Endochin Optimization: Structure−Activity and Structure−Property Relationship Studies of 3-Substituted 2-Methyl-4(1H)-quinolones with Antimalarial Activity

Abstract

Since the 1940s endochin and analogues thereof were known to be causal prophylactic and potent erythrocytic stage agents in avian models. Preliminary screening in a current in vitro assay identified several 4(1H)-quinolones with nanomolar EC(50) against erythrocytic stages of multidrug resistant W2 and TM90-C2B isolates of Plasmodium falciparum. Follow-up structure-activity relationship (SAR) studies on 4(1H)-quinolone analogues identified several key features for biological activity. Nevertheless, structure-property relationship (SPR) studies conducted in parallel revealed that 4(1H)-quinolone analogues are limited by poor solubilities and rapid microsomal degradations. To improve the overall efficacy, multiple 4(1H)-quinolone series with varying substituents on the benzenoid quinolone ring and/or the 3-position were synthesized and tested for in vitro antimalarial activity. Several structurally diverse 6-chloro-2-methyl-7-methoxy-4(1H)-quinolones with EC(50) in the low nanomolar range against the clinically relevant isolates W2 and TM90-C2B were identified with improved physicochemical properties while maintaining little to no cross-resistance with atovaquone.

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P4Q-158 have been shown to have potent activity against P. falciparum blood stage parasites in vitro (14; Cross et al, unpublished).…”

“…The drugs atovaquone (ATOV), chloroquine (CQ), and primaquine (PQ) used in these studies were obtained from Sigma (St. Louis, MO). The novel compounds ICI 56,780 (14,28), P4Q-146, and P4Q-158 were synthesized and purified by the Manetsch laboratory at the University of South Florida, Department of Chemistry (Cross et al, unpublished). Structures of the compounds are shown in Fig.…”

“…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).…”