Novel Benzo[d]imidazole-2(3H)-thiones as Potent Inhibitors of the .ALPHA.-Melanocyte Stimulating Hormone Induced Melanogenesis in Melanoma B16 Cells

Abstract

Melanin is a heterogeneous biopolymer which is principally responsible for human phenotypic appearance and has major role in protecting human skin from harmful effect of UV-radiation from the sun.1) Melanin is formed by a series of enzymatic catalyzed reactions in melanocytes.2,3) The biosynthesis of melanin is initiated with oxidation of tyrosine to dopaquinone catalyzed by tyrosinase.4) This first step is the rate limiting step in melanogenesis because the remaining reaction sequence can proceed spontaneously at a physiological pH. 5) However, over expression of tyrosinase lead to induction of hyperpigmentary disorders such as melasma, freckles, age spot, and post-inflammatory melanoderma. 6,7)It is also reported to be linked to Parkinson diseases and some other neurodegerative diseases.8,9) Therefore, the regulation of melanin synthesis by inhibiting the tyrosinase enzyme is the current research topic in context of preventing hyperpigmentation. In this regard, diverse tyrosinase inhibitors have been actively discovered such as kojic acid, 10,11) arbutin, 12) ascorbic acid derivatives, 13) hydroxylstilbine derivatives like resveratol [14][15][16] and methyl ester of genistic acid. 17,18) However, according to a recent study kojic acid has serious adverse effects such as skin cancer and dermatitis and has been banned as a cosmetic ingredient in many countries.17) Thus other type of molecules, which inhibit cyclic adenosine monophosphate (cAMP) dependent melanogenesis proteins other than tyrosinase, are gaining attention. Using bioassay system for measuring the amount of melanin formed from melanoma B16 cells upon stimulation of a-melanocyte stimulating hormone (a-MSH), we have screened many different compounds. As a result, 6-methyl-3-phenethyl-3,4-dihydro-1H-quinoline-2-thione (Fig. 1, IC 50 ϭ0.8 mM) was discovered as highly potent compound against melanogenesis in melanoma B16 cell line.18) The mechanism of action of compound 1 is very much unique and important due to its suppression of the melanogenesis without affecting the tyrosinase activity. The preliminary study on the structure-activity relationship (SAR) of 1 has revealed quinazolidine-2-thione in 1 as an essential motif. 18)In order to explore the necessity of 6-membered cyclic thiourea scaffold in 1, benzo[d]imidazol-2(3H)-ones 4 (Fig. 1) containing 5-membered cyclic thiourea were designed, synthesized and evaluated for their inhibitory activity against melanin production in melanoma B16 cells under the stimulation of a-MSH. ChemistryBenzo [d]imidazol-2(3H)-ones 4 and benzo [d]imidazole-2(3H)-thiones 5 were synthesized with the synthetic procedure as shown in Chart 1. In the first step, commercially available amine 6 was treated with appropriate alkyl bromide using pyridine or sodium hydroxide to give an intermediate 7. 18,19) In case of benzylated amines 7, the reduction reaction In order to determine the optimum size of heterocycle of lead compound 1 (6-methyl-3-phenethyl-3,4-dihydro-1H-quinoline-2-thione; IC 50 ‫8.0؍‬ mM) for inhibition of mela...

Ensemble-Based Virtual Screening Led to the Discovery of New Classes of Potent Tyrosinase Inhibitors

“…The sulfur replaces the position of the bridging oxygen between two coppers in the met states . Numerous sulfur containing molecules that are mainly derived from phenylthiourea have been reported to be inhibitors of tyrosinase. ,− We also found that our hits, 3 , 5 , 7 , 11 , 17 , 19 , and 21 , contain sulfurs at the same position to phenylthiourea. Many sulfur-containing chemicals are known to inhibit metalloenzyme by direct contact with metals through sulfur.…”

Evaluation of the serum metabolome of patients with alkaptonuria before and after two years of treatment with nitisinone using LC‐QTOF‐MS

“…4‐HBA is a naturally occurring compound that originates from the saprophytic perennial Gastrodia elata . Recent studies have reported the therapeutic effects of benzaldehydes in a number of areas including wound healing, cancer, vascular disease, and renal disease . In the context of AKU, the significance of 4‐HBA and benzaldehyde are unknown and require further investigation.…”

“…33 Recent studies have reported the therapeutic effects of benzaldehydes in a number of areas including wound healing, cancer, vascular disease, and renal disease. [34][35][36][37] In the context of AKU, the significance of 4-HBA and benzaldehyde are unknown and require further investigation. One may speculate that they relate to the benzoquinones, proposed as intermediates in the formation of ochronotic pigment observed in AKU.…”