Tetramethylpiperidine‐substituted phenazines as novel anti‐plasmodial agents

摘要: Two novel derivatives of clofazimine [3-(p-chloroanilino)-10-(p-chlorophenyl)-2,10-dihydro-2-isopropylimino)phenazine] and the tetramethylpiperidine (TMP)-substituted phenazines, B4119 [3-(3-chloro-4-fluoroanilino)-10-(3-chloro-4-fluorophenyl)-2,10-dihydro-2(2,2,6,6-tetramethylpiper-4-ylimino)phenazine] B4158 [3-(4-isopropylanilino)-10-(4-isopropylphenyl)-2,10-dihydro-2-(2,2,6,6-tetramethylpiper-4-ylimino)phenazine] (1–8 μM), were evaluated for activity against chloroquin-, quinine-, sulfadoxine/pyrimethamine-sensitive -resistant strains Plasmodium falciparum in vitro, as well their effects on polymerisation haeme to β-hematin. By using microscopic flow cytometric methods, it was found that B4158, but not clofazimine, inhibited growth sensitive, resistant P. with IC50 values between 0.22 0.7 μM, indicating lack cross-resistance. Augmentation anti-plasmodial observed when used combination chloroquin or mefloquine. Inhibition associated interference β-hematin while administration berghei-infected mice accompanied by a significant reduction parasitemia improved therapeutic this agent combined chloroquin. The data presented study demonstrate TMP-substitution at position 2 phenazine nucleus riminophenazines confers these compounds. These may prove be useful forerunners design pharmacologic agents. Drug Dev. Res. 50:195–202, 2000. © 2000 Wiley-Liss, Inc.