Development of Kojic Acid–3-Hydroxyindolin-2-one Conjugates: Structural Characterization and Pharmacological Evaluation

Kojic acid (KA), a natural compound with notable biological properties, is a versatile scaffold (5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one) for developing novel therapeutic agents. This study aimed to synthesize KA-based derivatives and evaluate their multifunctionality as anti-tyrosinase, anticancer, antioxidant, and anti-malarial agents. Exploring KA derivatives holds promise for advancing in skin brightening, malaria, and cancer therapeutics, and managing oxidative stress, addressing the demanding need for multifunctional compounds in modern medicine. KA derivative (DRC-01) was synthesized through one-pot aldol condensation chemical reactions and structurally confirmed using advanced spectroscopic techniques, including FTIR, NMR, and mass spectrometry. The anti-tyrosinase activity on Mushroom Tyrosinase protein from RCSB PDB (PDB: 2Y9X) and anticancer potential were evaluated in vitro using the MTT assay against human cancer cell lines: HCT-116 (colon cancer), PANC-1 (pancreatic cancer), MDA-MB-231 (triple-negative breast cancer), and MCF-7 (hormone-responsive breast cancer). Antioxidant activity was assessed using the DPPH assay to determine radical scavenging properties, and the Antimalarial activity was performed by SYBR GREEN assay in Plasmodium falciparum 3D7. DRC-01 showed binding energy -7.4kcal/mol compared to standard KA -5.8kcal/mol and dose-dependent cytotoxicity, demonstrating anticancer activity at higher concentrations (>50 µM) across all tested cell lines. Additionally, DRC-01 displayed moderate radical scavenging activity in the antioxidant assay, and Antimalarial potential was at IC₅₀ = 54.94±3.11µg/mL. These findings highlight that DRC-01 could be a candidate for therapeutic applications with its cosmeceutical properties. Further structural optimization is acceptable to enhance their potency and selectivity, reinforcing their value in the fight against cancer, malaria, and oxidative stress-related disorders.