Dexibuprofen amide derivatives as potential anticancer agents

Synthesis, in silico docking, bioevaluation, and molecular dynamic simulation

Zaman Ashraf, Tariq Mahmood, Mubashir Hassan, Samina Afzal, Hummera Rafique, Khurram Afzal, Jalifah Latip

Research output: Contribution to journalArticle

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,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 (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 IC50 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.

Original languageEnglish
Pages (from-to)1643-1657
Number of pages15
JournalDrug Design, Development and Therapy
Volume13
DOIs
Publication statusPublished - 1 Jan 2019

Fingerprint

Molecular Dynamics Simulation
Amides
Computer Simulation
Antineoplastic Agents
Growth
BRCA1 Protein
Pharmaceutical Preparations
Artemia
Cell Line
Neoplasms
Fourier Transform Infrared Spectroscopy
Inhibitory Concentration 50
Amines
Larva
Chlorides
Breast
Anti-Inflammatory Agents
Epithelial Cells
Breast Neoplasms
Acids

Keywords

  • Anticancer activity
  • Computational studies
  • Cytotoxicity
  • Dexibuprofen analogues
  • Preparation

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery

Cite this

Dexibuprofen amide derivatives as potential anticancer agents : Synthesis, in silico docking, bioevaluation, and molecular dynamic simulation. / Ashraf, Zaman; Mahmood, Tariq; Hassan, Mubashir; Afzal, Samina; Rafique, Hummera; Afzal, Khurram; Latip, Jalifah.

In: Drug Design, Development and Therapy, Vol. 13, 01.01.2019, p. 1643-1657.

Research output: Contribution to journalArticle

Ashraf, Zaman ; Mahmood, Tariq ; Hassan, Mubashir ; Afzal, Samina ; Rafique, Hummera ; Afzal, Khurram ; Latip, Jalifah. / Dexibuprofen amide derivatives as potential anticancer agents : Synthesis, in silico docking, bioevaluation, and molecular dynamic simulation. In: Drug Design, Development and Therapy. 2019 ; Vol. 13. pp. 1643-1657.
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