Synthesis and evaluation of cerebroprotective activity of novel 6,7-dimethoxyquinazolin-4(3H)-one derivatives containing residues of amino acids and dipeptides

Abstract

Neurodegenerative processes of the central nervous system are an important socially significant problem of modern society. They cause many diseases, such as Alzheimer's disease and cerebral ischemia, which significantly reduce the quality of human life and can lead to disability or death. The aim of this study was to synthesize novel 6,7-dimethoxyquinazolin-4(3H)-one derivatives with the remains of neuroactive amino acids and dipeptides in order to investigate their cerebroprotective properties. As a result of the study, 13 novel 6,7-dimetho-xyquinazolin-4(3H)-one derivatives were synthesized. Cerebral ischemia in rats was reproduced by irreversible right-sided occlusion of the middle cerebral artery using the Tamura method, and the area of brain necrosis was evaluated. Cognitive functions were evaluated in the Y-maze test. Among the studied quinazolinone derivatives, compounds 3i, 3j and 3k have the most pronounced cerebrotropic activity, which is not inferior to ethylmethylhydroxypyridine succinate in terms of pharmacological activity, making them promising objects for further research.

A literature review on pharmacological aspects, docking studies, and synthetic approaches of quinazoline and quinazolinone derivatives

“…Furthermore, novel quinazolinone candidates were tested for their anticonvulsant potential. [91] The authors designed the target compounds depending on similarities between methaqualone (31), mecloqualone (32) and the target compounds (34a-c). Compounds 34a-c were threefold-fourfold more potent than ethosuximide.…”

“…There are many synthetic and natural‐based drugs incorporating quinazoline and quinazolinone moieties which are utilized for curing many diseases [ 32–34 ] (Figure 1).…”

“…[28,29] Quinazolinone derivatives were building blocks for nearly 150 alkaloidal metabolites isolated from various families of plants, animals, and microorganisms. [30,31] There are many synthetic and natural-based drugs incorporating quinazoline and quinazolinone moieties which are utilized for curing many diseases [32][33][34] (Figure 1).…”

Spectrum of the neuro-cardio-angiotropic and protector activity of the quinazoline and quinazolinone derivatives

“…Замещенные хиназолиноны с немедленным высвобождением рекомендованы для лечения или предотвращения сердечно-сосудистых заболеваний, метаболического синдрома, болезни Альцгеймера, диабета [47]. Церебропротективное действие, сопоставимое с эффектом мексидола, проявляли 6,7-диметоксипроизводные хиназолин-4(3H)-она с остатками нейроактивных аминокислот и дипептидов на модели церебральной ишемии у крыс (правосторонняя окклюзия средней мозговой артерии с оценкой площади некроза головного мозга) при оценке когнитивных функций в тесте Y-образный лабиринт [48]. Церебропротекторная активность показана для производных хиназолин-4(3Н)-она с гуанидиновым заместителем [49].…”

Synthesis of 2-phenyl- and 2-benzyl derivatives of 4(3Н)-quinazolinone with analgesic activity

“…Volume XI, Issue 1, 2023 ВВЕДЕНИЕ Целенаправленный поиск новых высокоэффективных и безопасных субстанций лекарственных препаратов, влияющих на ЦНС, является актуальной задачей фармации [1][2][3]. Эмпирический подход, применяемый при синтетическом получении новых соединений с биологической активностью, недостаточно продуктивен и эффективен [4][5][6][7].…”