Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg Synthesis, computational molecular docking analysis and efectiveness on tyrosinase inhibition of kojic acid derivatives Gülşah Karakaya a , Aslı Türe b , Ayşe Ercan c , Selin Öncül c , Mutlu Dilsiz Aytemir a, ⁎ a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey b Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, İstanbul, Turkey c Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey ARTICLEINFO Keywords: Kojic acid Mannich reaction Tyrosinase inhibition Molecular docking ABSTRACT Tyrosinase inhibitors have become increasingly important as whitening agents and for the treatment of pig- mentary disorders. In this study, the synthesis of kojic acid derivatives having 2-substituted-3-hydroxy-6-hyr- oxymethyl/chloromethyl/methyl/morpholinomethylpiperidinyl- methyl/pyrrolidinylmethyl-4H-pyran-4-one structure (compounds 1–30) with inhibitory efects on tyrosinase enzyme were described. One-pot Mannich reaction was carried out by using kojic acid/chlorokojic acid/allomaltol and substituted benzylpiperazine de- rivatives in presence of formaline. Subsequently, cyclic amine (morpholine, piperidine and pyrrolidine) deri- vatives of the 6th-position of chlorokojic acid were obtained with nucleophilic substitutions in basic medium. The structures of new compounds were identifed by FT-IR, 1 H- and 13 C NMR, ESI-MS and elemental analysis data. The potential mushroom tyrosinase inhibitory activity of the compounds were evaluated by the spectro- photometric method using L-DOPA as a substrate and kojic acid as the control agent. The potential inhibitory activity was also investigated in silico using molecular docking simulation method. Tyrosinase inhibitory action was signifcantly more efcacious for several compounds (IC 50 : 86.2–362.1µM) than kojic acid (IC 50 : 418.2). Compound 3 bearing 3,4-dichlorobenzyl piperazine moiety was proven to have the highest inhibitory activity. The results of docking studies showed that according to the predicted conformation of compound 3 in the enzyme binding site, hydroxymethyl group provides a metal complex with copper ions and enzyme. Thus, this interaction explain the high inhibitory activities of the compounds 1, 3 and 4 possessing hydroxymethyl sub- stituent supporting the mushroom assay results with docking studies. In accordance with the results, it is sug- gested that Mannich bases of kojic acid bearing substituted benzyl piperazine groups (compounds 1, 3, 4, 11, 13, 14, 23, 24, 28, and 29) could be promising antityrosinase agents. Additionally, considering the relationship between tyrosinase inhibitory activity results and molecular docking, a new tyrosinase inhibition mechanism can be proposed. 1. Introduction Tyrosinase (EC 1.14.18.1), a copper-containing monooxy-genase enzyme, is a key regulatory enzyme widely distributed in nature, that is responsible for the melanin production. Pigmentation of the skin in animals and browning of fruits and vegetables occur by this process [1–3]. When the skin is exposed to excessive levels of UV radiation, hyperpigmentation occurs due to overproduction of melanin and causes several abnormal skin lesions (malign melanoma, hyperpigmentation, melasma, freckles, ephelide, sneile lentigines, etc.) particularly in middle-aged and elderly individuals. Contrarily, if there is no tyrosinase activityinmelanocytes,thepigmentcouldnotbeformedwhichleadsto localized albinism like white spots on the skin of some animals [4]. Furthermore, tyrosinase has shown to be involved in wound healing and contributed to the neurodegeneration associated with Parkinson’s disease [5]. Also, melanoma-specifc anticarcinogenic activity is also known to be linked with tyrosinase activity [6]. Therefore, the enzy- matic activity of tyrosinase has been target for the investigation of in- hibitors due to its potential applications in pharmaceutical and cos- metic products. Newly synthesized inhibitors possesing metal chelatig ability and phenolic structure represent the most promising class for tyrosinase inhibitors having similar inhibitory potential as the fungal metabolite kojic acid (5-hydroxy-2-hydroxymethyl-4H-pyran-4-one, KA). KA is a well-known antityrosinase agent exhibiting a wide range of pharmacological profle and its antityrosinase potential is mainly at- tributed to copper-chelating property [2]. However the use of KA in https://doi.org/10.1016/j.bioorg.2019.102950 Received 17 January 2019; Received in revised form 16 April 2019; Accepted 23 April 2019 ⁎ Corresponding author at: Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100 Sihhiye, Ankara, Turkey. E-mail address: mutlud@hacettepe.edu.tr (M.D. Aytemir). Bioorganic Chemistry 88 (2019) 102950 Available online 27 April 2019 0045-2068/ © 2019 Elsevier Inc. All rights reserved. T