Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)

Abstract

A program was undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron transport chain of the malaria parasite Plasmodium falciparum. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone (HDQ), and this was used along with a range of chemoinformatics methods in the rational selection of 17 000 compounds for high-throughput screening. Twelve distinct chemotypes were identified and briefly examined leading to the selection of the quinolone core as the key target for structure–activity relationship (SAR) development. Extensive structural exploration led to the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC50 against PfNDH2 of 16 nM), and demonstrates low cytotoxicity and high metabolic stability in the presence of human liver microsomes. This lead compound and its phosphate pro-drug have potent in vivo antimalarial activity after oral administration, consistent with the target product profile of a drug for the treatment of uncomplicated malaria. Other quinolones presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc1, and studies to determine the potential advantage of this dual-targeting effect are in progress.

Antimalarial 4(1H)-pyridones bind to the Q i site of cytochrome bc 1

“…A recent X-ray structure of cytochrome bc 1 from Saccharomyces cerevisiae has shown atovaquone bound in the catalytic Q o site, offering explanation for the cross-species resistance (20). Many different classes of compound have been investigated as potential drugs and much work has focused on inhibition of the Q o site (23,(29)(30)(31)(32). The 4(1H)-pyridones have been researched for their antimalarial properties since the 1960s, based on the compound clopidol (33,34) (Fig.…”

4(1H)-Quinolones with Liver Stage Activity against Plasmodium berghei

“…P4Q-146 and P4Q-158. Due to the remarkable antimalarial activity of 4(1H)-quinolones against erythrocytic and exoerythrocytic stages, the endochin series has recently been revived by several research teams (13,14,(16)(17)(18). Using previously developed reaction conditions (39), our team synthesized and tested Ͼ100 3-phenyl-substituted P4Qs, of which P4Q-146 and P4Q-158 have been shown to have potent activity against P. falciparum blood stage parasites in vitro (14; Cross et al, unpublished).…”

“…Salzer et al (11) found that endochin had liver and blood stage activity in avian malaria models; however, due to the lack of appropriate preclinical models, additional studies were not conducted (11). The compounds related to endochin also have activity against Plasmodium cynomolgi liver stages (12), and more recently, studies have shown these compounds to be potent in vitro and in vivo against Plasmodium falciparum and rodent malaria blood stage parasites (13)(14)(15)(16)(17)(18) …”

4-(1 H )-Quinolones and 1,2,3,4-Tetrahydroacridin-9(10 H )-Ones Prevent the Transmission of Plasmodium falciparum to Anopheles freeborni

“…Therefore, we investigated the transmission-blocking activity of 4(1H)-quinolones that have activity against the blood and liver stages of parasites in the avian, rodent, and rhesus monkey malaria models (13)(14)(15). Recent studies have demonstrated that 4(1H)-quinolones are active against P. falciparum blood and liver stages in vitro (16)(17)(18)(19)(20)(21)(22)(23)(24)(25), as well as against P. berghei rodent malaria liver stages in vitro and in vivo (26).In this work, we tested three 3-alkyl-or 3-phenyl-4(1H)-quinolones (P4Qs; P4Q-95, P4Q-105, P4Q-146), one 7-(2-phenoxyethoxy)-4(1H)-quinolone (PEQ; ICI 56,780), and one 1,2,3,4-tetrahydroacridin-9(10H)-one (THA-93) (16,17,23) for their gametocytocidal, gametocidal, and sporozontocidal activity against P. falciparum as well as their transmission activities in vivo against P. berghei. These compounds were chosen because of their strong efficacy against blood stages in vitro (16,17,23).…”

“…Therefore, we investigated the transmission-blocking activity of 4(1H)-quinolones that have activity against the blood and liver stages of parasites in the avian, rodent, and rhesus monkey malaria models (13)(14)(15). Recent studies have demonstrated that 4(1H)-quinolones are active against P. falciparum blood and liver stages in vitro (16)(17)(18)(19)(20)(21)(22)(23)(24)(25), as well as against P. berghei rodent malaria liver stages in vitro and in vivo (26).…”