3‘-C-Branched-Chain-Substituted Nucleosides and Nucleotides as Potent Inhibitors of Mycobacterium t uberculosis Thymidine Monophosphate Kinase

• Published in: Journal of medicinal chemistry Vol. 46; no. 18; pp. 3811 - 3821
• Main Authors: Vanheusden, Veerle, Munier-Lehmann, Hélène, Froeyen, Matheus, Dugué, Laurence, Heyerick, Arne, De Keukeleire, Denis, Pochet, Sylvie, Busson, Roger, Herdewijn, Piet, Van Calenbergh, Serge
• Format: Journal Article
• Language: English
• Published: American Chemical Society 28.08.2003
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm021108n

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 3‘-position was explored via the introduction 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) 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 μM, respectively. These results show that TMPKmt tolerates the introduction of sterically demanding substituents at the 3‘-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.