Analogues of thiolactomycin as potential antimalarial agents

Simon M. Jones, Jonathan E. Urch, Marcel Kaiser, Reto Brun, John L. Harwood, Colin Berry, Ian H. Gilbert

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    Abstract

    Analogues of the natural antibiotic thiolactomycin (TLM), an inhibitor of the condensing reactions of type II fatty acid synthase, were synthesized and evaluated for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum. Alkylation of the C4 hydroxyl group led to the most significant increase in growth inhibition (over a 100-fold increase in activity compared to TLM). To investigate the mode of action, the P. falciparum KASIII enzyme was produced for inhibitor assay. A number of TLM derivatives were identified that showed improved inhibition of this enzyme compared to TLM. Structure-activity relationships for enzyme inhibition were identified for some series of TLM analogues, and these also showed weak correlation with inhibition of parasite growth, but this did not hold for other series. On the basis of the lack of a clear correlation between inhibition of pfKASIII activity and parasite growth, we conclude that pfKASIII is not the primary target of TLM analogues. Some of the analogues also inhibited the growth of the parasitic protozoa Trypanosoma cruzi, T. brucei, and Leishmania donovani.
    Original languageEnglish
    Pages (from-to)5932-5941
    Number of pages10
    JournalJournal of Medicinal Chemistry
    Volume48
    Issue number19
    DOIs
    Publication statusPublished - Jan 2005

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    Antimalarials
    Growth
    Parasites
    Type II Fatty Acid Synthase
    Enzymes
    Leishmania donovani
    Falciparum Malaria
    Trypanosoma cruzi
    Alkylation
    Plasmodium falciparum
    Structure-Activity Relationship
    Hydroxyl Radical
    thiolactomycin
    Anti-Bacterial Agents

    Cite this

    Jones, S. M., Urch, J. E., Kaiser, M., Brun, R., Harwood, J. L., Berry, C., & Gilbert, I. H. (2005). Analogues of thiolactomycin as potential antimalarial agents. Journal of Medicinal Chemistry, 48(19), 5932-5941. https://doi.org/10.1021/jm049067d
    Jones, Simon M. ; Urch, Jonathan E. ; Kaiser, Marcel ; Brun, Reto ; Harwood, John L. ; Berry, Colin ; Gilbert, Ian H. / Analogues of thiolactomycin as potential antimalarial agents. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 19. pp. 5932-5941.
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    abstract = "Analogues of the natural antibiotic thiolactomycin (TLM), an inhibitor of the condensing reactions of type II fatty acid synthase, were synthesized and evaluated for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum. Alkylation of the C4 hydroxyl group led to the most significant increase in growth inhibition (over a 100-fold increase in activity compared to TLM). To investigate the mode of action, the P. falciparum KASIII enzyme was produced for inhibitor assay. A number of TLM derivatives were identified that showed improved inhibition of this enzyme compared to TLM. Structure-activity relationships for enzyme inhibition were identified for some series of TLM analogues, and these also showed weak correlation with inhibition of parasite growth, but this did not hold for other series. On the basis of the lack of a clear correlation between inhibition of pfKASIII activity and parasite growth, we conclude that pfKASIII is not the primary target of TLM analogues. Some of the analogues also inhibited the growth of the parasitic protozoa Trypanosoma cruzi, T. brucei, and Leishmania donovani.",
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    Jones, SM, Urch, JE, Kaiser, M, Brun, R, Harwood, JL, Berry, C & Gilbert, IH 2005, 'Analogues of thiolactomycin as potential antimalarial agents', Journal of Medicinal Chemistry, vol. 48, no. 19, pp. 5932-5941. https://doi.org/10.1021/jm049067d

    Analogues of thiolactomycin as potential antimalarial agents. / Jones, Simon M.; Urch, Jonathan E.; Kaiser, Marcel; Brun, Reto; Harwood, John L.; Berry, Colin; Gilbert, Ian H.

    In: Journal of Medicinal Chemistry, Vol. 48, No. 19, 01.2005, p. 5932-5941.

    Research output: Contribution to journalArticle

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    AU - Jones, Simon M.

    AU - Urch, Jonathan E.

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    AU - Brun, Reto

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    AU - Berry, Colin

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    N2 - Analogues of the natural antibiotic thiolactomycin (TLM), an inhibitor of the condensing reactions of type II fatty acid synthase, were synthesized and evaluated for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum. Alkylation of the C4 hydroxyl group led to the most significant increase in growth inhibition (over a 100-fold increase in activity compared to TLM). To investigate the mode of action, the P. falciparum KASIII enzyme was produced for inhibitor assay. A number of TLM derivatives were identified that showed improved inhibition of this enzyme compared to TLM. Structure-activity relationships for enzyme inhibition were identified for some series of TLM analogues, and these also showed weak correlation with inhibition of parasite growth, but this did not hold for other series. On the basis of the lack of a clear correlation between inhibition of pfKASIII activity and parasite growth, we conclude that pfKASIII is not the primary target of TLM analogues. Some of the analogues also inhibited the growth of the parasitic protozoa Trypanosoma cruzi, T. brucei, and Leishmania donovani.

    AB - Analogues of the natural antibiotic thiolactomycin (TLM), an inhibitor of the condensing reactions of type II fatty acid synthase, were synthesized and evaluated for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum. Alkylation of the C4 hydroxyl group led to the most significant increase in growth inhibition (over a 100-fold increase in activity compared to TLM). To investigate the mode of action, the P. falciparum KASIII enzyme was produced for inhibitor assay. A number of TLM derivatives were identified that showed improved inhibition of this enzyme compared to TLM. Structure-activity relationships for enzyme inhibition were identified for some series of TLM analogues, and these also showed weak correlation with inhibition of parasite growth, but this did not hold for other series. On the basis of the lack of a clear correlation between inhibition of pfKASIII activity and parasite growth, we conclude that pfKASIII is not the primary target of TLM analogues. Some of the analogues also inhibited the growth of the parasitic protozoa Trypanosoma cruzi, T. brucei, and Leishmania donovani.

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    Jones SM, Urch JE, Kaiser M, Brun R, Harwood JL, Berry C et al. Analogues of thiolactomycin as potential antimalarial agents. Journal of Medicinal Chemistry. 2005 Jan;48(19):5932-5941. https://doi.org/10.1021/jm049067d