Guanidine Derivatives of Quinazoline-2,4(1H,3H)-Dione as NHE-1 Inhibitors and Anti-Inflammatory Agents
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemistry
2.1.1. General
2.1.2. Dibenzyl 2,2’-(2,4-Dioxoquinazoline-1,3(2H,4H)-diyl)diacetate (2a)
2.1.3. Dibenzyl 2,2’-(6-Bromo-2,4-dioxoquinazoline-1,3(2H,4H)-diyl)diacetate (2b)
2.1.4. 2,2’-(2,4-Dioxoquinazoline-1,3(2H,4H)-diyl)bis(N-carbamimidoylacetamide) (3a)
2.1.5. 2,2’-(6-Bromo-2,4-dioxoquinazoline-1,3(2H,4H)-diyl)bis(N-carbamimidoylacetamide) (3b)
2.1.6. 1,3-Bis[(5-amino-4H-1,2,4-triazol-3-yl)methyl]quinazoline-2,4(1H,3H)-dione (4a)
2.1.7. 1,3-Bis[(5-amino-4H-1,2,4-triazol-3-yl)methyl]-6-bromoquinazoline-2,4(1H,3H)-dione (4b)
2.2. Cellular Assays
2.2.1. NHE-1 Inhibition Assay
2.2.2. Platelet Aggregation Assay
2.2.3. Isolation and Stimulation of Primary Macrophages
2.2.4. Assay of Nitric Oxide and Cytokines
2.2.5. Cytotoxicity Study
2.2.6. Phagocytosis Assay
2.3. Animal Studies
2.3.1. LPS-Induced Acute Lung Injury
2.3.2. Open Field Test
2.3.3. Bronchoalveolar Lavage and Blood Plasma Preparation
2.3.4. Intraocular Pressure Study
2.3.5. Tail Suspension Test
2.3.6. Histological Study
2.4. Data Analysis
3. Results
3.1. Chemistry
3.2. NHE-1 Inhibition
3.3. Antiplatelet Activity
3.4. IOP-Lowering Activity
3.5. Antidepressant Activity
3.6. Anti-Inflammatory Activity
3.7. Influence of Compound 4a on Macrophage Phagocytic Activity
3.8. Protective Activity of 4a in Murine Model of Acute Lung Injury
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
BAL | Bronchoalveolar lavage |
DMSO | Dimethyl sulfoxide |
LPI | Lung permeability index |
LPS | Lipopolysaccharide |
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Compound | NHE-1 Inhibition at (10 nM) (m ± SD, n = 6, %) | NHE-1 IC (nM) | Inhibition of Platelet Aggregation at (100 M) (m ± SD, n = 5, %) | Max IOP Reduction (m ± SD, n = 5, %). |
---|---|---|---|---|
3a | 37.20 ± 5.97 * | 37.2 | 44.3 ± 14.3 | 10.08 ± 5.8 |
3b | 10.17 ± 3.72 | 46.4 ± 9.2 * | 24.17 ± 5.05 | |
4a | 29.37 ± 4.40 * | 323.5 | 39.3 ± 11.9 | 28.25 ± 7.92 |
4b | 16.17 ± 3.75 * | 47.4 ± 8.9 * | 15.45 ± 9.39 | |
Amiloride | 5.39 ± 1.82 | 1230 | 67.6 ± 1.0 * | 18.39 ± 14.58 |
Acetylsalicylic acid | 31.6 ± 4.6 * |
Compound | Immobilization Time, Mean ± SD, n = 6 (s) |
---|---|
4a (4.0 mg/kg) | 164.4 ± 23.19 * |
4b (4.9 mg/kg) | 168.2 ± 19.52 |
Amiloride (2.6 mg/kg) | 172.7 ± 8.54 * |
Imipramine (8 mg/kg) | 112.5 ± 20.56 * |
Amitriptyline (10 mg/kg) | 50.2 ± 12.71 * |
Vehicle | 264.8 ± 11.6 |
Compound | NO Synthesis IC SE (M) | IL-6 Secretion IC SE (M) | LDH CC SE (M) |
---|---|---|---|
3a | >100 | >100 | >100 |
3b | >100 | >100 | >100 |
4a | 72.96 ± 7.83 | 51.75 ± 1.65 | >100 |
4b | 70.98 ± 4.89 | 64.82 ± 4.31 | >100 |
Dexamethasone | 0.003 ± 0.001 | 0.003 ± 0.001 | >100 |
Amiloride | 0.62 ± 0.05 | 9.52 ± 0.65 | >100 |
Zoniporide | EC 15.56 ± 3.76 | >100 | 406.6 ± 27.6 |
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Spasov, A.; Ozerov, A.; Kosolapov, V.; Gurova, N.; Kucheryavenko, A.; Naumenko, L.; Babkov, D.; Sirotenko, V.; Taran, A.; Borisov, A.; et al. Guanidine Derivatives of Quinazoline-2,4(1H,3H)-Dione as NHE-1 Inhibitors and Anti-Inflammatory Agents. Life 2022, 12, 1647. https://doi.org/10.3390/life12101647
Spasov A, Ozerov A, Kosolapov V, Gurova N, Kucheryavenko A, Naumenko L, Babkov D, Sirotenko V, Taran A, Borisov A, et al. Guanidine Derivatives of Quinazoline-2,4(1H,3H)-Dione as NHE-1 Inhibitors and Anti-Inflammatory Agents. Life. 2022; 12(10):1647. https://doi.org/10.3390/life12101647
Chicago/Turabian StyleSpasov, Alexander, Alexander Ozerov, Vadim Kosolapov, Natalia Gurova, Aida Kucheryavenko, Ludmila Naumenko, Denis Babkov, Viktor Sirotenko, Alena Taran, Alexander Borisov, and et al. 2022. "Guanidine Derivatives of Quinazoline-2,4(1H,3H)-Dione as NHE-1 Inhibitors and Anti-Inflammatory Agents" Life 12, no. 10: 1647. https://doi.org/10.3390/life12101647