Original article Further optimization of plakortin pharmacophore: Structurally simple 4-oxymethyl-1,2-dioxanes with promising antimalarial activity Marco Persico a, e , Silvia Parapini b, e , Giuseppina Chianese a, e , Caterina Fattorusso a, e, * , Marco Lombardo c, e, * , Luca Petrizza c , Arianna Quintavalla c, e, * , Francesca Rondinelli a, e , Nicoletta Basilico d, e , Donatella Taramelli b, e , Claudio Trombini c, e , Ernesto Fattorusso a, e , Orazio Taglialatela-Scafati a, e a Dipartimento di Farmacia, Università di Napoli “Federico II”, Via D. Montesano 49, I-80131 Napoli, Italy b Scienze Farmacologiche e Biomolecolari Università di Milano, Via Pascal 36, I-20133 Milano, Italy c Dipartimento di Chimica “Giacomo Ciamician”, Alma Mater Studiorum, Università di Bologna, Via Selmi 2, I-40126 Bologna, Italy d Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università di Milano, Via Pascal 36, I-20133 Milano, Italy e Italian Malaria Network e Centro Interuniversitario di Ricerche sulla Malaria (CIRM), Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Via del Giochetto, 06126 Perugia, Italy article info Article history: Received 2 July 2013 Received in revised form 16 October 2013 Accepted 18 October 2013 Available online 27 October 2013 Keywords: 1,2-Dioxanes Malaria Antimalarial drugs SAR DFT abstract For the optimization of the plakortin pharmacophore, we recently proposed a straightforward synthesis of 4-carbomethoxy-3-methoxy-1,2-dioxanes as potential antimalarial drug candidates. Herein we report the chemoselective reduction of the 4-carbomethoxy group which has allowed us to prepare in good yields twenty-four new endoperoxides carrying either the hydroxymethyl or the methoxymethyl group on C4 in various stereochemical arrangements with respect to the alkyl groups on C3 and C6 (the endoperoxide carbons). Some of these compounds showed promising in vitro antimalarial activities, both against chloroquine-resistant (CQ-R) and susceptible (CQ-S) strains of Plasmodium falciparum, with IC 50 values in the range of 0.5e1.0 mM. Compound 8g showed activity against the CQ-R strain comparable to that of the structurally more demanding plakortin. Ó 2013 Elsevier Masson SAS. All rights reserved. 1. Introduction Malaria exacts a devastating social and economic cost across the globe, striking hardest at some of the poorest nations and being itself a significant cause and consequence of poverty. There are five different types of protozoans of the genus Plasmodium that cause malaria in humans, but Plasmodium falciparum (Pf) is responsible for most of the fatal cases. The appearance of resistance, first to chloroquine (CQ) and more recently to artemisinins [1], created a tremendous therapeutic void and the rate at which resistance is growing outpaces the development of new effective antimalarials. During the intraerythocytic growth, the parasite is quite sensi- tive to small perturbation of its redox balance. Degradation of host hemoglobin within the acidic (pH z 5.5) food vacuole (FV) results in the production of toxic free heme which is oxidized from oxyferro-protoporphyrin IX (FPIX-Fe(II)) to hydroxyferri- protoporphyrin IX (FPIX-Fe(III), hematin), with the concomitant formation of reactive oxygen species (ROS). Free heme is mainly detoxified by crystallization into inert hemozoin, and only a minor portion [2] diffuses through the FV membrane into the cytoplasm where its toxic effects are inactivated by reduced glutathione [3]. Given its high toxicity, even small perturbations of heme detoxifi- cation mechanisms could lead to parasite death due to the excess generation of ROS. A number of well-known antimalarial drugs such as CQ and related 4-aminoquinoline, are reported to interfere with heme detoxification to hemozoin and thus to impair the plasmodium antioxidant defenses [4,5]. To date, an effective ther- apeutic option for the treatment of resistant malaria is represented by the natural endoperoxide artemisinin and its semisynthetic derivatives, although as mentioned above, data on artemisinin- resistant plasmodia in SE Asia are reported [6]. Despite the large use and clinical efficacy of artemisinin derivatives, the exact mo- lecular mechanism of their biological activity is still a matter of * Corresponding authors. Italian Malaria Network e Centro Interuniversitario di Ricerche sulla Malaria (CIRM), Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Via del Giochetto, 06126 Perugia, Italy. E-mail addresses: caterina.fattorusso@unina.it (C. Fattorusso), marco.lombardo@ unibo.it (M. Lombardo), arianna.quintavalla@unibo.it (A. Quintavalla). 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.2013.10.050 European Journal of Medicinal Chemistry 70 (2013) 875e886