Synthesis and Evaluation of 5-Substituted 2′-deoxyuridine Monophosphate Analogues As Inhibitors of Flavin-Dependent Thymidylate Synthase inMycobacterium tuberculosis
Journal of Medicinal Chemistry2011Vol. 54(13), pp. 4847–4862
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Martin Kögler, Bart Vanderhoydonck, Steven De Jonghe, Jef Rozenski, Kristien Van Belle, Jean Herman, Thierry Louat, Anastasia Parchina, Carol Hopkins Sibley, Eveline Lescrinier, Piet Herdewijn
Abstract
A series of 5-substituted 2'-deoxyuridine monophosphate analogues has been synthesized and evaluated as potential inhibitors of mycobacterial ThyX, a novel flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. A systematic SAR study led to the identification of compound 5a, displaying an IC(50) value against mycobacterial ThyX of 0.91 μM. This derivative lacks activity against the classical mycobacterial thymidylate synthase ThyA (IC(50) > 50 μM) and represents the first example of a selective mycobacterial FDTS inhibitor.
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