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221.
Marema E. Makgatho Ronald Anderson John F. O'Sullivan Timothy J. Egan Janet A. Freese Nicolene Cornelius Constance E.J. van Rensburg 《Drug development research》2000,50(2):195-202
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] and 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‐, and sulfadoxine/pyrimethamine‐sensitive and ‐resistant strains of Plasmodium falciparum in vitro, as well as for their effects on polymerisation of haeme to β‐hematin. By using microscopic and flow cytometric methods, it was found that B4119 and B4158, but not clofazimine, inhibited the growth of sensitive, as well as resistant strains of P. falciparum with IC50 values between 0.22 and 0.7 μM, indicating lack of cross‐resistance. Augmentation of anti‐plasmodial activity was observed when B4119 and B4158 were used in combination with chloroquin or mefloquine. Inhibition of the growth of P. falciparum was associated with interference with haeme polymerisation to β‐hematin in vitro, while administration of B4119 to P. berghei‐infected mice was accompanied by a significant reduction in parasitemia and improved therapeutic activity was observed when this agent was combined with chloroquin. The data presented in this study demonstrate that the TMP‐substitution at position 2 on the phenazine nucleus of riminophenazines confers anti‐plasmodial activity on these compounds. These may prove to be useful forerunners in the design of novel anti‐plasmodial pharmacologic agents. Drug Dev. Res. 50:195–202, 2000. © 2000 Wiley‐Liss, Inc. 相似文献