Design, synthesis, and <i>in silico</i> docking studies of novel cinnamaldehyde–chalcone derivatives with anti-cancer potential and <i>in vivo</i> acute oral toxicity profiling

Cinnamaldehyde is a natural compound known for its antimicrobial and anticancer properties. Fourteen novel cinnamaldehyde-chalcone analogues (5a-5n) were synthesized and evaluated for anti-cancer, anti-bacterial, and anti-fungal activities. Among these, bromoethane chalcone 5n exhibited significant cytotoxicity against DU145 (IC50: 8.719 ± 1.8 μM), SKBR-3 (IC50: 7.689 μM), and HEPG2 (IC50: 9.380 ± 1.6 μM) cell lines, surpassing other derivatives. Compounds para methyl benzyl chalcone 5j and 2,3-dichloro benzyl chalcone 5b also demonstrated notable activity against SKBR-3 (IC50 7.871 μM) and HEPG2 (IC50 9.190 μM) cell lines. Erythrocyte osmotic fragility (EOF) analysis showed higher erythrocyte fragility for 5n (MEF₅₀ = 0.457) and 5b (MEF₅₀ = 0.538), indicating membrane-disruptive potential compared to quercetin (MEF₅₀ = 0.431). Studies on antimicrobial activity revealed that compounds 5a-5e and 5n demonstrated moderate effectiveness against <i>Staphylococcus aureus</i>, while compound 5l showed activity against <i>Candida albicans</i> and <i>Candida tropicalis</i>. Docking studies revealed that compound 5n binds to succinate dehydrogenase, a key enzyme in the TCA cycle, ETC, with greater affinity (-12.9 kcal mol^-1) than the standard inhibitor, malonate (-4.8 kcal mol^-1). Acute oral toxicity assessment of 5n in Swiss albino mice demonstrated its safety at doses up to 1000 mg kg^-1 body weight with no morbidity, mortality, or significant changes in haematological, biochemical, and pathological parameters. These findings highlight 5n's potential as a lead compound for further preclinical studies targeting cancer therapeutics.