In Vitro and In Vivo Activities of 1-Hydroxy-2-Alkyl-4(1 H )Quinolone Derivatives against Toxoplasma gondii

Abstract

1-Hydroxy-2-dodecyl-4(1H)quinolone (HDQ) was recently identified as a Toxoplasma gondii inhibitor.We describe here two novel 1-hydroxyquinolones, which displayed 50% inhibitory concentrations 10-and 5-fold lower than that of HDQ. In a mouse model of acute toxoplasmosis, these two compounds and HDQ reduced the percentages of infected peritoneal cells and decreased the parasite loads in lungs and livers. Compound B showed a tendency toward lowering parasite loads in brains in a mouse model of toxoplasmic encephalitis.Apicomplexan parasites are widespread human pathogens causing diseases such as malaria and toxoplasmosis. Development of drug resistance, particularly in Plasmodium, is a major threat for human health and stock breeding, thus motivating the development of novel drug therapies (3, 7). The mitochondrial physiology of apicomplexan parasites differs in several aspects from the physiology of mammalian mitochondria (10,15). This feature can be exploited for drug therapy, as shown by treatment with the complex III inhibitor atovaquone (1, 2, 12, 16). 1-Hydroxy-2-dodecyl-4(1H)quinolone (HDQ) was recently shown to effectively inhibit parasite replication of Toxoplasma gondii and Plasmodium falciparum in tissue culture (13). The structural similarity of HDQ and coenzyme Q (6) suggests an inhibition of ubiquinol binding enzymes as a mode of action. Using inhibition kinetics on heterologously expressed enzymes, we recently demonstrated that HDQ is a high-affinity inhibitor of the T. gondii alternative NADH dehydrogenase (TgNDH2-I) (9). HDQ treatment in T. gondii results in a rapid loss of the mitochondrial membrane potential and a subsequent reduction of the cellular ATP concentration (8). HDQ was reported to inhibit the parasitic dihydroorotate dehydrogenase (DHODH) in P. falciparum (4), thus inhibiting the fourth step of the essential de novo pyrimidine synthesis, which uses ubiquinol reduction as an electron sink for dihydroorotate oxidation.Based on the structure of HDQ, we here describe four novel 1-hydroxyquinolones (compounds A to D) and their anti-Toxoplasma activities and provide the first data on the in vivo efficacy of HDQ, as well as those of compounds A and B, in a mouse model of acute toxoplasmosis. We had previously shown that a long alkyl side chain at C-2 in HDQ of more than five carbons is critical for the anti-Toxoplasma activities of 1-hydroxy-2-alkyl-4(1H)quinolones (13), and it was thus of interest to investigate whether its location at C-2 is strictly required for the antiparasitic effect. In addition, from previous investigations, it was not clear whether the hydrogen at C-3 in HDQ is needed. We therefore prepared the two new 1-hydroxyquinolones, compounds A and B (L. F. Tietze et al., unpublished data). In compound A, the hydrogen at C-3 in HDQ is replaced by a methyl group, and in compound B, the dodecyl and the methyl moiety were swapped (Fig. 1). Furthermore, we synthesized two HDQ derivatives, compounds C and D, containing a N,N-dimethylaminoethoxy group at C-6, in order to improve th...

Arrested Oocyst Maturation in Plasmodium Parasites Lacking Type II NADH:Ubiquinone Dehydrogenase

“…4) either in WT or ndh2(Ϫ) parasites. Interestingly, 32 mg of HDQ/kg bodyweight has been shown to affect Toxoplasma gondii growth in vivo (58). We interpret these findings as an indication for potential differences in energy requirements and ATP generation between Plasmodium parasites and T. gondii.…”

New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections

“…Further, cytochrome bc 1 expression is markedly increased in encysted EGS bradyzoites suggesting cytochrome bc 1 might be a viable drug target for this life stage. This mitochondrial membrane bound protein complex cytochome bc 1 , part of the electron transport chain responsible for generating ubiquinone for pyrimidine biosynthesis in Plasmodium , is the molecular target of the naphthoquinone, atovaquone 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 . Partial efficacy, rapid emergence of drug resistance in malaria and toxoplasmosis limit clinical usefulness of atovaquone.…”

Two internal type II NADH dehydrogenases of Toxoplasma gondii are both required for optimal tachyzoite growth

“…The 1‐Hydroxy‐2‐alkyl‐4(1H)quinolone HDQ was shown to be a high affinity inhibitor for Y. lipolytica NDH2 (Eschemann et al ., 2005), and a potent inhibitor of T. gondii replication (Saleh et al ., 2007; Bajohr et al ., 2010). TgNDH2‐I was demonstrated to be a target of HDQ by enzyme kinetic analysis (Lin et al ., 2008), but it is unclear whether in addition to TgNDH2‐I the second isoform is also inhibited, whether additional HDQ targets might exist, and most importantly, what the relevant HDQ target(s) is/are that cause the growth inhibition.…”