<p>Dexibuprofen amide derivatives as potential anticancer agents: synthesis, in silico docking, bioevaluation, and molecular dynamic simulation</p>

Abstract

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 ( 4a–j ) as potential anticancer agents. Methods: The title amides ( 4a–j ) were obtained by simple nucleophilic substitution reaction of dexibuprofen acid chloride with substituted amines in good yield and chemical structures were confirmed by FTIR, 1 H NMR, 13 C 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 ( 4e ) and N-(2-chlorophenyl)-2-(4-isobutylphenyl) propionamide ( 4g ) exhibited excellent antitumor activity compared to all other derivatives. The compound 4e bearing 2,5-dichloro substituted phenyl ring and 4g 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 4e exhibited excellent growth inhibition of cancer cells with IC 50 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 4e and 4g 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 4e and 4g . The MD simulation analysis assured that the 4e formed a more stable complex with the target protein than the 4g . 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 4e may serve as a lead structure for the design of more potent anticancer drugs. Keywords: dexibuprofen analogues, preparation, computational studies, cytotoxicity, anti­cancer activity