RESUMEN
Aim: The design, synthesis, docking studies and evaluation of the in vitro antifungal and cytotoxic properties of eugenol (EUG) containing 1,2,3-triazole derivatives are reported. Most of the derivatives have not been reported.Materials & methods: The EUG derivatives were synthesized, molecular docked and tested for their antifungal activity.Results: The compounds showed potent antifungal activity against Trichophyton rubrum, associated with dermatophytosis. Compounds 2a and 2i exhibited promising results, with 2a being four-times more potent than EUG. The binding mode prediction was similar to itraconazole in the lanosterol-14-α-demethylase wild-type and G73E mutant binding sites. Additionally, the pharmacokinetic profile prediction suggests good gastrointestinal absorption and potential oral administration.Conclusion: Compound 2a is a promising antifungal agent against dermatophytosis caused by T. rubrum.
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RESUMEN
Sesquiterpene lactones (SLs) are natural products with a variety of biological activities. Previously, we demonstrated the cytotoxic effects of three new α-santonin derivatives on different tumor cell lines with low toxic effects upon peripheral human leukocytes. Here, we evaluated the mechanism of action triggered by these derivatives. HL-60 cell cycle determined after 24h treatment revealed a significant inhibition on cell-cycle progression and leading to an increasing of cells in G2/M [7.6% and 9.0% for compound 3% and 9.0% and 8.6% for compound 4 (1 and 2 µM, respectively)]. However, after 48 h exposure, all compounds caused G2/M reduction and a significant DNA fragmentation. Compounds 2, 3 and 4 were able to induce apoptosis on leukemia cells, which was corroborated by phosphatidyserine externalization and activation of caspases-3 and -7 after 24h exposure. None of the derivatives analyzed caused depolarization of mitochondrial membrane within 24h of incubation, suggesting the involvement of the extrinsic apoptotic pathway in the death process. The antiproliferative action of these compounds is related to the DNA synthesis inhibition and cell cycle arrest, which probably lead to apoptosis activation. Therefore, these santonin derivatives are promising lead candidates for development of new cytotoxic agents.
Asunto(s)
Citotoxinas/farmacología , Santonina/análogos & derivados , Santonina/farmacología , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Fragmentación del ADN , Fase G2 , Células HL-60 , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacosRESUMEN
Reaction of [(2-alkyloxy)methyl]-1,4-dimethoxybenzene 10 (alkyl=butyl, hexyl, decyl, tridecyl, tetradecyl, hexadecyl, and octadecyl) with ceric ammonium nitrate in order to produce p-benzoquinones (=cyclohexa-2,5-diene-1,4-diones) afforded 5-[(alkyloxy)methyl]-2-(4-formyl-2,5-dimethoxyphenyl)benzo-1,4-quinones 12a-12g in yields that varied from 46 to 97%, accompanied by 2-[(alkyloxy)methyl]benzo-1,4-quinones 11a-11g in only small quantities (< or =5%). These quinones resemble the natural phytotoxic compound sorgoleone, found in Sorghum bicolor. This reaction exemplifies a general procedure for the synthesis of novel aryl-substituted p-benzoquinones. The selective effects of compounds 12a-12g, at the concentration of 5.5 ppm, on the growth of Cucumis sativus, Sorghum bicolor, Euphorbia heterophylla, and Ipomoea grandifolia were evaluated. All compounds caused some inhibition upon the aerial parts and root growth of the tested plants. The most active compound, 2-(4-formyl-2,5-dimethoxyphenyl)-5-[(tridecyloxy)methyl]-benzo-1,4-quinone (12d), caused between 3 and 18%, and 12 and 29% inhibition on the roots and aerial parts development of Cucumis sativus and Sorghum bicolor, respectively, and between 77 and 85%, and 34 and 52% inhibition on the roots and aerial parts growth of Euphorbia heterophylla and Ipomoea grandifolia, respectively.