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

In this study, microwave-assistedKnoevenagel condensationwasused to produce two novel series of derivatives (1-6) from benzylidenemalononitrile and ethyl 2-cyano-3-phenylacrylate.The synthesized compounds were characterized using Fourier transforminfrared (FT-IR) and H-1 NMR spectroscopies. The pharmacodynamics,toxicity profiles, and biological activities of the compounds wereevaluated through an in silico study using predictionof activity spectra for substances (PASS) and Absorption, Distribution,Metabolism, Excretion, and Toxicity (ADMET) studies. According tothe PASS prediction results, compounds 1-6 showed greater antineoplastic potency for breast cancerthan other types of cancer. Molecular docking was employed to investigatethe 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 thesederivatives were compared to those reference standards Tyrphostin1 (AG9) and Tyrphostin 23 (A23). Compound 3 showed astronger effect on two cell lines (HER2 and FPPS) than the referencedrugs. A 20 ns molecular dynamics (MD) simulation was also conductedto examine the ligand's behavior at the active binding siteof the modeled protein, utilizing the lowest docking energy obtainedfrom the molecular docking study. Enthalpies (& UDelta;H), Gibbs free energies (& UDelta;G), entropies (& UDelta;S), and frontier molecular orbital parameters (highest occupiedmolecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO)gap, hardness, and softness) were calculated to confirm the thermodynamicstability of all derivatives. The consistent results obtained fromthe in silico studies suggest that compound 3 has potential as a new anticancer and antiparasitic drug.Further research is required to validate its efficacy.

Automated summary

In this study, two novel series of derivatives (1-6) were synthesized using microwave-assisted Knoevenagel condensation. The synthesized compounds were characterized and evaluated for their pharmacodynamics, toxicity profiles, and biological activities. In silico studies, including prediction of activity spectra for substances (PASS) and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies, were conducted. Molecular docking and molecular dynamics (MD) simulation were employed to investigate the binding mode, interaction sites, and thermodynamic stability of the derivatives. Compound 3 showed promising potential as a new anticancer and antiparasitic drug, but further research is needed to validate its efficacy.