CHEMICALLY DIVERSIFICATED ESSENTIAL OILS AS SOURCE OF TYROSINASE INHBITORS

PARES, V; RAMALLO, IA; FURLAN, RLE

Rosario

Congreso; 4ª Reunión Internacional de Ciencias Faramacéuticas RICIFA; 2016

Biological selection makes natural products (NPs) an excellent source of substructures for the design of new drugs.1 The chemical diversification of NPs explores potentially useful scaffolds inspired by Nature.2 This approach involves the chemical transformation of reactive fragments commonly found in NPs to introduce functionalities that are relevant for bioactivity. We report the chemical diversification of 7 essential oils and 2 oleoresins with NH2OH.HCl in refluxing ethanol to produce mixtures with different composition, according to GC-MS/NMR analysis, and the evaluation of inhibitory properties. The chemically engineered Theobroma cacao L. oleorresin (TCOR-M) was the only mixture that showed inhibitory properties by tyrosinase bioautography.3 Quantitative biological analysis4 of TCOR-M and its starting oleorresin was performed giving IC50=71±1.05μg/mL and IC50=239.1±1.49μg/mL, respectively. Bioassay-guided fractionation of TCOR-M led to the purification of four compounds that were identified by NMR and HRMS: 4-hydroxy-3-methoxybenzonitrile (1), (E)-5-(ethoxymethyl)-furan-2-carbaldehíde-oxime (2), (Z)-5-(ethoxymethyl)-furan-2-carbaldehíde-oxime (3), and (Z)-4-hydroxy-3-methoxybenzaldehíde oxime (4). 1 presented a moderate potency with an IC50=171±1.17μM. 2 presented a very low potency with an IC50=2390±1.03μM, while 3 did not present any biological activity. Interestingly, mixtures of 2-3 presented lower IC50 than 2, suggesting some sort of synergism. 4 was the most remarkable because its IC50=7.62±1.08μM was lower than the IC50 of kojic acid reference (42.16±1.04μM). All the isolated structures contain the moieties N-OH or N≡ confirming that they were products of the reaction. 4 could be formed from vanillin. The subsequent dehydration of 4 could have led to 1. The N-OH moiety is crucial for the bioactivity since its replacement by N≡ leads to an increase of the IC50 value. 2 and 3 could be generated from the cyclization of a sugar to form 5-(hydroxymethyl)furfural that consequently reacts with ethanol and NH2OH.HCl.5 The results of this study reinforce the chemical diversification as a viable strategy for the future development of therapeutic agents.