Structure-based design, synthesis, molecular docking, and biological activities of 2-(3-benzoylphenyl) propanoic acid derivatives as dual mechanism drugs

Abstract

Purpose: 2-(3-benzoyl phenyl)propanohydroxamic acid (2) and 2-{3-[(hydroxyimino)(phenyl)methyl]phenyl}propanoic acid (3) were synthesized from non-steroidal anti-inflammatory drug, ketoprofen as dual-mechanism drugs.

Materials and methods: Structures of the synthesized compounds were established by IR, (1)H NMR, and mass spectroscopy. Both compounds were screened for their anti-inflammatory activity in rat paw edema model and in vitro antitumor activity against 60 human tumor cell lines. Flexible ligand docking studies were performed with different matrix metalloproteinases and cyclooxygenases to gain an insight into the structural preferences for their inhibition.

Results: Compound (2) proved out to be more potent than ketoprofen in rat paw edema model. Both compounds showed moderate anticancer activity ranging from 1% to 23% inhibition of growth in 38 cell lines of 8 tumor subpanels at 10 μM concentration in a single dose experiment. Hydroxamic acid analogue was found to be more potent than ketoximic analogue in terms of its antitumor activity.

Conclusion: Analysis of docking results together with experimental findings provide a good explanation for the biological activities associated with synthesized compounds which may be fruitful in designing dual-target-directed drugs that may inhibit cyclooxygenases and MMPs for the treatment of cancer.

Keywords: Anticancer; anti-inflammatory; docking; dual mechanism; ketoprofen.

Figure 1

Design of 2-(3-benzoylphenyl)propanoic acid derivatives as dual mechanism drugs based on some potential inhibitors of matrix metalloproteinases and cyclooxygenases

Scheme 1

Synthesis of 2-(3-benzoylphenyl)propanoic acid derivatives

Figure 2

Carrageenan-induced rat paw edema test (n = 7). Data is presented as %inhibition of inflammation. *P, 0.01 compared with corresponding value for control group evaluated by t-test. ** P, 0.001 compared with corresponding value for control group evaluated by t-test

Figure 3

Compound (2) (red) and (3) (yellow) docked into MMP-3 receptor site (PDB code: 2JT5) occupying the same position as the native cocrystallized ligand, MLC 88 (green) exhibiting RMSD of 1.21 Å and 0.43 Å, respectively.

Figure 4

Docking of compound (2) with MMP-8. The residues of binding pocket are shown as stick while compound (2) is presented as ball and stick style in cyan color. Dashed lines in green and orange indicate H-bonds and π-π stacking interactions, respectively. Bond distances are given in Å

Figure 5

Compound (2) (red) and (3) (cyan) docked into COX-2 receptor site (PDB code: 1CX2) occupying the same position as the native cocrystallized ligand, SC 558 (blue) exhibiting RMSD of 1.8 Å and 3.1 Å, respectively

Figure 6

Docking of compound (2) with COX-1. The residues of binding pocket are shown as stick in pink while compound (2) is presented as ball and stick in cyan color. Dashed lines in green indicate H-bonds. Bond distances are given in Å