Synthesis of New Derivatives of Benzylidinemalononitrile and Ethyl 2-Cyano-3-phenylacrylate: In Silico Anticancer Evaluation

[Image: see text] In this study, microwave-assisted Knoevenagel condensation was used to produce two novel series of derivatives (1–6) from benzylidenemalononitrile and ethyl 2-cyano-3-phenylacrylate. The synthesized compounds were characterized using Fourier transform infrared (FT-IR) and (1)H NMR spectroscopies. The pharmacodynamics, toxicity profiles, and biological activities of the compounds were evaluated through an in silico study using prediction of activity spectra for substances (PASS) and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies. According to the PASS prediction results, compounds 1–6 showed greater antineoplastic potency for breast cancer than other types of cancer. Molecular docking was employed to investigate the binding mode and interaction sites of the derivatives (1–6) with three human cancer targets (HER2, EGFR, and human FPPS), and the protein–ligand interactions of these derivatives were compared to those reference standards Tyrphostin 1 (AG9) and Tyrphostin 23 (A23). Compound 3 showed a stronger effect on two cell lines (HER2 and FPPS) than the reference drugs. A 20 ns molecular dynamics (MD) simulation was also conducted to examine the ligand’s behavior at the active binding site of the modeled protein, utilizing the lowest docking energy obtained from the molecular docking study. Enthalpies (ΔH), Gibbs free energies (ΔG), entropies (ΔS), and frontier molecular orbital parameters (highest occupied molecular orbital–lowest unoccupied molecular orbital (HOMO–LUMO) gap, hardness, and softness) were calculated to confirm the thermodynamic stability of all derivatives. The consistent results obtained from the in silico studies suggest that compound 3 has potential as a new anticancer and antiparasitic drug. Further research is required to validate its efficacy.