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

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.

Guanidine Derivatives of Quinazoline-2,4(1H,3H)-Dione as NHE-1 Inhibitors and Anti-Inflammatory Agents

“…Inhibition of rabbit platelet NHE-1 was determined according to the method of [ 8 , 9 ] in our modification, which was reported by us previously [ 7 ] using the laser aggregometer BIOLA-220 LA (Russia).…”

“…The activity of lactate dehydrogenase (LDH) in a cell culture medium was determined as reported by us previously [ 7 ] with a microplate reader Infinite M200 PRO (Tecan, Austria).…”

“…The phagocytic activity of peritoneal macrophages was assessed after staining with Azur-Eosin with Romanovsky’s modifications as reported by us previously [ 7 ] with a light microscopy using a Mikmed-6 (LOMO, Saint Petersburg, Russia) equipped with a digital camera.…”

“…The open field test was performed with the NPO “Open Science” (Russia) arena of 44 cm diameter and 32 cm wall height under 300 lux lighting as reported by us previously [ 7 ].…”

“…The major class of NHE-1 inhibitors is acylated guanidine derivatives, exemplified by amiloride, cariporide, and eniporide [ 6 ]. In an attempt to expand the chemical space of NHE-1 inhibitors, we reported -alkyl quinazoline-2,4(1 H ,3 H )-diones and quinazoline-4(3 H )-ones comprising an N -acylguanidine or 3-acyl(5-amino-1,2,4-triazole) side chain as NHE-1 inhibitors endowed with antiplatelet activity [ 7 ]. Some of them also reduced rat intraocular pressure and suppressed the formation of advanced glycation end-products, as well as LPS-induced activation of macrophages and also exhibited antidepressant activity comparable to amiloride.…”