Abstract

In an attempt to synthesise new tyrosinase inhibitors, we designed and synthesised a series of chalcone-hydroxypyridinone hybrids as potential tyrosinase inhibitors adopting strategic modifications of kojic acid. All the newly synthesised compounds were characterised by NMR and mass spectrometry. Initial screening of the target compounds demonstrated that compounds 1a, 1d, and 1n had relatively strong inhibitory activities against tyrosinase monophenolase, with IC₅₀ values of 3.07 ± 0.85, 2.25 ± 0.8 and 2.75 ± 1.19 μM, respectively. The inhibitory activity against monophenolase was 6- to 8-fold higher than that of kojic acid. Compounds 1a, 1d, and 1n also showed inhibition of diphenolase, with IC₅₀ values of 17.05 ± 0.07, 11.70 ± 0.03 and 19.3 ± 0.28 μM, respectively. The inhibition kinetics of diphenolase indicates that compounds 1a and 1d induce reversible inhibition on tyrosinase. Finally, we found that copper coordination should be one of the important inhibitory mechanism of these compounds in tyrosinase.

摘要

为了合成新的酪氨酸酶抑制剂，我们设计并合成了一系列查尔酮-羟基吡啶酮杂化物，作为采用曲酸进行战略修饰的潜在酪氨酸酶抑制剂。通过NMR和质谱对所有新合成的化合物进行表征。初步筛选目标化合物表明，化合物1a，1d和1n对酪氨酸酶单酚酶具有较强的抑制活性，IC ₅₀值分别为3.07±0.85、2.25±0.8和2.75±1.19μM。对单酚酶的抑制活性比曲酸高6至8倍。化合物1a，1d和1n还显示出对双酚酶的抑制作用，IC ₅₀值分别为17.05±0.07、11.70±0.03和19.3±0.28μM。双酚酶的抑制动力学表明化合物1a和1d诱导对酪氨酸酶的可逆抑制。最后，我们发现铜配位应该是酪氨酸酶中这些化合物的重要抑制机制之一。