Synthesis and cytotoxic evaluation of chalcone and ureido analogs of 4-ethylpiperic acid

This research presents a facile and scalable synthetic approach for the preparation of 4-ethylpiperic acid, addressing the scarcity of pipernal and facilitating access to piperic acid derivatives. The target molecules are synthesised in a multistep reaction scheme involving Friedel-Crafts acylation, Vilsmeier-Haack formylation and Wittig olefination reactions. Two structurally diverse series of 4-ethylpiperic acid: chalcone-type analogs (SC-1 to SC-6) and ureido derivatives (UD-1 to UD-4) were synthesised and evaluated for anticancer activity using MTT assay. SC-1 demonstrated significant and selective efficacy against SUM-159, 4T1, MIA-PaCa-2 and MDA-MB-231 with IC₅₀ values between 20-30 µM. Among the ureido series, UD-2 exhibited notable efficacy against UMSCC_22B with an IC₅₀ of 9.2 ± 0.86 µM and demonstrating a statistically significant dose-dependent relationship. The structure-activity relationship (SAR) indicated that electron-donating groups increased cytotoxicity. SC-1 and UD-2 may act as lead candidates for drug development against aggressive and drug-resistant malignancies.