Novel Substituted Azoloazines with Anticoagulant Activity
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biology
2.2.1. Anticoagulant Activity of the Target Compounds In Vitro
2.2.2. Ecarin Clotting Time
2.2.3. An Animal Study of Anticoagulant Activity
3. Materials and Methods
3.1. Chemistry
3.1.1. General Procedure for the Preparation of Nitro Derivatives of Azolo[1,5-a]pyrimidines 4c,d (Scheme 2)
3.1.2. General Procedure for the Preparation of Di(het)aryl-Substituted Azolo[1,5-a]pyrimidines 7a,b (Scheme 2)
3.1.3. General Procedure for the Preparation of 7-Aryl-5-methyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylates 10a,b (Scheme 2)
3.1.4. The General Synthesis of 6-Nitro-7-methoxy-4,7-dihydro-azolyl-4 guanidates 12a,b, 14 (Scheme 3)
3.1.5. The General Synthetic Method of 6-Guanidino-3-alkylthio-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazines 16a–c (Scheme 5)
3.2. Biology
3.2.1. Animals
3.2.2. In Vitro Anticoagulant Assay
3.2.3. Ecarin Clotting Time
3.2.4. Anticoagulant Assay in Animals
3.2.5. Statistical Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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No. | Compound | Structure | Coagulogram Parameters | ||
---|---|---|---|---|---|
APTT, s | TT, s | PT, s | |||
1 | Control | 46.23 ± 0.22 | 11.65 ± 0.06 | 14.60 ± 0.10 | |
2 | Dabigatran etexilate | 75.26 ± 2.61 * | 70.23 ± 3.15 * | 14.20 ± 0.38 * | |
3 | 1a | 22.1 ± 5.9 | 22.7 ± 2.0 * | 14.5 ± 0.0 | |
4 | 1b | 26.8 ± 2.4 | 23.9 ± 0.9 * | 13.3 ± 0.2 | |
5 | 1c | 27.1 ± 2.0 | 26.2 ± 1.0 * | 13.8 ± 0.4 | |
6 | 1d | 18.2 ± 0.5 | 26.7 ± 1.3 * | 13.4 ± 0.3 | |
7 | 1e | 29.6 ± 0.2 | 38.0 ± 0.5 * | 13.4 ± 0.1 | |
8 | 1f | 24.8 ± 4.2 | 39.3 ± 1.8 * | 13.1 ± 0.3 | |
9 | 1g | 30.6 ± 1.6 | 34.1 ± 0.9 * | 11.7 ± 0.4 | |
10 | 1h | 25.7 ± 3.1 | 35.6 ± 1.1 * | 13.9 ± 0.1 | |
11 | 1i | 32.1 ± 4.8 | 21.9 ± 1.2 * | 13.8 ± 0.3 | |
12 | 1j | 32.5 ± 0.1 | 22.0 ± 2.7 * | 14.2 ± 0.4 | |
13 | 5a | 26.3 ± 2.9 | 43.8 ± 4.3 * | 13.4 ± 0.1 | |
14 | 5b | 25.9 ± 2.2 | 21.0 ± 0.0 * | 15.8 ± 0.3 | |
15 | 5c | 27.6 ± 1.9 | 41.4 ± 3.1 * | 13.9 ± 0.2 | |
16 | 5d | 61.78 ± 4.58 * | 154.43 ± 11.14 * | 14.08 ± 0.4 | |
17 | 7a | 56.23 ± 5.05 | 66.58 ± 4.64 * | 11.62 ± 1.00 | |
18 | 7b | 35.0 ± 0.2 | 32.3 ± 0.9 * | 13.6 ± 0.5 | |
19 | 8c | 34.6 ± 0.7 | 34.7 ± 0.7 * | 14.2 ± 0.1 | |
20 | 10a | 30.9 ± 0.6 | 48.6 ± 22.4 * | 13.2 ± 1.0 | |
21 | 10b | 30.6 ± 2.6 | 27.1 ± 1.4 * | 12.7 ± 0.2 | |
22 | 12a | 25.1 ± 0.8 | 24.3 ± 3.5 * | 14.2 ± 0.1 | |
23 | 12b | 26.2 ± 1.5 | 25.6 ± 3.9 * | 14.8 ± 0.4 | |
24 | 14 | 24.5 ± 0.8 | 23.8 ± 3.5 * | 14.5 ± 0.5 | |
25 | 15a | 34.0 ± 0.6 | 32.8 ± 0.8 * | 14.5 ± 0.3 | |
26 | 15b | 34.1 ± 0.5 | 33.7 ± 0.6 * | 14.0 ± 0.2 | |
27 | 16a | 29.1 ± 1.4 | 34.3 ± 4.7 * | 12.2 ± 0.2 | |
28 | 16b | 24.7 ± 1.2 | 22.7 ± 1.7 * | 13.9 ± 0.5 | |
29 | 16 | 26.3 ± 1.1 | 25.9 ± 1.6 * | 14.1 ± 0.3 |
No. | Compound | Coagulogram Parameters | ||
---|---|---|---|---|
APTT, s | TT, s | PT, s | ||
1 | Control | 46.23 ± 0.22 | 11.65 ± 0.06 | 14.60 ± 0.10 |
2 | LPS control | 56.28 ± 1.60 * | 9.01 ± 0.37 * | 15.10 ± 0.07 |
3 | Dabigatran etexilate | 135.13 ± 15.17 *# | 125.45 ± 1.54 *# | 15.73 ± 0.20 |
4 | 5d | 61.78 ± 4.58 * | 154.43 ± 7.14 *# | 14.08 ± 0.4 |
Compound | Δ% of Thrombin Time Prolongation Relative to Control | EC50, μM | |||
10 μM | 5 μM | 1 μM | 0.1 μM | ||
Dabigatran etexilate | 302.0 ± 34.4 * | 176.1 ± 15.3 * | 42.3 ± 5.6 * | 1.4 ± 0.4 * | 1.4 |
5d | 467.1 ± 14.4 *# | 194.1 ± 10.0 *# | 46.5 ± 6.7 * | 4.3 ± 1.0 * | 1.3 |
Compound | Δ % of Thrombin Time Prolongation Relative To Control + LPS | IC50, μM | |||
10 μM | 5 μM | 1 μM | 0.1 μM | ||
Dabigatran etexilate | 292.0 ± 0.6 # | 292.0 ± 0.6 # | 51.7 ± 0.5 | 16.3 ± 0.2 # | 0.76 |
5d | 354.1 ± 6.5 #$ | 234.1 ± 4.2 #$ | 56.3 ± 1.1 * | 8.4 ± 1.6 | 0.78 |
Compound | Coagulogram Parameters of Animals without Hypercytokinemia | ||
APTT, s | TT, s | PT, s | |
Control group | 38.3 ± 1.4 | 57.7 ± 1.8 | 28.1 ± 1.4 |
Dabigatran etexilate | 137.5 ± 2.2 * | 603.9 ± 14.2 * | 31.2 ± 1.3 |
5d | 59.2 ± 8.3 * | 325.3 ± 5.1 * | 24.5 ± 1.1 |
Compound | Coagulogram Parameters of Animals with Hypercytokinemia | ||
APTT, s | TT, s | PT, s | |
LPS group | 18.4 ± 0.8 | 44.1 ± 1.7 | 21.2 ± 1.3 |
Dabigatran etexilate | 41.0 ± 2.0 # | 566.1 ± 11.5 # | 28.1 ± 1.0 |
5d | 28.7 ± 1.0 # | 640.3 ± 7.4 #$ | 26.4 ± 1.4 |
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Spasov, A.A.; Fedorova, O.V.; Rasputin, N.A.; Ovchinnikova, I.G.; Ishmetova, R.I.; Ignatenko, N.K.; Gorbunov, E.B.; Sadykhov, G.A.o.; Kucheryavenko, A.F.; Gaidukova, K.A.; et al. Novel Substituted Azoloazines with Anticoagulant Activity. Int. J. Mol. Sci. 2023, 24, 15581. https://doi.org/10.3390/ijms242115581
Spasov AA, Fedorova OV, Rasputin NA, Ovchinnikova IG, Ishmetova RI, Ignatenko NK, Gorbunov EB, Sadykhov GAo, Kucheryavenko AF, Gaidukova KA, et al. Novel Substituted Azoloazines with Anticoagulant Activity. International Journal of Molecular Sciences. 2023; 24(21):15581. https://doi.org/10.3390/ijms242115581
Chicago/Turabian StyleSpasov, Alexander A., Olga V. Fedorova, Nikolay A. Rasputin, Irina G. Ovchinnikova, Rashida I. Ishmetova, Nina K. Ignatenko, Evgeny B. Gorbunov, Gusein A. o. Sadykhov, Aida F. Kucheryavenko, Kseniia A. Gaidukova, and et al. 2023. "Novel Substituted Azoloazines with Anticoagulant Activity" International Journal of Molecular Sciences 24, no. 21: 15581. https://doi.org/10.3390/ijms242115581