Synthesis and analysis of carvacrol-derived Morita-Baylis-Hillman adducts as potential anticancer agents

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 concentration dependent 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. (author)