Malaria is a major health problem in poverty-stricken regions where new antiparasitic drugs are urgently required at an affordable price. We report herein the design, synthesis, and biological investigation of novel antimalarial agents with low potential to develop resistance and structurally based on a highly conjugated scaffold. Starting from a new hit, the designed modifications were performed hypothesizing a specific interaction with free heme and generation of radical intermediates. This approach provided antimalarials with improved potency against chloroquine-resistant plasmodia over known drugs. A number of structure-activity relationship (SAR) trends were identified and among the analogues synthesized, the pyrrolidinylmethylarylidene and the imidazole derivatives 5r, 5t, and 8b were found as the most potent antimalarial agents of the new series. The mechanism of action of the novel compounds was investigated and their in vivo activity was assessed. © 2008 American Chemical Society.

Fattorusso, C., Campiani, G., Kukreja, G., Persico, M., Butini, S., Romano, M.P., et al. (2008). Design, synthesis, and structure-activity relationship studies of 4-quinolinyl- and 9-acrydinylhydrazones as potent antimalarial agents. JOURNAL OF MEDICINAL CHEMISTRY, 51(5), 1333-1343 [10.1021/jm7012375].

Design, synthesis, and structure-activity relationship studies of 4-quinolinyl- and 9-acrydinylhydrazones as potent antimalarial agents

Campiani, Giuseppe;Kukreja, Gagan;Butini, Stefania;Romano, Maria Pia;Altarelli, Maria;Ros, Sindu;Brindisi, Margherita;Savini, Luisa;Nacci, Vito;Gemma, Sandra
2008-01-01

Abstract

Malaria is a major health problem in poverty-stricken regions where new antiparasitic drugs are urgently required at an affordable price. We report herein the design, synthesis, and biological investigation of novel antimalarial agents with low potential to develop resistance and structurally based on a highly conjugated scaffold. Starting from a new hit, the designed modifications were performed hypothesizing a specific interaction with free heme and generation of radical intermediates. This approach provided antimalarials with improved potency against chloroquine-resistant plasmodia over known drugs. A number of structure-activity relationship (SAR) trends were identified and among the analogues synthesized, the pyrrolidinylmethylarylidene and the imidazole derivatives 5r, 5t, and 8b were found as the most potent antimalarial agents of the new series. The mechanism of action of the novel compounds was investigated and their in vivo activity was assessed. © 2008 American Chemical Society.
2008
Fattorusso, C., Campiani, G., Kukreja, G., Persico, M., Butini, S., Romano, M.P., et al. (2008). Design, synthesis, and structure-activity relationship studies of 4-quinolinyl- and 9-acrydinylhydrazones as potent antimalarial agents. JOURNAL OF MEDICINAL CHEMISTRY, 51(5), 1333-1343 [10.1021/jm7012375].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/19233
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