| Abstract
| - Thymidine monophosphate kinase (TMPK) of Mycobacterium tuberculosis (TMPKmt) representsan attractive target for blocking the bacterial DNA synthesis. In an attempt to find high-affinity inhibitors of TMPKmt, a cavity in the enzyme at the 3‘-position was explored via theintroduction of various substituents at the 3‘-position of the thymidine monophosphate (dTMP)scaffold. Various 3‘-C-branched chain substituted nucleotides in the 2‘-deoxyribo (3−6) andribo series (7, 8) were synthesized from one key intermediate (23). 2‘-Deoxy analogues provedto be potent inhibitors of TMPKmt: 3‘-CH2NH2 (4), 3‘-CH2N3 (3), and 3‘-CH2F (5) nucleotidesexhibit the highest affinities within this series, with Ki values of 10.5, 12, and 15 μM,respectively. These results show that TMPKmt tolerates the introduction of stericallydemanding substituents at the 3‘-position. Ribo analogues experience a significant affinitydecrease, which is probably due to steric hindrance of Tyr103 in close vicinity of the 2‘-position.Although the 5‘-O-phosphorylated compounds have somewhat higher affinities for the enzyme,the parent nucleosides generally exhibit affinities for TMPKmt in the same order of magnitudeand display a superior selectivity profile versus human TMPK. This series of inhibitors holdspromise for the development of a new class of antituberculosis agents.
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