Synthesis and Evaluation of 5-Substituted 2′-deoxyuridine Monophosphate Analogues As Inhibitors of Flavin-Dependent Thymidylate Synthase in Mycobacterium tuberculosis

• Published in: Journal of medicinal chemistry Vol. 54; no. 13; pp. 4847 - 4862
• Main Authors: Kögler, Martin, Vanderhoydonck, Bart, De Jonghe, Steven, Rozenski, Jef, Van Belle, Kristien, Herman, Jean, Louat, Thierry, Parchina, Anastasia, Sibley, Carol, Lescrinier, Eveline, Herdewijn, Piet
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.07.2011; Amer Chemical Soc
• Subjects: Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Chemistry, Medicinal; Deoxyuracil Nucleotides - chemical synthesis; Deoxyuracil Nucleotides - chemistry; Deoxyuracil Nucleotides - pharmacology; Flavins - metabolism; Life Sciences & Biomedicine; Mycobacterium tuberculosis - enzymology; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Thymidylate Synthase - antagonists & inhibitors; Thymidylate Synthase - chemistry; TUMOR RESISTANCE; SELECTIVE PHOSPHORYLATION; ANTITUBERCULOSIS DRUGS; NUCLEOTIDES; ACID RELATED-COMPOUNDS; THYX; FLUORINATED PYRIMIDINES; NUCLEOSIDES; FUNCTIONAL-ANALYSIS; CATALYTIC MECHANISM
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm2004688

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 IC50 value against mycobacterial ThyX of 0.91 μM. This derivative lacks activity against the classical mycobacterial thymidylate synthase ThyA (IC50 > 50 μM) and represents the first example of a selective mycobacterial FDTS inhibitor.