Synthesis and multifaceted pharmacological activity of novel quinazoline NHE-1 inhibitors.
Sci Rep
; 11(1): 24380, 2021 12 21.
Article
em En
| MEDLINE
| ID: mdl-34934125
ABSTRACT
The Na+/H+ exchanger isoform 1 (NHE-1) attracts ongoing attention as a validated drug target for the management of cardiovascular and ocular diseases owing to cytoprotective, anti-ischemic and anti-inflammatory properties of NHE-1 inhibitors. Herein we report novel NHE-1 inhibitors realized via functionalization of N1-alkyl quinazoline-2,4(1H,3H)-dione and quinazoline-4(3H)-one with N-acylguanidine or 3-acyl(5-amino-1,2,4-triazole) side chain. Lead compounds show activity in a nanomolar range. Their pharmacophoric features were elucidated with neural network modeling. Several compounds combine NHE-1 inhibition with antiplatelet activity. Compound 6b reduces intraocular pressure in rats and effectively inhibits the formation of glycated proteins. Compounds 3e and 3i inhibit pro-inflammatory activation of murine macrophages, LPS-induced interleukin-6 secretion and also exhibit antidepressant activity similar to amiloride. Hence, novel compounds represent an interesting starting point for the development of agents against cardiovascular diseases, thrombotic events, excessive inflammation, long-term diabetic complications and glaucoma.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinazolinas
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Macrófagos Peritoneais
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Trocador 1 de Sódio-Hidrogênio
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Inflamação
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Anti-Inflamatórios
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Antidepressivos
Limite:
Animals
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2021
Tipo de documento:
Article