Synthesis and evaluation of thymidine-5′- O-monophosphate analogues as inhibitors of Mycobacterium tuberculosis thymidylate kinase

• Published in: Bioorganic & medicinal chemistry letters Vol. 12; no. 19; pp. 2695 - 2698
• Main Authors: Vanheusden, Veerle, Munier-Lehmann, Hélène, Pochet, Sylvie, Herdewijn, Piet, Van Calenbergh, Serge
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 07.10.2002; Elsevier
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antitubercular Agents - chemical synthesis; Antitubercular Agents - pharmacology; Biological and medical sciences; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Kinetics; Life Sciences; Medical sciences; Models, Molecular; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - enzymology; Nucleoside-Phosphate Kinase - antagonists & inhibitors; Pharmacology. Drug treatments; Thymidine Monophosphate - analogs & derivatives; Thymidine Monophosphate - chemical synthesis; Thymidine Monophosphate - chemistry; Thymidine kinase; Enzyme; Organic azide; Transferases; Enzyme inhibitor; Binding site; Deoxyribonucleotide; In vitro; Mycobacterium tuberculosis; Structure activity relation; Mycobacteriales; Chlorine Organic compounds; Dideoxynucleotide; Mycobacteriaceae; Bacteria; Actinomycetes; Antituberculous agent; Antibacterial agent; Chemical synthesis; Pyrimidine nucleotide
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(02)00551-6

A number of 2′- and 3′-modified thymidine 5′- O-monophosphate analogues were synthesized as potential leads for new anti-mycobacterial drugs. Evaluation of their affinity for Mycobacterium tuberculosis thymidine monophosphate kinase showed that a 2′-halogeno substituent and a 3′-azido function are the most favorable leads for further development of potent inhibitors of this enzyme. The synthesis and Mycobacterium tuberculosis thymidylate kinase inhibitory activity of 2′- and 3′-modified thymidine 5′- O-monophosphate analogues are reported.