5-Substituted 4-Thiouridines, 4-Thio-2’-deoxyuridines and their Oligoglycol Carbonate Prodrugs as Promising Antimicrobial Agents

The problem of antibiotic resistance is one of the challenges that science and medicine face in the 21st century. Nucleoside analogues have already proven as antiviral and antitumor agents, and currently there are more and more reports on their antibacterial and antifungal activity. The substitution of an oxygen atom by sulfur one leads to the emergence of unique properties. Here we report the synthesis of eight new 4-thioanalogues of 5-substituted (5-alkyloxymethyl and 5-alkyltriazolylmethyl) derivatives of 2'-deoxyuridine and uridine, that were active against Mycobacterium tuberculosis and Gram-positive bacteria. The novel sulfur-containing nucleosides were synthesized via activation of pyrimidine C4 position, followed by condensation with thioacetic acid and deblocking. Тo increase the solubility, oligoglycol carbonate depot forms were obtained via activation of 3'-hydroxyl group using N,N'-carbonyldiimidazole and condensation with triethylene glycol. The highest inhibitory activity was demonstrated by 3'-triethylene glycol depot forms of 4-thio-5-undecyl- and 5-dodecyloxymethyl-2'-deoxyuridine against two strains of M. smegmatis. The most promising compounds were 5-[4-decyl-(1,2,3-triazol-1-yl)methyl]-4-thio-2′-deoxy- and ribouridine and 5-undecyloxymethyl 4-thiouridine active toward clinical M. intracellulare isolates. Overall, novel sulfur-containing nucleoside analogues were low toxic, demonstrated better inhibitory activity compared to their C4-oxo ones, and thus are promiseable compounds for the development of new antibacterial agents.