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. 2021 Mar 12:15:1167-1180.
doi: 10.2147/DDDT.S296502. eCollection 2021.

Charge-Transfer Complex of Linifanib with 2,3-dichloro-3,5-dicyano-1,4-benzoquinone: Synthesis, Spectroscopic Characterization, Computational Molecular Modelling and Application in the Development of Novel 96-microwell Spectrophotometric Assay

Ibrahim A Darwish  1 , Nasr Y Khalil  1 , Nawaf A Alsaif  1 , Rashed N Herqash  2 , Ahmed Y A Sayed  1 , Hamdy M Abdel-Rahman  3   4
Affiliations

Charge-Transfer Complex of Linifanib with 2,3-dichloro-3,5-dicyano-1,4-benzoquinone: Synthesis, Spectroscopic Characterization, Computational Molecular Modelling and Application in the Development of Novel 96-microwell Spectrophotometric Assay

Ibrahim A Darwish et al. Drug Des Devel Ther. .

Abstract

Background: Linifanib (LFB) is a multi-targeted receptor tyrosine kinase inhibitor used in the treatment of hepatocellular carcinoma and other types of cancer. The charge-transfer (CT) interaction of LFB is important in studying its receptor binding mechanisms and useful in the development of a reliable CT-based spectrophotometric assay for LFB in its pharmaceutical formulation to assure its therapeutic benefits.

Purpose: The aim of this study was to investigate the CT reaction of LFB with 2,3-dichloro-3,5-dicyano-1,4-benzoquinone (DDQ) and its application in the development of a novel 96-microwell spectrophotometric assay for LFB.

Methods: The reaction was investigated, its conditions were optimized, the physicochemical and constants of the CT complex and stoichiometric ratio of the complex were determined. The solid-state LFB-DDQ complex was synthesized and its structure was analyzed by UV-visible, FT-IR, and 1H-NMR spectroscopic techniques, and also by the computational molecular modeling. The reaction was employed in the development of a novel 96-microwell spectrophotometric assay for LFB.

Results: The reaction resulted in the formation of a red-colored product, and the spectrophotometric investigations confirmed that the reaction had a CT nature. The molar absorptivity of the complex was linearly correlated with the dielectric constant and polarity index of the solvent; the correlation coefficients were 0.9526 and 0.9459, respectively. The stoichiometric ratio of LFB:DDQ was 1:2. The spectroscopic and computational data confirmed the sites of interaction on the LFB molecule, and accordingly, the reaction mechanism was postulated. The reaction was utilized in the development of the first 96-microwell spectrophotometric assay for LFB. The assay limits of detection and quantitation were 1.31 and 3.96 μg/well, respectively. The assay was successfully applied to the analysis of LFB in its bulk and tablets with high accuracy and precision.

Conclusion: The assay is simple, rapid, accurate, eco-friendly as it consumes low volumes of organic solvent, and has high analysis throughput.

Keywords: 2,3-dichloro-3,5-dicyano-1,4-benzoquinone; 96-microwell spectrophotometric assay; charge-transfer reaction; high-throughput pharmaceutical analysis; linifanib; spectroscopic techniques.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
The chemical structures of linifanib (LFB) and 2,3-dichloro-3,5-dicyano-1,4-benzoquinone (DDQ).
Figure 2
Figure 2
Absorption spectra of (1): LFB (1.33×10−4 M), (2): DDQ (1.39×10−3 M) and (3): reaction mixture of LFB and DDQ. LFB, DDQ and their reaction mixture were in methanol.
Figure 3
Figure 3
Tauc plot of energy (hυ) against (αhυ)2 against for CT complex of LFB with DDQ in methanol solvent (A). A segment of the same plot at in the energy range of 1.9–2.2 eV (B).
Figure 4
Figure 4
Effect of DDQ concentration (●) and time (■) on the CT reaction of LFB and DDQ.
Figure 5
Figure 5
Effect of solvent on the CT reaction of LFB and DDQ.
Figure 6
Figure 6
Correlation of molar absorptivity (ε) of LFB-DDQ CT complex versus dielectric constant (●, on left axis) and polarity index (▲, on right axis) of the solvent used for the reaction. Linear fitting equations and correlation coefficients (r) are given on the regression lines.
Figure 7
Figure 7
Benesi–Hildebrand plot of the CT complex of LFB with DDQ and the linear fitting equation with correlation coefficient (r), AAD and [D0] are the molar concentration of DDQ, absorbance of the complex reaction mixture, and molar concentration of LFB, respectively.
Figure 8
Figure 8
Job’s continuous variation (A) and spectrophotometric titration (B) plots for determination of molar ratio of the CT reaction of LFB with DDQ.
Figure 9
Figure 9
Energy-minimized LFB with charges on each atom (A) and the CT complex of LFB with DDQ (B) (one molecule of LFB and two molecules of DDQ). In panel (A), arrows point to the atoms having the highest electron densities.
Figure 10
Figure 10
Scheme for the CT reaction pathway of LFB with DDQ.
Figure 11
Figure 11
FT-IR spectra of DDQ (A), LFB (B) and CT complex of DDQ and LFB (C).
Figure 12
Figure 12
The 96-microwell spectrophotometric assay for determination of LFB based on its CT reaction with DDQ. Panel (A) an image of the assay plate containing the calibration solutions of varying LFB concentrations (upper wells) and test samples (lower wells). Panel (B) the generated calibration curve with the fitting equation and determination coefficient (r2).
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