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

Authors
  • Akama, Tsutomu1
  • Freund, Yvonne R.1
  • Berry, Pamela W.1
  • Carter, David S.1
  • Easom, Eric E.1
  • Jarnagin, Kurt1
  • Lunde, Christopher S.1
  • Plattner, Jacob J.1
  • Rock, Fernando1
  • Stefanakis, Rianna1
  • Fischer, Chelsea2
  • Bulman, Christina A.2
  • Lim, Kee Chong2
  • Suzuki, Brian M.3
  • Tricoche, Nancy4
  • Mansour, Abdelmoneim5
  • DiCosty, Utami5
  • McCall, Scott5
  • Carson, Ben5
  • McCall, John W.5
  • And 7 more
  • 1 Anacor Pharmaceuticals, Inc., United States , (United States)
  • 2 University of California San Francisco, United States , (United States)
  • 3 University of California San Diego, United States , (United States)
  • 4 New York Blood Center, United States , (United States)
  • 5 TRS Laboratories, Inc., United States , (United States)
  • 6 University Hospital Bonn, Germany , (Germany)
  • 7 Drugs for Neglected Diseases Initiative, Switzerland , (Switzerland)
Type
Published Article
Journal
ACS Infectious Diseases
Publisher
American Chemical Society
Publication Date
Dec 26, 2019
Volume
6
Issue
2
Pages
173–179
Identifiers
DOI: 10.1021/acsinfecdis.9b00396
PMID: 31876154
PMCID: PMC7026885
Source
PubMed Central
Keywords
Disciplines
  • Letter
License
Unknown

Abstract

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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