Preliminary communication Flavones as isosteres of 4(1H)-quinolones: Discovery of ligand efficient and dual stage antimalarial lead compounds Tiago Rodrigues a, * , 1 , Ana S. Ressurreição a, 1 , Filipa P. da Cruz b , Inês S. Albuquerque b , Jiri Gut c , Marta P. Carrasco a , Daniel Gonçalves a , Rita C. Guedes a , Daniel J.V.A. dos Santos a, d , Maria M. Mota b , Philip J. Rosenthal c , Rui Moreira a , Miguel Prudêncio b , Francisca Lopes a a Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto,1649-019 Lisbon, Portugal b Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal c Department of Medicine, San Francisco General Hospital, University of California, San Francisco, Box 0811, San Francisco, CA 94143, USA d REQUIMTE, Department of Chemistry & Biochemistry, Faculty of Sciences, University of Porto, R. do Campo Alegre, 4169-007 Porto, Portugal article info Article history: Received 14 July 2013 Received in revised form 1 September 2013 Accepted 3 September 2013 Available online 20 September 2013 Keywords: Malaria Flavone Ligand efficiency Dual stage inhibitor abstract Malaria is responsible for nearly one million deaths annually, and the increasing prevalence of multi- resistant strains of Plasmodium falciparum poses a great challenge to controlling the disease. A diverse set of flavones, isosteric to 4(1H)-quinolones, were prepared and profiled for their antiplasmodial activity against the blood stage of P. falciparum W2 strain, and the liver stage of the rodent parasite Plasmodium berghei. Ligand efficient leads were identified as dual stage antimalarials, suggesting that scaffold opti- mization may afford potent antiplasmodial compounds. Ó 2013 Elsevier Masson SAS. All rights reserved. 1. Introduction The success of drug discovery programs relies heavily on inno- vation, in particular on the design of new chemical entities capable of modulating drug target functions [1]. This is especially true in the case of malaria, which remains the world’s top-priority tropical disease due to its high mortality and morbidity. The emergence and spread of multidrug-resistant Plasmodium falciparum, the most virulent human malaria parasite, is still a major obstacle in con- trolling malaria [2]. Most currently used drugs act against the parasite forms that invade erythrocytes and cause malarial symp- toms [3]. However, the parasite’s life cycle in the human host also includes an asymptomatic, and obligatory developmental phase in the liver, where exo-erythrocytic forms (EEFs) develop in hepato- cytes prior to bloodstream infection [4]. The life cycles of two other human malaria parasites, Plasmodium vivax and Plasmodium ovale, also include hypnozoites, which persist in the liver for long periods of time, and can cause relapses after successful clearance of bloodstream infections. Primaquine (1 , Fig. 1) is the only available drug to treat hypnozoites of P. vivax and P. ovale, but its use is limited due to toxic effects [5,6]. Recently, efforts have focused on discovering safer drug candidates capable of blocking the devel- opment of the malarial liver stage [7e9], and of eliminating hyp- nozoites [10e12]. For example, 4(1H)-quinolones and analogs are highly effective against erythrocytic forms and EEFs of Plasmodium spp. [13e19]. Most commonly, cytochrome bc 1 is the main drug target for these compounds [20,21], but in some cases, such as 2 and 3 (Fig. 1), NADH:ubiquinone oxidoreductase (PfNDH2) is also blocked [17,22]. Docking studies using a crystal structure of the bc 1 complex from Saccharomyces cerevisiae suggest that 4(1H)-quino- lones bind to the Q o site of cytochrome b with a pose similar to that of stigmatellin, (4, Fig. 1). Key interactions in this binding model are the H-bond bridges with Glu 272 and His 181 (from the Rieske irone Abbreviations: CQ, chloroquine; DBU, 1,8-diazabicycloundec-7-ene; DMF, N, N-dimethylformamide; EEF, exo-erythrocytic form; LE, ligand efficiency; NBS, N-bromosuccinimide; PfNDH2, Plasmodium falciparum NADH:ubiquinone oxidore- ductase; SAR, structureeactivity relationships. * Corresponding author. Present address: ETH Zürich, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland. Tel.: þ41 44 633 91 13. E-mail address: tiago.rodrigues@pharma.ethz.ch (T. Rodrigues). 1 T.R. and A.S.R. contributed equally to this work. Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmech.2013.09.008 European Journal of Medicinal Chemistry 69 (2013) 872e880