The experimental chemotherapy of leishmaniasis, V

Abstract

Two methods were used to examine a variety of compounds for possible activity against a viscerotropic infection of ‘Leishmania infantum LV9’ in NMRI mice. The parasite originated from a human case of kala-azar in Ethiopia. The procedures followed were described in detail in the previous papers in this series.

Little activity was detected in a number of sulphonamides, dihydrofolate reductase inhibitors, antimalarials, schistosomicides, trypanocides, or antibiotics by these methods. Only cycloguanil HCl and primaquine phosphate among the antimalarials showed marked activity. Racemic 2-dehydroemetine and amphotericin B were moderately active. Pentamidine and diminazene aceturate in this model were marginally active only.

Among 46 chemical structures (selected partly on the basis of interesting activity against Leishmania discovered earlier in tissue culture) only two 6-aminoquinolines were fully active, but they were also toxic to the host. Good activity was displayed by two metronidazole analogues, and one thiophene. Activity in another 20 compounds was only marginal, and no activity at all was found in 21 of the 46 structures.

A very high level of activity was detected in a number of 4-methyl-6-methoxy-8-amino-quinolines (lepidines), the best being WR 226292 [4-methyl-5, 6-dimethoxy-8-(6-diethylamino-hexylamino)-quinoline], which is at least 150 times better than sodium stibogluconate in this model. Only four of 11 8-aminoquinolines other than lepidines failed to show some degree of activity, but several were relatively toxic.

A comparison is drawn between the use of various hamster models and the mouse for detection of drug action against viscerotropic Leishmania. It is concluded that ‘L. infantum LV9’ in the NMRI mouse is a practical and economic model that is valuable for drug screening.