ANNA WANDA KRAJCZYK
NUCLEOSIDES OF 4,5-DISUBSTITUTED 1,2,3-TRIAZOLE AND THEIR BICYCLIC
DERIVATIVES
ABSTRACT
Nowadays, bacterial infections are again considered to be a serious problem. Many
antibiotics are being reported as ineffective since a lot of bacteria have developed certain
mechanisms of drug resistance. In order to overcome this difficulty new compounds are
needed, necessarily targeted at specific bacterial enzymes, which were as yet not taken under
consideration in the drug design.
In the presented thesis, methods of synthesis of new salicyl-AMP structural
analogues in which the phosphate group is replaced by an isosteric sulfamoyl one are
discussed. Compounds in question instead of adenine possess 4-amine-1H-[1,2,3]triazole[4,5c]pirydyne substituted at position 6 with aryl group. Derivatives obtained are thought to be
potential inhibitors of bacterial enzymes involved in the biosynthesis of siderophores
(molecules that chelate Fe3+ ions, and thus enable bacteria their uptake). These enzymes do
not occur in human beings, and as such have been targeted in drug design for several years
(e.g. in developing drugs against tuberculosis).
Starting from 1,2,3,5-O-tetraacetyl-β-D-ribofuranose, an appropriately blocked
ribofuranose azide was obtained, and subsequently subjected to a modified Dimroth reaction
with cyanoacetamide to produce 5-amino-4-carboxyamido-1,2,3-triazole riboside. In due
course, dehydratation of carboxyamide group, followed by diazotization-iodination reaction
was performed using 1-(5-O-acetyl-2,3-O-izopropylidene-β-D-rybofuranosyl)-5-amine-1H[1,2,3]triazole-4-carboxyamide as the starting material, in order to synthesize appropriate
substrates for cross-coupling reaction with aromatic alkynes.
The method of cross-coupling was optimized and the reaction procedure was applied
in the synthesis of the series of 1,2,3-triazole 5-aroylalkyne-4-carbonitrile nucleoside
derivatives. Compounds obtained were subsequently used as substrates for a nucleophilic
cycloaddition reaction, leading to nucleosides of 6-substituted 4-amine-1H-[1,2,3]triazole[4,5c]pirydyne, which exhibited strong fluorescence. After further modification of 5’-OH group
of ribose, the desired products were obtained, i.e. structural analogues of salicyl-AMP.
When working on the thesis, additional compounds were synthesized, e.g. 5-bromo1,2,3-triazole-4-carboxyamide as well as 5’-O-sulfamoyl derivatives of 5-halogene-1-(β-Drybofuranosyl)-1H-[1,2,3]triazole-4-carboxyamide, which were tested for antiviral activity in
co-operation with foreign laboratories. Furthermore, two 8-aza-3-deazainosine derivatives
were obtained in order to test nucleophilic cyclization reaction procedures presented in the
literature.