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. 2022 Oct 20;12(10):1647.
doi: 10.3390/life12101647.

Guanidine Derivatives of Quinazoline-2,4(1 H,3 H)-Dione as NHE-1 Inhibitors and Anti-Inflammatory Agents

Alexander Spasov  1   2 , Alexander Ozerov  2   3 , Vadim Kosolapov  1   2 , Natalia Gurova  1 , Aida Kucheryavenko  1 , Ludmila Naumenko  1 , Denis Babkov  1   2 , Viktor Sirotenko  1 , Alena Taran  1 , Alexander Borisov  2 , Elena Sokolova  1 , Vladlen Klochkov  1   2 , Darya Merezhkina  3 , Mikhail Miroshnikov  1 , Nadezhda Ovsyankina  1 , Alexey Smirnov  4 , Yulia Velikorodnaya  4
Affiliations

Guanidine Derivatives of Quinazoline-2,4(1 H,3 H)-Dione as NHE-1 Inhibitors and Anti-Inflammatory Agents

Alexander Spasov et al. Life (Basel). .

Abstract

Quinazolines are a rich source of bioactive compounds. Previously, we showed NHE-1 inhibitory, anti-inflammatory, antiplatelet, intraocular pressure lowering, and antiglycating activity for a series of quinazoline-2,4(1H,3H)-diones and quinazoline-4(3H)-one guanidine derivatives. In the present work, novel N1,N3-bis-substituted quinazoline-2,4(1H,3H)-dione derivatives bearing two guanidine moieties were synthesized and pharmacologically profiled. The most potent NHE-1 inhibitor 3a also possesses antiplatelet and intraocular-pressure-reducing activity. Compound 4a inhibits NO synthesis and IL-6 secretion in murine macrophages without immunotoxicity and alleviates neutrophil infiltration, edema, and tissue lesions in a model of LPS-induced acute lung injury. Hence, we considered quinazoline derivative 4a as a potential agent for suppression of cytokine-mediated inflammatory response and acute lung injury.

Keywords: LPS; NHE-1; cytokine release; lung injury; macrophage; quinazoline-2,4(1H,3H)-dione.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; nor in the decision to publish the results.

Figures

Figure 1
Figure 1
Putative role of NHE-1 in inflammation.
Figure 2
Figure 2
Synthesis of the target compounds: (i) BrCH2C(O)OBn, K2CO3, DMF, 25 °C, 24 h, 62–65%; (ii) NH2C(NH)NH2 · HCl, KOH, 95% EtOH, reflux, 10 min, 68–81%; (iii) NH2C(NH)NHNH2 ·12H2CO3, KOH, 95% EtOH, reflux, 1 h, 60–63%.
Figure 3
Figure 3
Compound 4a has minimal impact on phagocytic activity and viability of C57bl/6j peritoneal macrophages. Data as the mean and 95% C.I. (n = 100). Statistical significance: ** p < 0.01, *** p < 0.001, **** p < 0.0001 vs. DMSO; #### p < 0.0001 vs. intact cells (1-way ANOVA, Dunnet’s post-test).
Figure 4
Figure 4
Compound 4a alleviated sickness behavior in the C57bl/6j murine model of LPS-induced acute lung injury. Data as the mean and SD, n = 5.
Figure 5
Figure 5
Compound 4a limits IL-6 secretion in the C57bl/6j murine model of LPS-induced acute lung injury. Data as the mean and SD, n = 5. Statistical significance vs. LPS (1-way ANOVA, Dunnet’s post-test): ** p < 0.01.
Figure 6
Figure 6
Compound 4a preserves normal permeability of alveolar vessels in the C57bl/6j murine model of LPS-induced acute lung injury. Data as the mean and SD, n = 5.
Figure 7
Figure 7
Compound 4a prevents leukocyte infiltration and lymphocyte recruitment in the C57bl/6j murine model of LPS-induced acute lung injury. Data as the mean and SD, n = 5. Statistical significance (1-way ANOVA, Dunnet’s post-test): * p < 0.05 vs. Vehicle + LPS (1-way ANOVA, Dunnet’s post-test); ** p < 0.01 vs. LPS; # p < 0.05 vs. Vehicle.
Figure 8
Figure 8
Sections of lung tissue, hematoxylin and eosin staining, ×400 total magnification: (a) vehicle; (b) LPS + vehicle; (c) LPS + dexamethasone; (d) LPS + 4a.
Figure 9
Figure 9
Sections of lung tissue, CD68+ immunostaining, nuclei stained with Mayer’s hematoxylin, ×400 total magnification: (a) vehicle; (b) LPS + vehicle; (c) LPS + dexamethasone; (d) LPS + 4a.
See this image and copyright information in PMC

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