Dexibuprofen amide derivatives as potential anticancer agents: synthesis, in silico docking, bioevaluation, and molecular dynamic simulation.

BACKGROUND

The amide derivatives of nonsteroidal anti-inflammatory drugs have been reported to possess antitumor activity. The present work describes the synthesis of dexibuprofen amide analogues () as potential anticancer agents.

METHODS

The title amides () were obtained by simple nucleophilic substitution reaction of dexibuprofen acid chloride with substituted amines in good yield and chemical structures were confirmed by FTIR, 1H NMR, 13C NMR and mass spectral data.

RESULTS

The brine shrimp lethality assay results showed that all of the synthesized compounds are non-toxic to shrimp larvae. The inhibitory effects on tumor growth were evaluated and it was observed that N-(2,5-dichlorophenyl)-2-(4-isobutylphenyl) propionamide () and N-(2-chlorophenyl)-2-(4-isobutylphenyl) propionamide () exhibited excellent antitumor activity compared to all other derivatives. The compound bearing 2,5-dichloro substituted phenyl ring and possesses 2-chloro substituted phenyl ring exhibited 100% inhibition of the tumor growth. The anticancer activity was evaluated against breast carcinoma cell line (MCF-7) and it was observed that derivative exhibited excellent growth inhibition of cancer cells with IC value of 0.01±0.002 µm, which is better than the standard drugs. The docking studies against breast cancer type 1 susceptibility protein BRCA1 (PDBID 3K0H) exhibited good binding affinities, which are in good agreement with the wet lab results. The compounds and showed the binding energy values of -6.39 and -6.34 Kcal/mol, respectively. The molecular dynamic (MD) simulation was also carried out to evaluate the residual flexibility of the best docking complexes of compounds and . The MD simulation analysis assured that the formed a more stable complex with the target protein than the . The synthesized amide derivatives exhibited were devoid of gastrointestinal side effects and no cytotoxic effects against human normal epithelial breast cell line (MCF-12A) were found.

CONCLUSION

Based upon our wet lab and dry lab findings we propose that dexibuprofen analogue may serve as a lead structure for the design of more potent anticancer drugs.