75(P-65) キナゾリンアルカロイドfebrifugineとその代謝物を基軸とした新規抗マラリア物質の創製(ポスター発表の部)

概要

論文の詳細を見る
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 in malaria. Due to 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 (5 and 6) were isolated as the major metabolites of 1. In addition to 5 and 6, feb-C and D (7 and 8) were also purified from the metabolic mixture of 3.5 and 6 were compounds oxidized at C-6 and C-2 of the quinazolinone ring of 1, respectively. Compounds 7 and 8, derived from 3, also bear febrifugine-type structures in which 1 were oxidized at C-4" and C-6", respectively. In vitro antimalarial and cytotoxic tests using synthetically obtained racemic 5-7 and enantiomerically pure 8 demonstrated that 5 and 7 had antimalarial activity against P. falciparum, of similar potency to that of 1, with high selectivity. Antimalarial activity of 6 and 8, however, was dramatically decreased in the test. The results suggest that basicity of both the 1 and 1"-nitrogen atoms of 1 is crucial in conferring powerful antimalarial activity. Racemic 5 and 7 exhibited powerful in vivo antimalarial activity against mouse malaria P. berghei, and especially no serious side effects were observed with 5 and 7. Thus, the metabolites 5 and 7 appear to be promising lead compounds for development of new types of antimalarial drugs.
天然有機化合物討論会の論文
2003-09-01

75(P-65) キナゾリンアルカロイドfebrifugineとその代謝物を基軸とした新規抗マラリア物質の創製(ポスター発表の部)

スポンサーリンク

概要

著者

関連論文

スポンサーリンク