A series of 2-methoxyphenyl-9-dialkylaminoethyl derivatives of imidazo[1,2-a]benzimidazole have been synthesized and their pharmacological properties have been studied. Some of the synthesized compounds exhibit antioxidant, radioprotector, antiarrythmic, spasmolytic, antiaggregant, anticalmodulin, and antisecretory properties. Some substances exhibit the properties of phosphodiesterase inhibitors, decrease calcium ion transport through membranes, increase myocardium resistance to hypoxia, and reduce the arterial pressure. The obtained data show good prospects for the synthesis and screening of biologically active substances in this chemical group.Imidazo[1,2-a]benzimidazole contains a guanidine pharmacophore and is a very promising system in the search for new biologically active compounds [1 -8]. In continuation of the previous investigations, we have synthesized a series of new derivatives of 2-phenylimidazo[1,2-a]-benzimidazole containing one or two methoxy groups in various positions of the phenyl ring. The aim of this study was to determine the effect of these substituents on the manifestations of some particular types of biological activity.2-Methoxyphenyl-substituted 9-dialkylaminoethylimidazo[1,2-a]benzimidazoles (VIII -XII) were synthesized using a somewhat modified standard scheme described previously [1,9], proceeding from 1-dialkylaminoethyl-2-aminobenzimidazoles (Ia -Id) and methoxy-substituted phenacylbromides (IIa -IIe).The process of quaternization of the initial amines I was previously carried out in ethanol. However, the high solubility of the target quaternary salts in this medium complicated isolation of the target components and made necessary their conversion into less soluble hydrobromides, which was achieved by adding HBr. In this study, the reactions were performed in aprotic solvents (acetone or acetonitrile), which led to the precipitation of bromides III -VII from the reaction mixtures with good yields. The only exception is the case of 2,5-dimethoxyphenacylbromides VII, which are readily soluble in acetone.Ia -Id; IIa -IId; III -VII; VIII -XII; XIIIa, XIIIb I, III -XII: R = Net 2 (a), N(CH 2 ) 5 (b), N(CH 2 CH 2 ) 2 O (c), NMe 2 (d); IIa, III, VIII: R 1 = 4-OCH 3 , R 2 = H; IIb, IV, IX: R 1 = 3-OCH 3 , R 2 = H; IIc, V, X: R 1 = R 2 = 3,4-(OCH 3 ) 2 ; IId, VI, XI: R 1 = R 2 = 2,4-(OCH 3 ) 2 ; IIe, VII, XII: R 1 = R 2 = 2,5-(OCH 3 ) 2 ; XIII: R = NEt 2 (a), N(CH 2 ) 5 (b).Compounds III -VII crystallize in the form of 2-aminobenzimidazolium salts. This is confirmed by the IR spectra, where two absorption bands due to stretching vibrations of the primary amino groups are observed at 3100 -3350 cm -1 and the characteristic absorption bands of carbonyl groups are found at 1680 -1700 cm -1 (Table 1). 476 0091-150X/05/3909-0476
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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.
A series of 3-(2,2,2-trichloro-1-hydroxyethyl)imidazo[1, 2-a]benzimidazole dihydrochlorides have been synthesized and their pharmacological properties have been studied. It is established that the synthesized compounds exhibit weak antioxidant activity. In addition, they possess platelet and erythrocyte antiaggregant properties, show pronounced spasmolytic action, and have low toxicity. Some of them also exhibit antiradiomimetic, hypotensive, and antiarrhythmic properties.
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