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

Alexander A. Ozerov; Daria V. Merezhkina; Natalia A. Gurova; Lyudmila V.  Naumenko; Denis A. Babkov; Victor S. Sirotenko; Roman A. Litvinov; Alena S. Taran; Nadezhda V. Stepanova; Umida M. Ibragimova; Alexander A. Spasov; Vadim A. Kosolapov

doi:10.18413/rrpharmacology.10.486

Authors

Alexander A. Ozerov Volgograd State Medical University https://orcid.org/0000-0002-4721-0959
Daria V. Merezhkina Volgograd State Medical University https://orcid.org/0000-0002-9848-7149
Natalia A. Gurova Volgograd State Medical University https://orcid.org/0000-0002-0670-1444
Lyudmila V. Naumenko Volgograd State Medical University https://orcid.org/0000-0002-2119-4233
Denis A. Babkov Volgograd State Medical University https://orcid.org/0000-0002-9645-3324
Victor S. Sirotenko Volgograd State Medical University https://orcid.org/0000-0003-2249-020X
Roman A. Litvinov Volgograd State Medical University https://orcid.org/0000-0002-0162-0653
Alena S. Taran Volgograd State Medical University https://orcid.org/0000-0001-8477-254X
Nadezhda V. Stepanova Volgograd State Medical University https://orcid.org/0000-0002-6629-3729
Umida M. Ibragimova Volgograd State Medical University https://orcid.org/0000-0001-9141-4417
Alexander A. Spasov Volgograd State Medical University https://orcid.org/0000-0002-7185-4826
Vadim A. Kosolapov Volgograd State Medical University https://orcid.org/0000-0002-6702-1207

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 (IC₅₀15.64 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

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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.