Synthesis and Analysis of Carvacrol-Derived Morita-Baylis-Hillman Adducts as Potential Anticancer Agents
Aliny Pereira de Vasconcelos, Francisco Josimar Ricardo Xavier, Aleff Castro, Matheus S.R. Lima, Lucas E. L. Terceiro, Fábio Silva, Mário L. A. A. Vasconcellos, Bruna Braga Dantas, Andrezza Barbosa, Sâmia Sousa Duarte, Demétrius A. M. Araújo, Cláudio Gabriel Lima-Júnior · Journal of the Brazilian Chemical Society · 2024
This study investigates the potential of Morita-Baylis-Hillman adducts derived from carvacrol as anticancer agents. The synthesis process, involving the reaction of aromatic aldehydes with carvacrol acrylate as a Michael acceptor, resulted in stable adducts with impressive yields ranging from 60 to 92%, achieved within a maximum reaction time of 24 h. Through a screening process utilizing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test, compound 6, identified as the acrylate/2-naphthyl adduct, emerged as the most active within the series among twelve compounds tested. Specifically, compound 6 exhibited a remarkably potent impact on neuroblastoma cell lines, particularly SH-SY5Y cells, with half-maximal inhibitory concentration (IC50) of 8.7 µM after 72 h (42 times more potent than carvacrol, IC50 = 374.1 μM). The exploration of the selectivity index (SI) against normal cell lines demonstrated an outstanding SI of 4.28 compared to other compounds. Mechanistic studies on SH-SY5Y cells revealed a concentrationdependent apoptotic effect attributed to caspase 3/7 activation. In silico modeling showcased favorable pharmacokinetic properties for compound 6, including effective absorption after oral administration. Assessment of toxicity of compound 6 profile using brine shrimp and the Irwin test indicated low toxicity, highlighting its potential for future anticancer agent development.