New 5-Modified Pyrimidine Nucleoside Inhibitors of Mycobacterial Growth

Abstract

The WHO has declared tuberculosis ( TB ) a global health emergency. Therefore, there is an urgent need to discover and develop new anti– TB drugs. Here we report on a new category of 5–substituted pyrimidine nucleosides as potent inhibitors of Myco–bacterium tuberculosis growth in vitro. A series of 2ʹ–deoxy–, 3ʹ–azido–2ʹ,3ʹ–dideoxy–, and 3ʹ–amino–2ʹ,3ʹ–dideoxypyrimidine nucleoside analogues bearing lengthy flexible alkyloxymethyl substituents exhibited marked inhibitory activity against M. tuberculosis in vitro. 5–Dodecyloxymethyl–2ʹ–deoxyuridine was found to be a potent inhibitor of M. tuberculosis propagation in vitro. In contrast, monophosphates of the tested nucleosides were devoid of antimycobacterial activity. This new class of inhibitors seems to be a promising chemotherapeutic agent against TB and merits further studies.

5‐Substituted Uridines with Activity against Gram‐Positive Bacteria

“…Synthesis of alkyloxymethyl 2 a , b , alkylthiomethyl 3 c , d and alkyltriazolylmethyl 4 b , d derivatives of uridine was carried out based on the methods [12,14,19] previously developed by us to obtain 5‐modified 2′‐deoxyuridines in a mmol scale. In all cases, the first stage of the synthesis was the preparation of 2′,3′,5′‐tri‐ O ‐acetyl‐5‐bromomethyluridine 8 (Scheme 1) from the starting 2′,3′,5′‐tri‐ O ‐acetyl‐5‐methyluridine 7 by radical bromination [20,21] .…”

“…They showed high activity against two Mycobacterium tuberculosis strains in vitro, laboratory H37Rv and clinical MDR MS‐115 strain resistant to five top antitubercular drugs [13–14] . The most active of the obtained nucleosides were derivatives 1 a – d (Figure 1) with minimal inhibitory activity (MIC) of 10–20 μg/mL for the laboratory strain M. tuberculosis H37Rv and MIC of 10–50 μg/mL for the resistant strain MDR MS‐115 [12] …”