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

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.