Original article Targeting the human malaria parasite Plasmodium falciparum: In vitro identification of a new antiplasmodial hit in 4-phenoxy-2- trichloromethylquinazoline series Caroline Castera-Ducros a , Nadine Azas b, ** , Pierre Verhaeghe a , Sébastien Hutter b , Philippe Garrigue a , Aurélien Dumètre b , Litaty Mbatchi a , Michèle Laget b , Vincent Remusat a , France Sifredi a , Sylvain Rault c , Pascal Rathelot a , Patrice Vanelle a, * a Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Universités d’Aix-Marseille I, II et III e UMR CNRS 6264, Laboratoire Chimie Provence, 27 Boulevard Jean Moulin, 13385 Marseille cedex 05, France b Relation Hôte-Parasites, Pharmacologie et Thérapeutique, UMR MD3, Faculté de Pharmacie, Université de la Méditerranée (Aix-Marseille II), 27 Boulevard Jean Moulin, 13385 Marseille cedex 05, France c Centre d’Etudes et de Recherche sur le Médicament de Normandie (CERMN), UPRES EA 4258, FR CNRS 3038, UFR des Sciences Pharmaceutiques, Université de Caen Basse Normandie, Boulevard Becquerel, 14032 Caen cedex, France article info Article history: Received 9 March 2011 Received in revised form 11 June 2011 Accepted 16 June 2011 Available online 23 June 2011 Keywords: Malaria Plasmodium falciparum Phenoxquinazolines Trichloromethyl group abstract From the promising results we previously obtained in quinazoline series and to complete the evaluation of the in vitro antiplasmodial activity of original 2-trichloromethylquinazolines, we synthesized new quinazolines possessing a variously substituted phenoxy group at position 4 through a simple and efficient two-step-synthesis approach. The studies of their activity toward the multi-resistant W2 Plas- modium falciparum strain and of their cytotoxicity on the human hepatocyte HepG2 cell line highlighted a hit compound (molecule 7) displaying a W2 IC 50 value of 1.1 mM and a HepG2 CC 50 value of 50 mM, comparable to chloroquine and doxycycline. Structure-activity- and toxicity relationships indicate that the trichloromethyl group plays a key role in the antiplasmodial activity of such chemical scaffold and also that the phenoxy group substitution as a direct influence on the molecules selectivity. Moreover, molecule 7 displays significant specific activity against the Plasmodium genus in comparison with Toxoplasma and does not show any mutagenic property at the Ames test. Ó 2011 Elsevier Masson SAS. All rights reserved. 1. Introduction Plasmodium falciparum is a protozoan parasite belonging to the Apicomplexa phylum and is the causative agent of the most severe type of malaria: cerebral malaria. According to the W.H.O., 225 million people were suffering from malaria in 2009 among which about 800.000 died, especially African children aged less than 5 years [1]. Because of the emergence of multi-drug-resistant P. falciparum strains, new antimalarial drug-compounds present- ing original mechanisms of action are needed in order to contribute to solving such alarming public health problem [2]. Since more than 40 years, it is well known that the quinazoline ring can display antiplasmodial properties, as many 2,4- diaminoquinazolines were known to inhibit strongly P. falciparum dihydrofolate reductase (PfD.H.F.R.), an essential enzyme to the parasite DNA synthesis [3]. Quite recently, new molecules belonging to the quinazoline series, substituted at position 2, 4 or 6, were identified as exerting promising antiplasmodial activities [4e8]. Among them, three different series were issued from our research team (Fig. 1) specialized on the design and the synthesis of original molecules with anti-infectious properties [9e11]. In order to carry on with the investigation of the antiplasmodial potential of new quinazoline derivatives, we focused on the eval- uation of the influence of the substitution of position 4 of the quinazoline ring toward this activity by preparing a new series of 2- trichloromethylquinazolines bearing a phenoxy group at position 4. Then, their in vitro antiplasmodial properties on the W2 multi- resistant P. falciparum strain were evaluated. In parallel, a cytotox- icity study was conducted on the human HepG2 cell line, in order to * Corresponding author. Tel.: þ33 491 835 528. ** Corresponding author. Tel.: þ33 491 835 564. E-mail addresses: nadine.azas@univmed.fr (N. Azas), patrice.vanelle@univmed. fr (P. Vanelle). 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 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2011.06.021 European Journal of Medicinal Chemistry 46 (2011) 4184e4191