Synthesis and pharmacological properties of novel guanidine derivatives of quinazoline-2,4(1H,3H)-dione

Authors

DOI:

https://doi.org/10.18413/rrpharmacology.10.486

Abstract

Introduction: Na+/H+ exchanger type 1 (NHE-1) is a validated drug target for the treatment of cardiovascular and ophthalmic diseases due to the cytoprotective, anti-ischemic and anti-inflammatory properties of NHE-1 inhibitors. This article presents data on the synthesis and pharmacological activity studies of novel guanidine derivatives of quinazoline-2,4(1H,3H)-dione 6-11 and reference drugs amiloride, rimeporide, zoniporide, dexamethasone, aminoguanidine, and acetylsalicylic acid.

Materials and Methods: Pharmacological properties were assessed using pH-dependent platelets deformation assay, anti-inflammatory activity assay on LPS-stimulated peritoneal macrophages, antiglycation assay, analysis of platelet aggregation in vitro and measurement of intraocular pressure in vivo.

Results: Several compounds combine NHE-1 inhibition with antiglaucomic and antiplatelet activity. Compound 11 significantly inhibits pro-inflammatory activation of murine macrophages (IC50 15.64 μM) and effectively suppresses the formation of glycated proteins (38.1±2.6% in C 1 mM).

Conclusion: The investigated compounds represent a promising scaffold for development of agents for the treatment of cardiovascular pathologies, glaucoma, excessive inflammation, and late diabetic complications including retina diabetics and thrombosis.

Graphical Abstract

Keywords:

Na /H -exchanger, NHE-1, guanidine derivatives of quinazoline, antiglaucomic action, antiglycation, antiplatelet activity

References

Al-Humimat G, Marashdeh I, Daradkeh D, Kooner K (2021) Investigational rho kinase inhibitors for the treatment of glaucoma. Journal of Experimental Pharmacology 13: 197–212. https://doi.org/10.2147/JEP.S259297 [PubMed] [PMC]

Ansari NA, Rasheed Z (2010) Non-enzymatic glycation of proteins: from diabetes to cancer. Biomedical Сhemistry [Biomeditsinskaya Khimiya] 56(2): 168–178. https://doi.org/10.18097/pbmc20105602168 [PubMed] [in Russian]

Avila MY, Seidler RW, Stone RA, Civan MM (2002) Inhibitors of NHE-1 Na+/H+ exchange reduce mouse intraocular pressure. Investigative Ophthalmology & Visual Science 43(6): 1897–1902. [PubMed]

Cao Y, Redd MA, Fang C, Mizikovsky D, Li X, Macdonald PS, King GF, Palpant NJ (2023) New drug targets and preclinical modelling recommendations for treating acute myocardial infarction. Heart, Lung and Circulation 32(7): 852–869. https://doi.org/10.1016/j.hlc.2022.12.015 [PubMed]

Chen S, Coronel R, Hollmann MW, Weber NC, Zuurbier CJ (2022) Direct cardiac effects of SGLT2 inhibitors. Cardiovascular Diabetology 21(1): 45. https://doi.org/10.1186/s12933-022-01480-1 [PubMed] [PMC]

Correale M, Tricarico L, Croella F, Alfieri S, Fioretti F, Brunetti ND, Inciardi RM, Nodari S (2023) Novelties in the pharmacological approaches for chronic heart failure: new drugs and cardiovascular targets. Frontiers in Cardiovascular Medicine 10: 1157472. https://doi.org/10.3389/fcvm.2023.1157472 [PubMed] [PMC]

Cummings BS, Schnellmann RG (2021) Measurement of cell death in mammalian cells. Current Protocols 1(8): e210. https://doi.org/10.1002/cpz1.210 [PubMed]

De Vito P (2006) The sodium/hydrogen exchanger: a possible mediator of immunity. Cellular Immunology 240(2): 69–85. https://doi.org/10.1016/j.cellimm.2006.07.001[PubMed]

Eskandariyan Z, Esfahani Zadeh M, Haj Mohammad Ebrahim Tehrani K, Mashayekhi V, Kobarfard F (2014) Synthesis of thioether derivatives of quinazoline-4-one-2-thione and evaluation of their antiplatelet aggregation activity. Archives of Pharmacal Research 37(3): 332–339. https://doi.org/10.1007/s12272-013-0192-5 [PubMed]

Freddo TF, Civan M, Gong H (2022) Aqueous humor and the dynamics of its flow: Mechanisms and routes of aqueous humor drainage. Albert and Jakobiec’s Principles and Practice of Ophthalmology. Cham: Springer International Publishing, 1989–033 pp..https://doi.org/10.1007/978-3-030-42634-7_163

Gabbasov ZA, Popov EG, Gavrilova IY, Pozin EY, Markosyan RA (1989) A new highly sensitive method of analysis of thrombocyte aggregation. Laboratornoe Delo 10: 15–18.[PubMed] [in Russian]

García-Díez G, Ramis R, Mora-Diez N (2020) Theoretical study of the copper complexes with aminoguanidine: Investigating secondary antioxidant activity. ACS Omega 5(24): 14502–14512. https://doi.org/10.1021/acsomega.0c01175 [PubMed] [PMC]

Khodjaev NS, Sidorova AV, Smirnova EDA, Eliseeva MA, Starostina AV (2020) Therapy of neovascular glaucoma. National Journal of Glaucoma [Natsional'nyy Zhurnal Glaukоma] 19(2): 76–87. [in Russian]

Kumaksheva TN (2021) Diabetic retinopathy-modern aspects of development, diagnosis and treatment (literature review). Proceedings of the All-Russian Scientific Conference with International Participation. In 3 parts. Part 2. Saransk, 06-11 December; pp. 371–378. [in Russian]

Kwon HW, Shin JH, Lim DH, Ok WJ, Nam GS, Kim MJ, Kwon HK, Noh JH, Lee JY, Kim HH, Kim JL, Park HJ (2016) Antiplatelet and antithrombotic effects of cordycepin-enriched WIB-801CE from Cordyceps militaris ex vivo, in vivo, and in vitro. BMC Complementary Medicine and Therapies 16(1): 508. https://doi.org/10.1186/s12906-016-1463-8[PubMed] [PMC]

Liu Y, Kintner DB, Chanana V, Algharabli J, Chen X, Gao Y, Chen J, Ferrazzano P, Olson JK, Sun D (2010) Activation of microglia depends on Na+/H+ exchange-mediated H+ homeostasis. The Journal of Neuroscience 30(45): 15210–15220. https://doi.org/10.1523/JNEUROSCI.3950-10.2010 [PubMed] [PMC]

Ma Y, Han J, Li S, Zhang A, Cao W, Sun X (2019) Association between platelet parameters and glaucoma severity in primary open-angle glaucoma. Journal of Ophthalmology 2019: 3425023 https://doi.org/10.1155/2019/3425023 [PubMed] [PMC]

Marcus AJ, Iezhitsa I, Agarwal R, Vassiliev P, Spasov A, Zhukovskaya O, Anisimova V, Mohd Ismail N (2018) Data on the effects of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole compounds on intraocular pressure of ocular normotensive rats. Data in Brief 18: 523–554. https://doi.org/10.1016/j.dib.2018.03.019 [PubMed] [PMC]

Metwally SAH, Paruchuri SS, Yu L, Capuk O, Pennock N, Sun D, Song S (2023) Pharmacological inhibition of NHE1 protein increases white matter resilience and neurofunctional recovery after ischemic stroke. The International Journal of Molecular Sciences 24(17): 13289. https://doi.org/10.3390/ijms241713289 [PubMed] [PMC]

Nikitin E, Mironova E, Shpakovsky D, Gracheva Y, Koshelev D, Utochnikova V, Lyssenko K, Oprunenko Y, Yakovlev D, Litvinov R, Seryogina M, Spasov A, Milaeva E (2022) Cytotoxic and luminescent properties of novel organotin complexes with chelating antioxidant ligand. Molecules 27(23): 8359. https://doi.org/10.3390/molecules27238359 [PubMed] [PMC]

Pease ME, Hammond JC, Quigley HA (2006) Manometric calibration and comparison of TonoLab and TonoPen tonometers in rats with experimental glaucoma and in normal mice. Journal of Glaucoma 15(6): 512–519.https://doi.org/10.1097/01.ijg.0000212276.57853.19 [PubMed]

Pedersen SF, Counillon L (2019) The SLC9A-C mammalian Na+/H+ exchanger family: Molecules, Mechanisms, and Physiology. Physiological Reviews 99(4): 2015–2113. https://doi.org/10.1152/physrev.00028.2018 [PubMed]

Percie du Sert N, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, Clark A, Cuthill IC, Dirnagl U, Emerson M, Garner P, Holgate ST, Howells DW, Hurst V, Karp NA, Lazic SE, Lidster K, MacCallum CJ, Macleod M, Pearl EJ, Petersen OH, Rawle F, Reynolds P, Rooney K, Sena ES, Silberberg SD, Steckler T, Würbel H (2020) Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biology 18(7): e3000411. https://doi.org/10.1371/journal.pbio.3000411 [PubMed] [PMC]

Rosskopf D, Morgenstern E, Scholz W, Osswald U, Siffert W (1991) Rapid determination of the elevated Na(+)-H+ exchange in platelets of patients with essential hypertension using an optical swelling assay. Journal of Hypertension 9(3): 231–238. [PubMed]

Shahidullah M, Mandal A, Delamere NA (2009) Responses of sodium-hydrogen exchange to nitric oxide in porcine cultured nonpigmented ciliary epithelium. Investigative Ophthalmology & Visual Science 50(12): 5851–5858. https://doi.org/10.1167/iovs.09-3453[PubMed] [PMC]

Shi Y, Kim D, Caldwell M, Sun D (2013) The role of Na(+)/h (+) exchanger isoform 1 in inflammatory responses: maintaining H(+) homeostasis of immune cells. Advances in Experimental Medicine and Biology 961: 411–418. https://doi.org/10.1007/978-1-4614-4756-6_35 [PubMed]

Soto I, Howell GR (2014) The complex role of neuroinflammation in glaucoma. Cold Spring Harbor Perspectives in Medicine 4(8): a017269. https://doi.org/10.1101/cshperspect.a017269 [PubMed] [PMC]

Spasov A, Ozerov A, Kosolapov V, Gurova N, Kucheryavenko A, Naumenko L, Babkov D, Sirotenko V, Taran A, Borisov A, Sokolova E, Klochkov V, Merezhkina D, Miroshnikov M, Ovsyankina N, Smirnov A, Velikorodnaya Y (2022) Guanidine derivatives of quinazoline-2,4(1H,3H)-Dione as NHE-1 inhibitors and anti-inflammatory agents. Life 12(10): 1647. https://doi.org/10.3390/life12101647 [PubMed] [PMC]

Spasov A, Ozerov A, Vassiliev P, Kosolapov V, Gurova N, Kucheryavenko A, Naumenko L, Babkov D, Sirotenko V, Taran A, Litvinov R, Borisov A, Klochkov V, Merezhkin D, Miroshnikov M, Uskov G, Ovsyankina N (2021) Synthesis and multifaceted pharmacological activity of novel quinazoline NHE-1 inhibitors. Scientific Reports 11(1): 24380. https://doi.org/10.1038/s41598-021-03722-w [PubMed] [PMC]

Taran AS, Naumenko LV, Govorova YA, Gurova NA, Spasov AA, Ozerov AA, Merezhkina DV (2023) Effect of guanidine derivatives of quinazoline on Na+/H+-exchanger and intraocular pressure. Bioorganic Chemistry 49(2): 207–215. https://doi.org/10.31857/S0132342323020215

Vasan S, Foiles P, Founds H (2003) Therapeutic potential of breakers of advanced glycation end product-protein crosslinks. Archives of Biochemistry and Biophysics 419(1): 89–96. https://doi.org/10.1016/j.abb.2003.08.016 [PubMed]

Vishnevskaya VV, Gurova NA, Spasov AA, Ozerov AA, Ovsyankina NV (2022) Effect of NHE-1 inhibitors zoniporide and BMA-1321 on myocardial contractility in animals with chronic heart failure. Experimental and Clinical Pharmacology 4(85): 3–8. https://doi.org/10.30906/0869-2092-2022-85-4-3-8

Wang B, Kasper M, Laffer B, Meyer Zu Hörste G, Wasmuth S, Busch M, Jalilvand TV, Thanos S, Heiligenhaus A, Bauer D, Heinz C (2020) Increased hydrostatic pressure promotes primary M1 reaction and secondary M2 polarization in macrophages. Frontiers in Immunology 11: 573955. https://doi.org/10.3389/fimmu.2020.573955 [PubMed] [PMC]

Watanabe Y, Hamanaka T, Takemura T, Murakami A (2010) Involvement of platelet coagulation and inflammation in the endothelium of Schlemm’s canal. Investigative Ophthalmology & Visual Science 51(1): 277–283. https://doi.org/10.1167/iovs.08-3279[PubMed]

Weissman BA, Gross SS (2001) Measurement of NO and NO synthase. Current Protocols in Neuroscience Chapter 7: Unit 7.13. https://doi.org/10.1002/0471142301.ns0713s05[PubMed]

Wichaiyo S, Saengklub N (2022) Alterations of sodium-hydrogen exchanger 1 function in response to SGLT2 inhibitors: what is the evidence? Heart Failure Reviews 27(6): 1973–1990. https://doi.org/10.1007/s10741-022-10220-2 [PubMed]

Yeves AM, Ennis IL (2020) Na+/H+ exchanger and cardiac hypertrophy. Hipertensión y Riesgo Vascular 37(1): 22–32. https://doi.org/10.1016/j.hipert.2019.09.002 [PubMed]

Zhang X, Goncalves R, Mosser DM (2015) The isolation and characterization of murine macrophages. Current Protocols in Immunology 111: 14.1.1-14.1.16. https://doi.org/10.1002/0471142735.im1401s111 [PubMed] [PMC]

Author Contribution

Alexander A. Ozerov, Volgograd State Medical University

Doctor of Chemical Sciences (DSc), Chairman of the Department of  Pharmaceutical & Toxicological Chemistry, Head of the Department of Synthesis and Pharmaceutical Technologies of Scientific Center for Innovative Medicines, Volgograd State Medical University, Professor, Volgograd, Russia; e-mail: dds.ozerov@gmail.com; ORCID ID https://orcid.org/0000-0002-4721-0959. The author advised on the design of the study, took part in the synthesis of novel compounds and edited the text of the article.

Daria V. Merezhkina, Volgograd State Medical University

Teaching Fellow of the Department of Pharmaceutical & Toxicological Chemistry, Employee of the Department of Synthesis and Pharmaceutical Technologies of Scientific Center for Innovative Medicines, Volgograd State Medical University, Volgograd, Russia; e-mail: merezhkinad@mail.ru, ORCID ID https://orcid.org/0000-0002-9848-7149. The author was engaged in conducting the synthesis of novel compounds.

Natalia A. Gurova, Volgograd State Medical University

Doctor Habil. of Medical Sciences (DSc), Professor of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd, Russia; e-mail: gurova.vlgmed@mail.ru; ORCID ID https://orcid.org/0000-0002-0670-1444. The author took part in conducting experimental work and analyzing the material.

Lyudmila V. Naumenko, Volgograd State Medical University

Doctor Habil. of Medical Sciences (DSc), Professor of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd, Russia; e-mail: milanaumenko@mail.ru; ORCID ID https://orcid.org/0000-0002-2119-4233. The author took part in conducting experimental work and analyzing the material.

Denis A. Babkov, Volgograd State Medical University

Doctor of Pharmaceutical Sciences (DSc), Assistant Professor of the Department of Pharmacology and Bioinformatics, Head of Scientific Center for Innovative Medicines, Volgograd State Medical University, Volgograd, Russia; e-mail: denis.a.babkov@gmail.com; ORCID IDhttps://orcid.org/0000-0002-9645-3324. The author took part in conducting experimental work and analyzing the material, and translation.

Victor S. Sirotenko, Volgograd State Medical University

Candidate of Pharmaceutical Sciences (PhD), Assistant Professor of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd, Russia; e-mail: sirotenko.viktor@yandex.ru; ORCID ID https://orcid.org/0000-0003-2249-020X. The author took part in conducting experimental work and analyzing the material.

Roman A. Litvinov, Volgograd State Medical University

Candidate of  Medical Sciences (PhD), Assistant Professor of the Department of Pharmacology and Bioinformatics, Senior scientist of laboratory for metabotropic drugs of Scientific Center for Innovative Medicines, Volgograd State Medical University, Volgograd, Russia; e-mail: litvinov.volggmu@mail.ru; ORCID ID https://orcid.org/0000-0002-0162-0653. The author took part in conducting experimental work and analyzing the material.

Alena S. Taran, Volgograd State Medical University

Candidate of Medical Sciences (PhD) Assistant Professor of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd, Russia; e-mail: alena-beretta-taran@mail.ru; ORCID ID https://orcid.org/0000-0001-8477-254X. The author was engaged in conducting the experimental work.

Nadezhda V. Stepanova, Volgograd State Medical University

Teaching Fellow of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd, Russia; e-mail: ovsyankina99@mail.ru; ORCID IDhttps://orcid.org/0000-0002-6629-3729. The author was engaged in conducting the experimental work.

Umida M. Ibragimova, Volgograd State Medical University

Teaching Fellow of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd, Russia; e-mail: iumida@list.ru; ORCID ID https://orcid.org/0000-0001-9141-4417. The author was engaged in conducting the experimental work.

Alexander A. Spasov, Volgograd State Medical University

Doctor of Medical Sciences (DSc), Chairman of the Department of Pharmacology and Bioinformatics, Scientific advisor of Scientific Center for Innovative Medicines, Volgograd State Medical University,  Academician of RAS, Professor, Volgograd, Russia; e-mail: aspasov@mail.ru, ORCID  ID https://orcid.org/0000-0002-7185-4826. The author advised on the research idea, the concept and design of the study, analyzed the results and edited the text of the article.

Vadim A. Kosolapov, Volgograd State Medical University

Doctor Habil. of Medical Sciences (DSc), Professor of the Department of Pharmacology and Bioinformatics, Head of laboratory for metabotropic drugs of Scientific Center for Innovative Medicines, Volgograd State Medical University, Professor, Volgograd, Russia; e-mail: vad-ak@mail.ru; ORCID ID https://orcid.org/0000-0002-6702-1207. The author advised on the design of the study, analyzed the results and edited the text of the article.

Downloads

Published

23-09-2024

How to Cite

Ozerov AA, Merezhkina DV, Gurova NA, Naumenko LV, Babkov DA, Sirotenko VS, Litvinov RA, Taran AS, Stepanova NV, Ibragimova UM, Spasov AA, Kosolapov VA (2024) Synthesis and pharmacological properties of novel guanidine derivatives of quinazoline-2,4(1H,3H)-dione. Research Results in Pharmacology 10(3): 73–84. https://doi.org/10.18413/rrpharmacology.10.486

Issue

Section

Experimental Pharmacology

Most read articles by the same author(s)

1 2 > >>