Background: Malignant melanoma is an agressive tumour related to the overproduction of melanin, which
provides colors of skin, eyes and hair. In addition contributing to the risk of malignant melanoma, abnormal production
of melanin has many drawbacks, including hyperpigmentation, post-inflammatory pigmentation, melasma and
skin aging. Kojic acid is currently employed in order to lighten skin pigmentation and provide depigmentation.
Objective: Mannich bases of kojic acid with the structure of 2-substituted-3-hydroxy-6-hyroxymethyl/chloromethyl/
methyl/morpholinomethyl/piperidinylmethyl/pyrrolidinylmethyl-4H-pyran-4-one (compounds 1-23) were synthesized
by the reaction of kojic acid/chlorokojic acid/allomaltol and substituted benzylpiperazine derivatives in the presence of
formaline. To obtain the cyclic amine (morpholine, piperidine and pyrrolidine) derivatives, nucleophilic substitutions
were carried out.
Method: Cytotoxic effects on A375 human malignant melanoma, HGF-1 human gingival fibroblasts, and MRC-5
human lung cell lines were investigated by sulphorhodamine B assay. Control agents were vemurafenib, dacarbazine,
temozolomide, and lenalidomide, which are the commercially available drugs for the treatment of malignant
Results: Cytotoxic action against melanoma cells was significantly more efficacious (IC50: 11.26-68.58 μM) than the
FDA-approved drugs except for vemurafenib. Fourteen of the compounds were proven to have higher IC50 values
for the non-cancerous cell lines, HGF-1, and MRC-5 cells. Melanogenesis inhibition assay was performed to observe
the ability of the drugs to inhibit melanin production and certain compounds were shown to be capable of actively
inhibiting melanin production in melanoma cells.
Conclusion: Mannich bases of kojic acid derivatives may be promising therapeutic agents, since some have more
potent effects on melanoma cells than previously FDA-approved drugs for the treatment of malignant melanoma.