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4140874 
Journal Article 
Tetrazole derivatives of chitosan: synthetic approaches and evaluation of toxicity 
Berezin, AS; Ishmetova, RI; Rusinov, GL; Skorik, YuA 
2014 
1 
Russian Chemical Bulletin
ISSN: 1066-5285
EISSN: 1573-9171 
63 
7 
1624-1632 
English 
WOS:000350878300025 
Three synthetic routes are considered for the preparation of water-soluble chitosan conjugates with 5-R-tetrazoles (R = C6H5, 4-OCH3C6H4, 3,4-(OCH3)(2)C6H4, 4-ClC6H4): (1) via the reaction of N-hydroxymethyl-5-R-tetrazoles with N-(2-carboxyethyl)chitosan, (2) via the Mannich reaction of 5-R-tetrazoles with N-(2-carboxyethyl)chitosan, and (3) via the reaction of 5-R-tetrazoles with N-(3-chloro-2-hydroxypropyl)chitosan followed by phosphorylation. Conjugates with the highest content of active substance were prepared using methods (2) and (3) where the degrees of substitution were 0.17-0.25 and 0.12-0.31, respectively. The degree of substitution in reactions (2) and (3) substantially depends on the presence of substituents in the benzene ring of 5-aryltetrazoles and changes in the series C6H5 < 4-ClC6H4 < < 4-OCH3C6H4 < 3,4-(OCH3)(2)C6H3. Synthesis using reaction (3) results in conjugates having 32-84% of 3-chloro-2-hydroxypropyl groups of N-(3-chloro-2-hydroxypropyl)chitosan involved in the binding of 5-R-tetrazoles, while the remaining groups reacted with the amino groups of the polymer leading to intra- or intermolecular crosslinking. Ultrasound sonication accelerates the modification but induces a partial degradation of the polymer matrix. The obtained conjugates showed a 2-3-fold decrease in toxicity compared to the corresponding tetrazoles in a toxicity test using terrestrial slugs Limax flavus. The least toxic conjugates were prepared by method (2). 
chitosan; tetrazole; conjugates; Mannich reaction; drug delivery systems; toxicity; Limax flavus