A Novel Ibuprofen Derivative and Its Complexes: Physicochemical Characterization, DFT Modeling, Docking, In Vitro Anti-Inflammatory Studies, and DNA Interaction

Abbas M Abbas; Ahmed Aboelmagd; Safaa M Kishk; Hossam H Nasrallah; Warren Christopher Boyd; Haitham Kalil; Adel S Orabi

doi:10.3390/molecules27217540

A Novel Ibuprofen Derivative and Its Complexes: Physicochemical Characterization, DFT Modeling, Docking, In Vitro Anti-Inflammatory Studies, and DNA Interaction

Molecules. 2022 Nov 3;27(21):7540. doi: 10.3390/molecules27217540.

Authors

Abbas M Abbas¹, Ahmed Aboelmagd¹, Safaa M Kishk², Hossam H Nasrallah^{1

3}, Warren Christopher Boyd⁴, Haitham Kalil^{1

4}, Adel S Orabi¹

Affiliations

¹ Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt.
² Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
³ Chemistry Department, Faculty of Dentistry, Sinai University, Kantara 41612, Egypt.
⁴ Chemistry Department, Cleveland State University, Cleveland, OH 44115, USA.

Abstract

A novel derivative of ibuprofen and salicylaldehyde N'-(4-hydroxybenzylidene)-2-(4-isobutylphenyl) propane hydrazide (HL) was synthesized, followed by its complexation with Cu, Ni, Co, Gd, and Sm. The compounds obtained were characterized by ¹HNMR, mass spectrometry, UV-Vis spectroscopy, FT-IR spectroscopy, thermal analysis (DTA and TGA), conductivity measurements, and magnetic susceptibility measurements. The results indicate that the complexes formed were [Cu(L)(H₂O)]Cl·2H₂O, [Ni(L)₂], [Co(L)₂]·H₂O, [Gd(L)₂(H₂O)₂](NO₃)·2H₂O and [Sm(L)₂(H₂O)₂](NO₃)·2H₂O. The surface characteristics of the produced compounds were evaluated by DFT calculations using the MOE environment. The docking was performed against the COX2 targeting protein (PDB code: 5IKT Homo sapiens). The binding energies were -7.52, -9.41, -9.51, -8.09, -10.04, and -8.05 kcal/mol for HL and the Co, Ni, Cu, Sm, and Gd complexes, respectively, which suggests the enhancement of anti-inflammatory behaviors compared with the binding energy of ibuprofen (-5.38 kcal/mol). The anti-inflammatory properties of the new compounds were assessed in vitro using the western blot analysis method and the enzyme-linked immunosorbent assay (ELISA), consistent with the outcomes obtained from docking. The half-maximal inhibitory concentration (IC₅₀) values are 4.9, 1.7, 3.7, 5.6, 2.9, and 2.3 µM for HL and the Co, Ni, Cu, Sm, and Gd complexes, respectively, showing that they are more effective inhibitors of COX2 than ibuprofen (IC₅₀ = 31.4 µM). The brain or intestinal estimated permeation method (BOILED-Egg) showed that HL and its Co complex have high gastrointestinal absorption, while only the free ligand has high brain penetration. The binding constants of Co, Cu, and Gd complexes with DNA were recorded as 2.20 × 10⁴, 2.27 × 10^6, and 4.46 × 10³ M^-1, respectively, indicating the intercalator behavior of interaction. The newly synthesized ibuprofen derivative and its metal complexes showed greater anti-inflammatory activity than ibuprofen.

Keywords: DFT; DNA interaction; anti-inflammatory; docking; ibuprofen; pharmacokinetic.

MeSH terms

Anti-Inflammatory Agents / pharmacology
Coordination Complexes* / chemistry
Copper / chemistry
Cyclooxygenase 2
DNA / chemistry
Humans
Ibuprofen* / pharmacology
Ligands
Spectroscopy, Fourier Transform Infrared

Substances

Ibuprofen
Copper
Cyclooxygenase 2
Coordination Complexes
DNA
Ligands
Anti-Inflammatory Agents

Grants and funding

This research received no external funding.