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. 2022 Sep 1;5(10):945-962.
doi: 10.1021/acsptsci.2c00118. eCollection 2022 Oct 14.

Synthesis of Morpholine-, Piperidine-, and N-Substituted Piperazine-Coupled 2-(Benzimidazol-2-yl)-3-arylquinoxalines as Novel Potent Antitumor Agents

Vakhid A Mamedov  1 , Nataliya A Zhukova  1 , Alexandra D Voloshina  1 , Victor V Syakaev  1 , Tat'yana N Beschastnova  1 , Anna P Lyubina  1 , Syumbelya K Amerhanova  1 , Aida I Samigullina  1 , Aidar T Gubaidullin  1 , Daina N Buzyurova  1 , Il Dar Kh Rizvanov  1 , Oleg G Sinyashin  1
Affiliations

Synthesis of Morpholine-, Piperidine-, and N-Substituted Piperazine-Coupled 2-(Benzimidazol-2-yl)-3-arylquinoxalines as Novel Potent Antitumor Agents

Vakhid A Mamedov et al. ACS Pharmacol Transl Sci. .

Abstract

A novel series of 2-(benzimidazol-2-yl)quinoxalines with three types of pharmacophore groups, namely, piperazine, piperidine, and morpholine moieties, which are part of known antitumor drugs, was designed and synthesized. The compounds have been characterized by NMR and IR spectroscopy, high- and low-resolution mass spectrometry, and X-ray crystallography. 2-(Benzimidazol-2-yl)quinoxalines with N-methylpiperazine substituents showed promising activity against a wide range of cancer lines, without causing hemolysis and showing little cytotoxicity against normal human Wi-38 cells (human fetal lung). A mixture of regioisomers 2-(benzimidazol-2-yl)-3-(4-fluorophenyl)-6(and 7)-(4-methylpiperazin-1-yl)quinoxalines (mri BIQ 13da/14da) showed a highly selective cytotoxic effect against human lung adenocarcinoma (cell line A549) with a half-maximal inhibitory concentration at the level of doxorubicin with a selectivity index of 12. The data obtained by flow cytometry, fluorescence microscopy, and multiparametric fluorescence analysis suggested that the mechanism of the cytotoxic effect of the mri BIQ 13da/14da on A549 cells may be associated with the stopping of the cell cycle in phase S and inhibition of DNA synthesis as well as with the induction of mithochondrial apoptosis. Thus, mri BIQ 13da/14da can be considered as a leading compound deserving further study, optimization, and development as a new anticancer agent.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Examples of benzimidazole-containing drugs and promising structures of quinoxaline derivatives.
Figure 2
Figure 2
Structures of 2-heteroarylbenzimidazole derivative as potent antitumor agents.
Figure 3
Figure 3
Design strategy using a concept of molecular hybridization in a novel series of compounds as potent antitumor agents: target compounds 13/14.
Figure 4
Figure 4
Structures of compounds 15 and 16.
Figure 5
Figure 5
Molecular structures of 13da (A) and 14da (B) obtained by X-ray crystallography. The triclinic unit cell of 13da contained two independent molecules with different conformations; the monoclinic unit cell of 14da contained four independent different conformers.
Scheme 1
Scheme 1. Synthesis of Starting Compounds 9
Reagents and conditions: (a) benzene-1,2-diamine, AcOH, rt. (b) DMF, NaN3, rt. (c) aq. AcOH, reflux.
Scheme 2
Scheme 2. Synthesis of Starting Compounds 12
Reagents and conditions: (a) 1-methyl(phenyl)piperazine, piperidine or morpholine, K2CO3, DMF, 120 °C. (b) H2, 10% Pd/C, EtOAc-MeOH (4:1).
Figure 6
Figure 6
Real-time monitoring of A549 cell proliferation. (1) Control. (2) 100 μM mriBIQ 13da/14da. (3) 50 μM mriBIQ 13da/14da. (4) 25 μM mriBIQ 13da/14da. (5) 5 μM mriBIQ 13da/14da. (6) 1 μM mriBIQ 13da/14da.
Figure 7
Figure 7
Cell growth rate calculated by the slope of the line between the values at time points. (A) Time point (25–35) h. (B) Time point (35–40) h. (1) Control. (2) 100 μM mriBIQ 13da/14da. (3) 50 μM mriBIQ 13da/14da. (4) 25 μM mriBIQ 13da/14da. (5) 5 μM mriBIQ 13da/14da. (6) 1 μM mriBIQ 13da/14da.
Figure 8
Figure 8
Effect of mriBIQ 13da/14da on A549 cell cycle arrest. (1) mriBIQ 13da/14da at concentration 1 μM. (2) mriBIQ 13da/14da at concentration 2.5 μM. (3) mriBIQ 13da/14da at concentration 5 μM. (A) Cell distribution histograms. (B) Percentage of cells in the G0/G1, S, and G2/M phases (data are presented as mean ± standard deviation of three independent experiments). *Values indicate P < 0.05.
Figure 9
Figure 9
Multiplex analysis of markers DNA Damage/genotoxicity in A549 cells treated mriBIQ 13da/14da. (1) mriBIQ 13da/14da at concentration 2.5 μM. (2) mriBIQ 13da/14da at concentration 5 μM. A549 cells untreated with the test substance (control).
Figure 10
Figure 10
Flow cytometry analysis of A549 cells treated with mriBIQ 13da/14da. (1) mriBIQ 13da/14da at concentration 1 μM. (2) mriBIQ 13da/14da at concentration 2.5 μM. (3) mriBIQ 13da/14da at concentration 5 μM. (A) Cell distribution histograms. (B) Quantitative determination of % cells with red aggregates.
Figure 11
Figure 11
Induction of the production of intracellular ROS in A549 cells incubated with mriBIQ 13da/14da. (1) mriBIQ 13da/14da at concentration 1 μM. (2) mriBIQ 13da/14da at concentration 2.5 μM. (3) mriBIQ 13da/14da at concentration 5 μM.
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