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In the present study, 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 presence of formaline. To obtain the cyclic amine (morpholine, piperidine and pyrrolidine) derivatives of the 6th-position of chlorokojic acid derivatives, nucleophilic substitutions were carried out. Thereafter, 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. Efficacy of all these compounds has been compared to those of vemurafenib, dacarbazine, temozolomide, and lenalidomide, which are the commercially available drugs for the treatment of malignant melanoma. 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. In 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.

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Hepatocellular carcinoma is one of the most pervasive cancers with low prognosis, high frequency of recurrence, and metastasis. Studies conducted have focused on extricating novel strategies for successful treatment. Kojic acid and its derivatives are already proven to have depigmenting, anti‐inflammatory, and anti‐neoplastic properties. In the present study, kojic acid and its 10 distinct derivatives were tested on HEPG2 cell line for their possible anti‐cancer effect and seven of them were observed to be cytotoxic. Compound 6 was chosen to proceed as the IC50 dosage for HEPG2 cells was lower in comparison with the other derivatives and kojic acid itself. Further experiments pointed out that intrinsic apoptotic pathway was triggered with the exposure of the cells to IC50 concentration of the derivative as the treatment led to escalation of intracellular ROS, induction of TP53 gene, and activation of caspase 3/7. Pro‐apoptotic Jnk and Bax genes were not triggered suggesting that the apoptotic pathway advance through an alternative route. Complementary experiments are in need; howbeit, the current findings suggest that the derivative offers a novel promising approach against hepatocellular carcinoma as it is not detrimental to healthy cells within the concentrations applied, and it does not induce drug resistance.

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Malignant melanoma is a serious type of skin cancer with high mortality rates, arising from melanocytic cells responsible for the pigmentation of the skin. Besides, the excessive accumulation of melanin pigment can lead to many other hyperpigmentation disorders. Kojic acid is used as a skin lightening agent of medicinal and cosmetic products used in hyperpigmentation and sunburn cases. In the present study, substituted halogen containing benzylpiperazine derivatives of kojic acid (compounds 1-9) were synthesized via Mannich reaction in mild conditions. Afterwards, the cyclic amine derivatives (compounds 10-26) were obtained as a result of nucleophilic substitutions. Cytotoxic effects of all the compounds on A375 human malignant melanoma cell lines were explored by sulphorhodamine B assay and efficacies has been compared to those of anticancer FDA-approved drugs dacarbazine, temozolomide, and lenalidomide, currently used in the treatment of malignant melanoma. Also, the most active two compounds were also tested on healthy cell lines (HGF-1 and MRC-5 cell lines). These compounds have shown highest activity (IC50: 71.27 for compound 9 and 73.74 µM for compound 1) than temozolomide (IC50: 95.6 µM) and lenalidomide (IC50: 143.1 µM) against A375 cells though giving less harm to non-cancerous cell lines. In conclusion, these compounds stand out as promising anticancer agents for further studies.

Medicinal Chemistry and Drug Design 2 browning in fruits and vegetables. In the food industry, tyrosinase is important in controlling the quality and economics of fruits and vegetables. Hence, tyrosinase inhibitors from natural sources have great potential in the food industry, as they are considered to be safe and largely free from adverse effects. Also in insects, tyrosinase is involved in melanogenesis wound healing, parasite encapsulation and sclerotisation (Seo, 2003). Therefore, tyrosinase inhibitors used as insecticides and insect control agents. Moreover, the tyrosinase is responsible from melanization in animals and is the key enzyme for the regulation of melanogenesis in mammals. Melanogenesis is the process by which melanin is produced and subsequently distributed by melanocytes within the skin and hair follicles. This process results in the synthesis of melanin pigments, which play a protective role against skin photocarcinogenesis (