New NO‐Donors with Antithrombotic and Vasodilating Activities, V: Oligonitroso Sydnone Imines

Abstract

Nine 4,4'-bis- and four 4,4'-tris-N-nitroso syndrome imines were synthesized. The sydnone imine moiety is connected either by aromatic 1,3-phenylene or 1,3,5-benzene or aliphatic methylene or propylene bridges. Compared to the corresponding sydnone imines the collagen induced platelet aggregation inhibiting activity is increased by several orders of magnitude by the nitroso derivatives. The most potent compound bears a hexyl substituent in 3-position (1d: IC50 = 0.05 mumol/L). These data show that aromatic bridges (1d, 2d) are more favourable than aliphatic ones (4b). This indicates the mutual influence of the nitroso-imino moieties via the aromatic bridges. In the series of 3,3'-bis-nitrososydnone imines (13 compounds) mostly additive effects of the nitroso groups are seen. The activities range from IC50 = 0.2 mumol/L (5i; 1,3-xylene bridge) to IC50 = 8 mumol/L (5b; trimethylene bridge). The differences suggest different affinities to the platelet membrane.

Oxadiazoles

“…Sydnocarb acts on the central nervous system and has been used as a psychostimulant and an antidepressive. Nitrososydnonimines 96 and 97 showed potent antithrombotic activity [113,114]. A series of derivatives -98 and 99 -prepared by manipulation of the carboxylic group of 3-(3-carboxyphenyl)-and 3-(3-carboxyphenyl)sydnones, or by Claisen-Schmidt condensation of 3-(4-acetylphenyl)sydnone with aldehydes or malononitrile, showed high antibacterial activity against both Gram-positive and Gram-negative organisms [115].…”

Nitric Oxide Donors: Chemical Activities and Biological Applications

“…They are the N -nitrosation products of their corresponding imines. Several types of nitrosimines have been reported such as 1,3-disubstituted nitrosiminobenzimidazoles ( 22 ), 1,3,4-thiadiazole-2-nitrosimines ( 23 ), benzothiazole-2(3H)-nitrosimines ( 24 ), thiazole-2-nitrosimines ( 25 ), oligonitroso sydnonimines ( 26 ), 3-alkyl- N -nitroso-sydnonimines ( 27 ), − and 2 H -1,3,4-thiadiazine nitrosimines ( 28 ) (Figure ) . These nitrosimines have the ability to inhibit platelet aggregation in vitro.…”

Electronic Structure Analysis and Synthesis of Nitroso N‐Heterocyclic Imines

“…NNHIs found application in medicinal chemistry and the NNHI formation has been shown to lead to environmental protection [11] . Many NNHIs are reported in the literature such as 3‐alkyl‐N‐nitroso‐sydnone Imines, [10a–c] thiazol‐2‐nitrosoimines, [10d] benzothiazol‐2(3H)‐nitrosoimines, [10e] 1,3,4‐thiadiazol‐2‐nitrosoimines, [10f] 1,3‐disubstituted nitrosobenzimidazoles, [10g] and mesoionic oxatriazoles (Figure 2). [10h] These NNHIs possess various therapeutic activities such as (i) vasodilation (via NO release), (ii) ability to inhibit platelet aggregation in vitro , (iii) as antithrombotic agents and (iv) possess blood pressure lowering abilities [10] .…”