Synthesis, Characterization, and Biological Evaluation of Gabapentinoid Hybrids with Isoindole-1,3-(2H) Dione Moiety as potential antioxidant, antimicrobial, and anticancer

Purpose: To synthesize new Isoindole-1,3-(2H) Dione derivatives by molecular hybridization of Gabapentin, and Pregabalin with phthalic anhydride derivatives, and to evaluate their biological activity as promising antioxidant, antimicrobial, and anticancer agents. Method: Molecular hybridization was successfully achieved by two procedures; synthesized compounds were characterized using analytical and spectral methods. Free radical scavenging properties of synthesized compounds were evaluated using DPPH method. Antibacterial activity of synthesized compounds, and parent compounds was evaluated against two microbial gram-positive and gram-negative strains by well diffusion method. Furthermore, we have studied effect of compounds on proliferation, cell cycle and cell death of two human cancer cell lines (Caco-2 and HCT-116). Results: : Compounds 1 , 3 , 4 exhibited good free radical scavenging effect, compound 3 is the most effective with IC 50 value 2.525 µmol/mL. All Compounds showed antibacterial activity against E. coli and Staphylococcus Aureus related to concentration while parent drugs did not exhibit any antibacterial effect. Compounds 1 and 2 showed good zone of inhibition against Escherichia Coli at micromolar concentrations, and they are more effective than gentamycin sulfate. Treatment with studied compounds suppresses proliferation, arrests progress throughout the cell cycle and induces apoptosis in Caco-2 and HCT-116 cancer cells. Compound 2 is highly effective against Caco-2 cells and more effective than Thalidomide, with IC 50 value less than 1 µmol/L. Conclusion: Our results showed that molecular hybridization of Gabapentin, and Pregabalin in Isoindole-1,3(2H) Dione moiety result in promising anti-cancer and antimicrobial molecules. Results of this preliminary study show that halogenation of Isoindole-1,3-(2H) dione moiety improves antimicrobial, and anticancer activity, and that tetra-brominated derivatives are comparable or more effective than related tetra-chlorinated derivatives.