Original article Antimalarial activity of imidazo[2,1-a]isoindol-5-ol derivatives and related compounds Esther del Olmo a, * , Bianca Barboza a , Louise D. Chiaradia b , Alicia Moreno c , Juana Carrero-Lérida d , Dolores González-Pacanowska d , Victoria Muñoz e , José L. López-Pérez a , Alberto Giménez e , Agustín Benito c , Antonio R. Martínez f , Luis M. Ruiz-Pérez d , Arturo San Feliciano a a Departamento de Química Farmacéutica, Facultad de Farmacia, CIETUS, Universidad de Salamanca, Spain b Departamento de Química, Universidade Federal de Santa Catarina, Campus Universitário Trindade, Florianópolis-SC, Brazil c Centro Nacional de Medicina Tropical, ISCIII, Madrid, Spain d Instituto de Parasitología y Biomedicina “López Neyra”, Consejo Superior de Investigaciones Científicas, Armilla, Granada, Spain e Instituto de Investigaciones Fármaco-Bioquímicas, Universidad Mayor de San Andrés, La Paz, Bolivia f Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Spain article info Article history: Received 9 June 2011 Received in revised form 30 August 2011 Accepted 31 August 2011 Available online 7 September 2011 Keywords: Synthesis Imidazoisoindoles In vitro assays Plasmodium falciparum Structureeactivity relationship In vivo assays Mouse model Plasmodium berghei abstract The synthesis of several series of imidazo[2,1-a]isoindol-5-ol derivatives and the results of their evalu- ation against Plasmodium falciparum are presented and discussed. The effects of electron-withdrawing or-donating substituents on different parts of the molecule, as well as those produced by the incorpo- ration of an additional fused ring, were analyzed. Several compounds showed significant antimalarial activity in vitro with IC 50 values as low as 60 nM and a certain efficacy in vivo by reducing parasitemia in Plasmodium berghei mouse models. Ó 2011 Elsevier Masson SAS. All rights reserved. 1. Introduction Malaria is a tropical disease mainly caused by Plasmodium fal- ciparum, that kills more than one million people per year [1]. About 3.3 billion people -half of the world’s population and living in the poorest countries- are at risk of being infected with malaria. It represents a major public heath problem in more than 109 coun- tries [2]. Early diagnosis and prompt treatment are two basic elements of malaria control. Inappropriate use of antimalarial drugs in the past century contributed to widespread resistance in the malaria parasite to drugs such as chloroquine, and sulfadoxine- pyrimethamine [3] and in South-East Asia resistance to third- and fourth-line antimalarial drugs has been reported [4]. Therefore, the development of new alternative agents, especially useful in cases of multiple drug resistance becomes necessary. During the last decades increasing efforts have been done aiming to discover better therapeutic agents against malaria. The research has been focused either on natural products as medicinal plants [5], marine organ- isms [6] or even bacteria [7], as well as on synthetic processes to prepare new heterocyclic [8] and organometallic [9] compounds. In a previous study, we synthesized and tested in vitro against the F32-Tanzania chloroquine sensitive strain of P. falciparum several families of heterocyclic compounds, sharing in common the presence of a natural carbonated dihydrostilbene fragment and including 4-benzylphthalazin-1-ones, 5-benzylimidazo[2,1-a]iso- indol-5-ols and 6-benzylpyrimido[2,1-a]isoindolols [10]. Of the compounds evaluated, the imidazo[2,1-a]isoindolol derivatives displayed the best antiplasmodial activity, with IC 50 values similar to that of the reference drug chloroquine (CQ). In order to further explore the antiplasmodial potential of this active series and with * Corresponding author. Fax: þ34 923294515. E-mail address: olmo@usal.es (E. del Olmo). Contents lists available at SciVerse 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.2011.08.043 European Journal of Medicinal Chemistry 46 (2011) 5379e5386