery of a variety of natural or synthetic chemicals to regulate melanin biosynthesis (Figure 1). Most of the reported melanogenesis inhibitors decrease tyrosinase activity, and a few small molecules such as arbutin and kojic acid are available on the market as skin lightening agents. However, arbutin has shown insufficient activity and kojic acid has toxicity issue. We have reported cyclohepta[d]isoxazole derivatives as novel melanogenesis inhibitors that decrease the expression of tyrosinase. Investigation of the Structure-activity relationship (SAR) has been explored through modification of regions B and C, which led to the identification of potent melanogensis inhibitors in our previous study (Figure 1). In order to explore and further extend the SAR of this series of melanogenesis inhibitors, a variety of the ring contracted derivatives were synthesized. Herein, we describe the synthesis and melanogenesis activity of 4,5,6,7-tetrahydrobenzo[d]isoxazole derivatives. Compounds 4a-j were synthesized by amide coupling of arylpiperazines with 4,5,6,7-tetrahydrobenzo[d]isoxazole-3carboxylic acid chloride in the presence of triethylamine in dry THF. The acid chlorides 3a-b were obtained by reaction of commercially available 4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxylic acid with oxalyl chloride and a catalytic amount of DMF in dichloromethane (Scheme 1). O-alkylation of 4f with iodoethane gave compound 5 (Scheme 2). Melanogenesis activity of melanin synthesis inhibition is shown in Table 1. The para-methoxy derivative 4b exhibited slightly greater potency than the phenol 4a. However, cytotoxicity was observed at 10 M. A shift of the methoxy group on the aryl group from the para to ortho position (4c) greatly reduced activity. The introduction of trifluoromethyl at para position (4d) resulted in almost complete loss of potency at even 10 μM. The para-fluoro substituent (4j) did not improve activity. Next, we synthesized compounds removing tert-butyl group in region A. Phenol 4f retained activity at 1 μM but showed cytotoxicity at 10 μM. Figure 1. Representative melanin biosynthesis inhibitors and a validated hit compound (MMS1001) as a down-regulator of tyrosinase expression. Scheme 1. (a) oxalyl chloride, DMF (cat.), CH2Cl2, rt, 2 h; (b) arylpiperazines, Et3N, THF, rt, 1 h, 60-79% for 2 steps.

Synthesis and Bioevaluation of 4,5,6,7-Tetrahydrobenzo[d]isoxazole Derivatives as Melanogenesis Inhibitors