Metabolites of Febrifugine and Its Synthetic Analogue by Mouse Liver S9 and Their Antimalarial Activity against Plasmodium Malaria Parasite

Abstract

Quinazolinone type alkaloids, febrifugine (1) and isofebrifugine (2), isolated from Dichroa febrifuga roots, show powerful antimalarial activity against Plasmodium falciparum. Unfortunately, their emetic effect and other undesirable side effects have precluded their clinical use for malaria. Because of their antimalarial potency, analogues were searched for, with the goal of preserving the strong antimalarial activity, while dramatically reducing side effects. We expected that compounds useful in drug development would exist in metabolites derived from 1 and Df-1 (3), the condensation product of 1 with acetone, by mouse liver S9. Feb-A and -B (4 and 5) were isolated as the major metabolites of 1. In addition to 4 and 5, feb-C and -D (6 and 7) were also purified from the metabolic mixture of 3. Compounds 4 and 5 were compounds oxidized at C-6 and C-2 of the quinazolinone ring of 1, respectively. Compounds 6 and 7, derived from 3, also bear febrifugine type structures in which the 4' '- and 6' '-positions of the piperidine ring of 1 were oxidized. In vitro antimalarial and cytotoxic tests using synthetically obtained racemic 4-6 and enantiomerically pure 7 demonstrated that 4 and 6 had antimalarial activity against P. falciparum, of similar potency to that of 1, with high selectivity. The antimalarial activity of 5 and 7, however, was dramatically decreased in the test. The in vitro antimalarial activity of analogues 22 and 43, which are stereoisomers of 4 and 6, was also evaluated, showing that 22 is active. The results suggest that basicity of both the 1- and the 1' '-nitrogen atoms of 1 is crucial in conferring powerful antimalarial activity. Racemic 4 and 6 exhibited powerful in vivo antimalarial activity against mouse malaria P. berghei, and especially, no serious side effects were observed with 4. Thus, the metabolite 4 appears to be a promising lead compound for the development of new types of antimalarial drugs.

Antimalarial Activities and Therapeutic Properties of Febrifugine Analogs

“…Because mice do not possess a vomiting reflex, the emetic effects could not be observed in tests with mice. However, the mice treated subcutaneously in our tests did not display apparent diarrhea or gastrointestinal tract hemorrhage, similar to data reported previously (6). This phenomenon implies that the diarrhea and intestinal hemorrhage caused by febrifugine analogs are acquired merely through contact with the host gastrointestinal tract.…”

“…For example, it was found that the administration of febrifugine analogs did not cause changes to body or liver weights, irritation of the gastrointestinal tract, or alteration of the levels of hepatic enzyme markers in infected mice (6,20). Febrifugine altered the production of nitric oxide and tumor necrosis factor alpha in mouse macrophages (19).…”

DJ‐1‐binding compounds prevent oxidative stress‐induced cell death and movement defect in Parkinson’s disease model rats

“…Several compounds that have a high binding constant (docking score) to the region containing C106 (C106 region) but not to other regions were obtained. Structures of compounds A and B (Kametani et al 1974a,b), which had the highest docking score to the C106 regions of reduced and of oxidized DJ-1 as the SO 2 H form, respectively, and the structure of compound C (Hirai et al 2003), which had the lowest docking score to oxidized DJ-1, are shown in Fig. 1(b).…”

Recent advances in antimalarial drug development

“…24) had antimalarial activity against P. falciparum, of similar potency to that of natural product febrifugine, with high selectivity. 223 The results also suggest that basicity of both the 1-and the 1 00 -nitrogen atoms of febrifugine is crucial in conferring powerful antimalarial activity. Compound 124 exhibited highest in vivo antimalarial activity against P. berghei, with no serious side effects (ED 50 ¼ 0.6 mg/kg).…”