Quaternary ammonium hydrazones based on 1-(pyridin-3-ylmethyl)indoline-2,3-dione: synthesis, reactivity features, antiaggregation and anticoagulation activity

The ease of modification of the acylhydrazone platform allows obtaining materials with high stability under neutral and alkaline conditions, which makes them promising candidates in the search for effective agents with a wide range of sequential action. According to modern sources, acylhydrazones have oxidation-reduction, anti-tuberculosis, antimicrobial, antiviral and other effects. Alkylation of isatin with 2-chloro-5-(chloromethyl)pyridine with irreversible yields yielded a number of new 1-(pyridin-3-yl)methyl)indolin-2,3-diones. The condensation reaction with quaternary ammonium hydrazides based on trimethyl- and (diethyl)methylamines, occurring under conditions of boiling in ethanol for 90 minutes, yielded water-soluble isatin-3-acylhy-drazones (halides) 2-(2-(1-((6-chloropyridin-3-yl)methyl)-2-oxoindolin-3-ylidene)hy-drazinyl)-N,N,N-trialkyl-2-oxoethyl-1-ammonium) containing a pyridine substituent at the endocyclic nitrogen atom of the oxindole. The structure of all new isatin derivatives was unambiguously proven by IR and 1H and 13C NMR spectroscopy, the composition -by ESI and MALDI mass spectrometry and elemental analysis. According to the results of general systemic studies of the hemostasis system in vitro, it was established that the greatest antiaggregatory activity is produced by 5-fluorisatin derivatives 3a and ammonium salts based on the 6-bromisatin derivative 5c and 5d, reducing the level of platelet aggregation by an average of 17.3%, 14.4% and 18.1% (p<0.05) relative to the control, which occurs with the indices of acetylsalicylic acid. It should be noted that, unlike acetylsalicylic acid, the leading compounds extended the lag period in sequential measurement by 4.6%-10.3% (p<0.05). Depending on the structure of activity, compounds containing bromine atoms in position 6 exhibit higher antiaggregatory activity in the direction with 5-fluoro derivatives. The obtained experimental data demonstrate the superiority of further development of drugs based on this class of isatin derivatives. The authors thank the Collective Spectroanalytical Center for the Study of the Structure, Composition and Properties of Substances and Materials of the Federal Research Center of the Kazan Scientific Center of the RAS for technical support of the research. Contribution of the authors: the authors contributed equally to this article. The authors declare no conflicts of interests.

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