In Vitro Activities of DU-1102, a New Trioxaquine Derivative, againstPlasmodium falciparumIsolates

Abstract

The antimalarial trioxaquine derivative DU-1102, synthesized by covalent linkage between aminoquinoline and trioxane moieties, was highly active against Cameroonian isolates (mean 50% inhibitory concentration of 43 nmol/liter) of Plasmodium falciparum. There was no correlation between the responses to DU-1102 and chloroquine and only a low correlation between the responses to DU-1102 and pyrimethamine, suggesting an independent mode of action of the trioxaquine against the parasites.Because of the extensive spread of drug resistance involving primarily 4-aminoquinolines and antifolate drugs in most of the geographic areas where Plasmodium falciparum is endemic, there is a need for a sustained search for promising compounds with new chemical structures and mechanisms of action. In the past 2 decades, only a few compounds belonging to a new class of antimalarial drugs, including aminoalcohols (mefloquine, halofantrine, lumefantrine), sesquiterpene trioxanes (artemisinin derivatives), and naphthoquinones (atovaquone), were developed for commercialization.DU-1102 (Fig. 1a) is a new candidate compound that belongs to a novel chemical class named trioxaquine (7, 11) (Fig. 1b). Trioxaquines are new modular molecules obtained by covalently attaching a trioxane motif, present in artemisinin, to a 4-aminoquinoline entity, contained in chloroquine. As the trioxane moiety is a potential alkylating agent after reductive activation by heme (6,10,(15)(16)(17)(18) and the 4-aminoquinoline entity is known to easily penetrate within infected erythrocytes (9) and then interact with heme, such modular molecules are expected to combine the properties of both fragments. Although it remains to be experimentally confirmed, we hypothesized that trioxaquine is able to penetrate infected red blood cells and then interact with the free heme liberated during the hemoglobin digestion.The in vitro activity of DU-1102 was assessed against clinical isolates of P. falciparum obtained in Yaoundé, Cameroon, where previous in vitro and in vivo studies have shown a high proportion (Ͼ40%) of chloroquine and/or pyrimethamine resistance (3, 14). We also evaluated the potential for in vitro cross-resistance between DU-1102 and chloroquine and pyrimethamine, which are first-and second-line (pyrimethaminesulfadoxine combination) drugs in Cameroon, respectively.Fresh clinical isolates of P. falciparum were obtained before treatment from adult Cameroonian patients attending the Nlongkak Catholic missionary dispensary in Yaoundé in 2000.The patients presented with signs and symptoms of acute uncomplicated malaria and had at least 0.1% asexual parasitemia. The Saker-Solomons colorimetric test for 4-aminoquinolines, quinine, and antifolate drugs in urine was negative for each patient (12). The patients were treated with oral amodiaquine, according to the national antimalarial guidelines set by the Cameroonian Ministry of Public Health. The study was approved by the Cameroonian National Ethics Committee and the Cameroonian Ministry of Public Health.Chloroquine...

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

“…[217,218] [219] This compound has been shown to alkylate heme in vitro. [220] In a related approach, biologically cleavable (compound 47) and noncleavable (compound 48) chimeras of mefloquine (29) and a 10-trifluoromethylartemisinin were prepared.…”

Synthesis and Antimalarial Activity of Trioxaquine Derivatives

“…The doses required to decrease parasitemia by 50 % (ED 50 ) were 5 and 18 mg kg À1 d À1 after intraperitoneal and oral administration, respectively. Parasitemia clearance was complete without recrudescence at an intraperitoneal dose of 20 mg kg À1 d methamine-resistant human isolates of P. falciparum, [9] we aimed to synthesize a series of new trioxaquines (Figure 1) in an effort to increase the antimalarial activity of this series. In particular, we wanted to gain an understanding into the influence of several structural parameters, such as: 1) the length of the tether between the 4-aminoquinoline and the trioxane fragments [trioxaquines 5 b (DU1106) and 5 c (DU1108)]; 2) the use of different starting dienes [trioxaquines 10 (DU1402) and cis-15 (DU1302 c), obtained from 1,3-cyclohexadiene and a-terpinene, respectively]; and 3) the nature of the diketone used in the synthesis of the trioxane [trioxaquines 6 a (DU1112) and 6 b (DU1114) were obtained from cis-bicyclo[3.3.0]octane-3,8-dione, [10] rather than cyclohexane-1,4-dione, which has always been used previously].…”

Synthetic peroxides as antimalarials

“…Trioxaquines combine a Fenozan-type trioxane and a 4-aminoquinoline in a single hybrid structure. 22,[111][112][113] Three trioxaquines were obtained by reductive amination reactions of a trioxane ketone 77 with the corresponding quinoline primary amines. Trioxaquine 51, the best of these, was only 2-fold less potent than 1.…”