Synthesis, Biological Screening, and Molecular Dockingof Drug Carrier Maleimide Derivatives

Objective: New maleimide-drug derivatives (Ia–Ic) were synthesized and tested for their anticancer activity against MCF-7 cell line, and anti-bacterial (E. coli and S. aureus). The prepared compounds were characterized using 1H and 13C NMR, Mass, and FT-IR spectroscopy. The cytotoxic activity against the MCF-7 cell line was estimated by MTT reduction test. Methods: Maleimide-drug derivatives (Ia–Ic) were synthesized by the reaction of 3-amino benzoic acid and maleic anhydride in acetone to afford 3-[3-carboxyacrylamido]-benzoic acid and cyclodehydration of 3-[3-carboxyacrylamido]-benzoic acid using acetic anhydride and sodium acetate as cyclo-dehydrating agents. The resulting 3-maleimide benzoic acid was then converted into an acid chloride derivative by reaction with thionyl chloride. The corresponding 3-[2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl]-benzoyl chloride was then treated with 3 different amino-containing drugs (4-aminoantipyrrine, theophylline, and mesalzine) in the presence of triethylamine (TEA) as a catalyst in dimethylacetamide. Results and Discussion: Among the synthesized derivatives, compound (Ic) expressed high cytotoxicity with IC50 value of 6.12 µg/mL and showed a high inhibition zone for both types of the selected bacteria, whereas compounds (Ia) and (Ib) exhibited reasonable cytotoxicity with IC50 values of 26.078 and 22.019 µg/mL respectively against MCF7 cells. Molecular Docking modeling was achieved on the binding sites of two proteins, human 3-alpha hydroxysteroid dehydrogenase type 3 (PDB ID: 4XO7) and Estrogen Receptor alpha Er (PDB ID: 6WOK). Conclusions: We propose that, all compounds have a higher potential to inhibit the receptor of 4XO7 than 6WOK, which are dominant during breast cancer. The small binding energies and many H-bonds obtained by molecular docking modeling suggest that the maleimidedrug derivatives may be viable anti-breast cancer agents.