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

J Med Chem. 2008 Mar 13;51(5):1333-43. doi: 10.1021/jm7012375.

Caterina Fattorusso ¹, Giuseppe Campiani, Gagan Kukreja, Marco Persico, Stefania Butini, Maria Pia Romano, Maria Altarelli, Sindu Ros, Margherita Brindisi, Luisa Savini, Ettore Novellino, Vito Nacci, Ernesto Fattorusso, Silvia Parapini, Nicoletta Basilico, Donatella Taramelli, Vanessa Yardley, Simon Croft, Marianna Borriello, Sandra Gemma

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1 [email protected].

PMID: 18278859 DOI: 10.1021/jm7012375

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.

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