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 analogs 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 a sulfur one leads to the emergence of unique properties. Here, we report the synthesis of eight new 4-thioanalogs of 5-substituted (5-alkyloxymethyl and 5-alkyltriazolylmethyl) derivatives of 2′-deoxyuridine and uridine, which were active against Mycobacterium tuberculosis and Gram-positive bacteria. The novel sulfur-containing nucleosides were synthesized via activation of the pyrimidine C4 position, followed by condensation with thioacetic acid and deblocking. To increase the solubility, oligoglycol carbonate depot forms were obtained via activation of the 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 (4a,b) 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 (3c,g) and 5-undecyloxymethyl 4-thiouridine (3e) active toward clinical M. intracellulare isolates. Overall, novel sulfur-containing nucleoside analogs were low toxic, demonstrated better inhibitory activity compared to their C4-oxo ones, and, thus, are promising compounds for the development of new antibacterial agents.