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.
Highlights
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 Na+/H+ exchangers (NHEs)-1 inhibitors
The step involved treatment of esters 2a-f with guanidine generated in situ from guanidine hydrochloride and potassium hydroxide in boiling 95% ethanol, which leads to rapid cleavage of the ester bond and formation of N-acyl derivatives of guanidine 3a-d in 57-84% yield
When aminoguanidine was used as a nucleophilic reagent, which was obtained in situ from aminoguanidine carbonate and potassium hydroxide in boiling 95% ethanol, the reaction is accompanied by cyclization to form 5-amino-1,2,4-triazole and leads to quinazoline-2,4(1H,3H)-dione derivatives 3e-i with a yield of 60-81%
Summary
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. Several compounds combine NHE-1 inhibition with antiplatelet activity. Compounds 3e and 3i inhibit pro-inflammatory activation of murine macrophages, LPS-induced interleukin-6 secretion and exhibit antidepressant activity similar to amiloride. Inhibition of NHE-1 reduced the production of superoxide anion and pro-inflammatory cytokines IL-6, IL-1β and TNF-α induced by LPS in microglia[5]. Antiplatelet activity of NHE-1 inhibitors is believed to be mediated by inhibition of cytoplasmic C a2+ mobilization and arachidonic acid formation[9]. Na+/H+ and Cl-/HCO3- exchangers in epithelial cells of the ciliary body are involved in the first stage of intraocular fluid secretion Blocking these transporters in the cell culture of bovine pigment and non-pigment epithelium of the ciliary body prevents the absorption of Na+ ions and reduces the aqueous humor formation. NHE-1 prevents intracellular acidosis, plays a role in the proliferation of retinal vascular smooth muscle cells, and may mediate the action of endothelin on vasculature[12,13]
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