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Antiparasitic activities of novel, orally available fumagillin analogs.

ABSTRACT: Fumagillin, an irreversible inhibitor of MetAP2, has been shown to potently inhibit growth of malaria parasites in vitro. Here, we demonstrate activity of fumagillin analogs with an improved pharmacokinetic profile against malaria parasites, trypanosomes, and amoebas. A subset of the compounds showed efficacy in a murine malaria model. The observed SAR forms a basis for further optimization of fumagillin based inhibitors against parasitic targets by inhibition of MetAP2.

SUBMITTER: Arico-Muendel C

PROVIDER: S-EPMC2745105 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Antiparasitic activities of novel, orally available fumagillin analogs.

Arico-Muendel Christopher C Centrella Paolo A PA Contonio Brooke D BD Morgan Barry A BA O'Donovan Gary G Paradise Christopher L CL Skinner Steven R SR Sluboski Barbara B Svendsen Jennifer L JL White Kerry F KF Debnath Anjan A Gut Jiri J Wilson Nathan N McKerrow James H JH DeRisi Joseph L JL Rosenthal Philip J PJ Chiang Peter K PK

Bioorganic & medicinal chemistry letters 20090710 17

Fumagillin, an irreversible inhibitor of MetAP2, has been shown to potently inhibit growth of malaria parasites in vitro. Here, we demonstrate activity of fumagillin analogs with an improved pharmacokinetic profile against malaria parasites, trypanosomes, and amoebas. A subset of the compounds showed efficacy in a murine malaria model. The observed SAR forms a basis for further optimization of fumagillin based inhibitors against parasitic targets by inhibition of MetAP2. ...[more]

PMID: 19648008

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