jsmsJournal of Siberian Medical SciencesJournal of Siberian Medical Sciences2542-1174Federal state budgetary educational institution of higher education "Novosibirsk state medical university" of Ministry of Health of the Russian Federation (FSBEI HE NSMU MOH Russia)10.31549/2542-1174-2023-7-3-27-36jsms-946Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHВлияние новых производных 6,7-диметоксихиназолин-4(3H)- она с остатками аминокислот и дипептидов на активность главной (Mpro) и папаиноподобной (PLpro) протеаз SARS-CoV-2Effect of new derivatives of 6,7-dimethoxyquinazoline-4(3H)-one with amino acid residues and dipeptide fragments on the activity of the main protease (Mpro) and papain-like protease (PLpro) of SARS-CoV-2https://orcid.org/0000-0002-5595-8182ПоздняковД. И.PozdnyakovD. I.

Поздняков Дмитрий Игоревич – канд. фармацевт. наук, заведующий кафедрой фармакологии с курсом клинической фармакологии

Пятигорск

Dmitry I. Pozdnyakov – Cand. Sci. (Pharmaceut.), Head, Department of Pharmacology with a course of Clinical Pharmacology

Pyatigorsk

https://orcid.org/0000-0001-8207-2953ЧиряпкинА. С.ChiriapkinA. S.

Чиряпкин Алексей Сергеевич – преподаватель кафедры фармацевтической химии

Пятигорск

Alexey S. Chiriapkin – Lecturer, Department of Pharmaceutical Chemistry

Pyatigorsk

https://orcid.org/0000-0003-1333-3472КодонидиИ. П.KodonidiI. P.

Кодониди Иван Панайотович – д-р фармацевт. наук, профессор кафедры органической химии

Пятигорск

Ivan P. Kodonidi – Dr. Sci. (Pharmaceut.), Professor, Department of Organic Chemistry

Pyatigorsk

Пятигорский медико-фармацевтического институт – филиал ФГБОУ ВО «Волгоградский государственный медицинский университет»РоссияPyatigorsk Medical and Pharmaceutical Institute, branch of the Volgograd State Medical UniversityRussian Federation202323092023032736Copyright © Поздняков Д.И., Чиряпкин А.С., Кодониди И.П., 20232023Поздняков Д.И., Чиряпкин А.С., Кодониди И.П.Pozdnyakov D.I., Chiriapkin A.S., Kodonidi I.P.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://jsms.elpub.ru/jour/article/view/946Введение

Введение . Новая коронавирусная инфекция, вызванная вирусом SARS-CoV-2, является высококонтагиозным заболеванием со значительным риском развития осложнений вплоть до летального исхода. Разработка анти- SARS-CoV-2 препаратов началась практически сразу после идентификации вируса, при этом обозначились две перспективные фармакологические мишени – основная и папаиноподобная протеазы.

Цель

Цель . Оценка влияния новых производных 6,7-диметоксихиназолин-4(3H)-она с остатками аминокислот и дипептидов на активность протеаз SARS-CoV-2 in vitro.

Материалы и методы

Материалы и методы . Изучаемые вещества получали из коммерчески доступной 2-амино-4,5- диметоксибензойной кислоты, которую гетероциклизовали до 2-алкил-6,7-диметокси-3,1-бензоксазин-4-онов с последующим взаимодействием с аминокислотами и дипептидами. Изменение активности вирусных протеаз оценивали спектрофотометрически с использованием соответствующих субстратов. В ходе исследования рассчитывали коэффициент полуингибиции IC50.

Результаты

Результаты . В ходе исследования было установлено, что полученные соединения проявляют выраженную ингибирующую активность по отношению как к основной, так и папаиноподобной протеазе SARS-CoV-2 с диапазоном IC50 0.012–0.100 и 0.013–0.100 мкМ/мл соответственно. Наиболее выраженное действие установлено для соединения 3h с фрагментом дипептида глицил-триптофан с изопропильным радикалом, которое снижало активность основной протеазы (IC50 0.012 ± 0.005 мкМ/мл) и папаиноподобной протеазы (IC50 0.013 ± 0.009 мкМ/мл).

Заключение

Заключение . Соединение 3h, содержащее изопропильный радикал и дипептид глицил-триптофан, может стать перспективным объектом для дальнейшего изучения и разработки на его основе нового противовирусного средства.

Introduction

Introduction . A novel coronavirus infection caused by the SARS-CoV-2 virus is a highly contagious disease with a signifi cant risk of complications up to mortality. The development of anti-SARS-CoV-2 drugs began almost immediately after the identifi cation of the virus, while two promising pharmacological targets were identifi ed: the main and papain-like proteases.

Aim

Aim . Evaluation of the eff ect of new derivatives of 6,7-dimethoxyquinazoline-4(3H)-one with amino acid residues and dipeptide fragments on the activity of SARS-CoV-2 proteases in vitro.

Materials and methods

Materials and methods . The studied substances were obtained from commercially available 2-amino- 4,5-dimethoxybenzoic acid which were cyclized into 2-alkyl-6,7-dimethoxy-3,1-benzoxazine-4-ones, followed by reaction with amino acids and dipeptides. The changes in the activity of viral proteases were evaluated with spectrophotometry using the appropriate substrates. During the study, the half maximal inhibitory concentration (IC50) was calculated. 

Results

Results . As a result, it was found that the obtained compounds exhibit pronounced inhibitory activity with respect to both the main and papain-like protease of SARS-CoV-2 with an IC50 range of 0.012–0.100 and 0.013-0.100 μM/ml, respectively. The most pronounced eff ect was shown for the 3h compound with a fragment of the glycyl-tryptophan dipeptide with the isopropyl radical, which reduced the activity of the main protease (IC50 0.012 ± 0.005 μM/ml) and the papainlike protease (IC50 0.013 ± 0.009 μM/ml).

Conclusion

Conclusion . Compound 3h containing the isopropyl radical and the glycyl-tryptophan dipeptide may become a promising object for further study and development of a new antiviral agent based on it.

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The authors declare that there are no conflicts of interest present.