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Synthesis and evaluation of ?-thymidine analogues as novel antimalarials.

ABSTRACT: Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea-?-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this point, we designed, synthesized and evaluated a number of thymidine analogues as antimalarials. Both 5'-urea-?- and ?-thymidine derivatives were moderate inhibitors of PfTMPK and furthermore showed moderate inhibition of parasite growth. The structure of several enzyme-inhibitor complexes provides a basis for improved inhibitor design. However, we found that certain 5'-urea-?-thymidine analogues had antimalarial activity where inhibition of PfTMPK is not the major mode of action. Optimization of this series resulted in a compound with potent antimalarial activity (EC(50) = 28 nM; CC(50) = 29 ?M).

SUBMITTER: Cui H

PROVIDER: S-EPMC3530961 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Synthesis and evaluation of α-thymidine analogues as novel antimalarials.

Cui Huaqing H Carrero-Lérida Juana J Silva Ana P G AP Whittingham Jean L JL Brannigan James A JA Ruiz-Pérez Luis M LM Read Kevin D KD Wilson Keith S KS González-Pacanowska Dolores D Gilbert Ian H IH

Journal of medicinal chemistry 20121214 24

Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea-α-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this point, we designed, synthesized and evaluated a number of thymidine analogues as antimalarials. Both 5'-urea-α- and β-thymidine derivatives were moderate inhibitors of PfTMPK and furthermore showed moderate inhibition of parasite growth. The stru ...[more]

PMID: 23240776

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