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

Александр А. Озеров; Дарья В. Мережкина; Наталья А. Гурова; Людмила В. Науменко; Денис А. Бабков; Виктор С. Сиротенко; Роман А. Литвинов; Алена С. Таран; Надежда В. Степанова; Умида М. Ибрагимова; Александр А. Спасов; Вадим А. Косолапов

doi:10.18413/rrpharmacology.10.486

Авторы

Александр А. Озеров Волгоградский государственный медицинский университет https://orcid.org/0000-0002-4721-0959
Дарья В. Мережкина Волгоградский государственный медицинский университет https://orcid.org/0000-0002-9848-7149
Наталья А. Гурова Волгоградский государственный медицинский университет https://orcid.org/0000-0002-0670-1444
Людмила В. Науменко Волгоградский государственный медицинский университет https://orcid.org/0000-0002-2119-4233
Денис А. Бабков Волгоградский государственный медицинский университет https://orcid.org/0000-0002-9645-3324
Виктор С. Сиротенко Волгоградский государственный медицинский университет https://orcid.org/0000-0003-2249-020X
Роман А. Литвинов Волгоградский государственный медицинский университет https://orcid.org/0000-0002-0162-0653
Алена С. Таран Волгоградский государственный медицинский университет https://orcid.org/0000-0001-8477-254X
Надежда В. Степанова Волгоградский государственный медицинский университет https://orcid.org/0000-0002-6629-3729
Умида М. Ибрагимова Волгоградский государственный медицинский университет https://orcid.org/0000-0001-9141-4417
Александр А. Спасов Волгоградский государственный медицинский университет https://orcid.org/0000-0002-7185-4826
Вадим А. Косолапов Волгоградский государственный медицинский университет https://orcid.org/0000-0002-6702-1207

DOI:

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

Аннотация

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.

Графическая аннотация

Ключевые слова:

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

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Вклад авторов

Александр А. Озеров, Волгоградский государственный медицинский университет

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.

Дарья В. Мережкина, Волгоградский государственный медицинский университет

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.

Наталья А. Гурова, Волгоградский государственный медицинский университет

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.

Людмила В. Науменко, Волгоградский государственный медицинский университет

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.

Денис А. Бабков, Волгоградский государственный медицинский университет

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.

Виктор С. Сиротенко, Волгоградский государственный медицинский университет

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.

Роман А. Литвинов, Волгоградский государственный медицинский университет

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.

Алена С. Таран, Волгоградский государственный медицинский университет

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.

Надежда В. Степанова, Волгоградский государственный медицинский университет

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.

Умида М. Ибрагимова, Волгоградский государственный медицинский университет

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.

Александр А. Спасов, Волгоградский государственный медицинский университет

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.

Вадим А. Косолапов, Волгоградский государственный медицинский университет

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.