2. Academic Validation
  3. Boron-Pleuromutilins as Anti- Wolbachia Agents with Potential for Treatment of Onchocerciasis and Lymphatic Filariasis

Boron-Pleuromutilins as Anti- Wolbachia Agents with Potential for Treatment of Onchocerciasis and Lymphatic Filariasis

  • J Med Chem. 2019 Mar 14;62(5):2521-2540. doi: 10.1021/acs.jmedchem.8b01854.
Robert T Jacobs 1,  Christopher S Lunde 1,  Yvonne R Freund 1,  Vincent Hernandez 1,  Xianfeng Li 1,  Yi Xia 1,  David S Carter 1,  Pamela W Berry 1,  Jason Halladay 1,  Fernando Rock 1,  Rianna Stefanakis 1,  Eric Easom 1,  Jacob J Plattner 1,  Louise Ford 2,  Kelly L Johnston 2,  Darren A N Cook 2,  Rachel Clare 2,  Andrew Cassidy 2,  Laura Myhill 2,  Hayley Tyrer 2,  Joanne Gamble 2,  Ana F Guimaraes 2,  Andrew Steven 2,  Franziska Lenz 3,  Alexandra Ehrens 3,  Stefan J Frohberger 3,  Marianne Koschel 3,  Achim Hoerauf 3,  Marc P Hübner 3,  Case W McNamara 4,  Malina A Bakowski 4,  Joseph D Turner 2,  Mark J Taylor 2,  Stephen A Ward 2
Affiliations

Affiliations

  • 1 Anacor Pharmaceuticals , 1020 East Meadow Circle , Palo Alto , California 94303 , United States.
  • 2 Centre for Drugs and Diagnostics, Department of Parasitology , Liverpool School of Tropical Medicine , Pembroke Place , Liverpool L3 5QA , U.K.
  • 3 Institute for Medical Microbiology, Immunology and Parasitology , University Hospital Bonn , Sigmund Freud Str. 25 , 53127 Bonn , Germany.
  • 4 Calibr , 11119 North Torrey Pines Road , Suite 100, La Jolla , California 92037 , United States.
PMID: 30730745 DOI: 10.1021/acs.jmedchem.8b01854
Abstract

A series of pleuromutilins modified by introduction of a boron-containing heterocycle on C(14) of the polycyclic core are described. These analogs were found to be potent anti- Wolbachia Antibiotics and, as such, may be useful in the treatment of filarial infections caused by Onchocerca volvulus, resulting in Onchocerciasis or river blindness, or Wuchereria bancrofti and Brugia malayi and related parasitic nematodes resulting in lymphatic filariasis. These two important neglected tropical diseases disproportionately impact patients in the developing world. The lead preclinical candidate compound containing 7-fluoro-6-oxybenzoxaborole (15, AN11251) was shown to have good in vitro anti- Wolbachia activity and physicochemical and pharmacokinetic properties providing high exposure in plasma. The lead was effective in reducing the Wolbachia load in filarial worms following oral administration to mice.

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