Synthesis and Analysis of Carvacrol-Derived Morita-Baylis-Hillman Adducts as Potential Anticancer Agents

Abstract

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.

Carvacrol and Thymol Hybrids: Potential Anticancer and Antibacterial Therapeutics

“…Molecules 2024, 29, x FOR PEER REVIEW 9 of 19 benzoic acid moieties into thymol and carvacrol via ester linkers improved their anticancer activity [52]. [53]. Most of the hybrids exhibited an anticancer effect that was 10-fold more effective than carvacrol (IC50 = 374.1 µM) with IC50 values between 9.79 and 64.72 µM [53].…”

“…Additionally, SAR indicated that the nitro position favouring para positions and the type of halogen present were influential on the anticancer effect of these compounds. Due to its promising anticancer effect, in vivo mechanistic studies and clinical trials were suggested for compound 10c [53]. [53].…”

“…Due to its promising anticancer effect, in vivo mechanistic studies and clinical trials were suggested for compound 10c [53]. [53]. Most of the hybrids exhibited an anticancer effect that was 10-fold more effective than carvacrol (IC 50 = 374.1 µM) with IC 50 values between 9.79 and 64.72 µM [53].…”

“…[53]. Most of the hybrids exhibited an anticancer effect that was 10-fold more effective than carvacrol (IC 50 = 374.1 µM) with IC 50 values between 9.79 and 64.72 µM [53]. Notably, compounds 10a-c (Figure 12) were the most active anticancer hybrids with a selective index of more than 3.0 compared to that of carvacrol (0.93), suggesting that the derivatives have more anticancer properties compared to the parent drug.…”

“…Additionally, SAR indicated that the nitro position favouring para positions and the type of halogen present were influential on the anticancer effect of these compounds. Due to its promising anticancer effect, in vivo mechanistic studies and clinical trials were suggested for compound 10c [53]. Interesting anticancer findings on two generations of coumarin-monoterpenes, including thymol and carvacrol moieties, were reported by Zengin et al [54].…”