Results
Title

Synthesis and multifaceted pharmacological activity of novel quinazoline NHE-1 inhibitors.

Authors

Spasov, Alexander; Ozerov, Alexander; Vassiliev, Pavel; Kosolapov, Vadim; Gurova, Natalia; Kucheryavenko, Aida; Naumenko, Ludmila; Babkov, Denis; Sirotenko, Viktor; Taran, Alena; Litvinov, Roman; Borisov, Alexander; Klochkov, Vladlen; Merezhkina, Darya; Miroshnikov, Mikhail; Uskov, Georgy; Ovsyankina, Nadezhda

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.

Subjects

AMILORIDE; QUINAZOLINE; ARTIFICIAL neural networks; MACROPHAGE activation; DRUG target; CARDIOVASCULAR diseases

Publication

Scientific Reports, 2021, Vol 11, Issue 1, p1

ISSN

2045-2322

Publication type

Academic Journal

DOI

10.1038/s41598-021-03722-w