Macrofilaricidal Benzimidazole-Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness. Part 1. Amide Linked Analogs.

A series of benzimidazole-benzoxaborole hybrid molecules linked via an amide linker are described that exhibit good in vitro activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis, also known as River Blindness. The lead identified in this series, 8a, was found to have acceptable pharmacokinetic properties to enable evaluation in animal models of human filariasis. Compound 8a was effective in killing Brugia malayi, B. pahangi and Litomosoides sigmodontis worms present in Mongolian gerbils when dosed subcutaneously as a suspension at 100 mg/kg/day for 14 days, but not when dosed orally at 100 mg/kg/day for 28 days. Measurement of plasma levels of 8a at the end of the dosing period, and at the time of sacrifice revealed an interesting dependence of activity on extended exposure for both 8a and the positive control, flubendazole.