Novel Bis(2‐cyanoacrylamide) Linked to Sulphamethoxazole: Synthesis, DNA Interaction, Anticancer, ADMET, Molecular Docking, and DFT Studies

Abstract

In the light of advancement and potential extensive use of medication design and therapy, new bis(cyanoacrylamides) incorporating sulphamethoxazole derivatives (7a‐7f) were synthesized and confirmed by different spectral tools. In vitro anticancer activity towards different human cancer cells (HCT116, MDA‐MB‐231 and A549) was assessed using MTT assay. Among all derivatives, 4C‐ and 6C‐spacer derivatives (7e and 7f) had the most potent growth inhibitory activities against HCT116 cells with IC50 values of 39.7 and 28.5 µM, respectively. 7e and 7f induced apoptosis and suppressed migration of HCT116 cells. These compounds also induced a significant increase in caspase‐3 activities, and downregulation of Bcl2 and CDH1 using ELISA. pBR322 DNA cleavage activities of cyanoacrylamides were determined using agarose gel electrophoresis. Furthermore, 7e and 7f showed good DNA and BSA binding affinities using different spectroscopic techniques. Furthermore, molecular docking for 7e and 7f was performed to anticipate their binding capabilities toward various proteins (Bcl2, CDH1 and BSA). The docking results were well correlated with those of experimental results. Additionally, density functional theory and ADMET study were performed to evaluate the molecular and pharmacokinetic features of 7e and 7f, respectively. Thus, this work reveals promising antitumor lead compounds that merit future research and activity enhancement.