期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 46, 期 18, 页码 3811-3821出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm021108n
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Thymidine monophosphate kinase (TMPK) of Mycobacterium tuberculosis (TMPKmt) represents an 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 X-position was explored via the introduction of various substituents at the X-position of the thymidine monophosphate (dTMP) scaffold. Various 3'-C-branched chain substituted nucleotides in the 2'-deoxyribo (3-6) and ribo series (7, 8) were synthesized from one key intermediate (23). 2'-Deoxy analogues proved to be potent inhibitors of TMPKmt: 3'-CH2NH2 (4), 3'-CH2N3 (3), and 3'-CH2F (5) nucleotides exhibit the highest affinities within this series, with K-i values of 10.5, 12, and 15 muM, respectively. These results show that TMPKmt tolerates the introduction of sterically demanding substituents at the X-position. Ribo analogues experience a significant affinity decrease, 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 magnitude and display a superior selectivity profile versus human TMPK. This series of inhibitors holds promise for the development of a new class of antituberculosis agents.
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