期刊
ACS INFECTIOUS DISEASES
卷 6, 期 2, 页码 173-+出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.9b00396
关键词
onchocerciasis; lymphatic filariasis; flubendazole; tubulin; organoboron
资金
- Bill AMP
- Melinda Gates Foundation [23629, OPP1134310, OPP1017584]
- Bill and Melinda Gates Foundation [OPP1134310] Funding Source: Bill and Melinda Gates Foundation
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 (AN8799), 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. The 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 the extended exposure for both 8a and the positive control, flubendazole.
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