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

Robert T. Jacobs; Christopher S. Lunde; Yvonne R. Freund; Vincent Hernandez; Xianfeng Li; Yi Xia; David S. Carter; Pamela W. Berry; Jason Halladay; Fernando Rock; Rianna Stefanakis; Eric Easom; Jacob J. Plattner; Louise Ford; Kelly Johnston; Darren A.N. Cook; Rachel Clare; Andrew Cassidy; Laura Myhill; Hayley Tyrer; Joanne Gamble; Ana F. Guimaraes; Andrew Steven; Franziska Lenz; Alexandra Ehrens; Stefan J. Frohberger; Marianne Koschel; Achim Hoerauf; Marc P. Hübner; Case W. McNamara; Malina A. Bakowski; Joseph Turner; Mark Taylor; Steve Ward

doi:10.1021/acs.jmedchem.8b01854

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

Robert T. Jacobs, Christopher S. Lunde, Yvonne R. Freund, Vincent Hernandez, Xianfeng Li, Yi Xia, David S. Carter, Pamela W. Berry, Jason Halladay, Fernando Rock, Rianna Stefanakis, Eric Easom, Jacob J. Plattner, Louise Ford, Kelly Johnston, Darren A.N. Cook, Rachel Clare, Andrew Cassidy, Laura Myhill, Hayley TyrerJoanne Gamble, Ana F. Guimaraes, Andrew Steven, Franziska Lenz, Alexandra Ehrens, Stefan J. Frohberger, Marianne Koschel, Achim Hoerauf, Marc P. Hübner, Case W. McNamara, Malina A. Bakowski, Joseph Turner, Mark Taylor, Steve Ward

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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 Onchocherca 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 (NTDs) disproportionately impact patients in the developing world. The lead preclinical candidate compound containing a 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.

Original language	English
Pages (from-to)	2521-2540
Number of pages	20
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	5
Early online date	7 Feb 2019
DOIs	https://doi.org/10.1021/acs.jmedchem.8b01854
Publication status	E-pub ahead of print - 7 Feb 2019

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Jacobs, R. T., Lunde, C. S., Freund, Y. R., Hernandez, V., Li, X., Xia, Y., Carter, D. S., Berry, P. W., Halladay, J., Rock, F., Stefanakis, R., Easom, E., Plattner, J. J., Ford, L., Johnston, K., Cook, D. A. N., Clare, R., Cassidy, A., Myhill, L., ... Ward, S. (2019). Boron-Pleuromutilins as Anti-Wolbachia Agents with Potential for Treatment of Onchocerciasis and Lymphatic Filariasis. Journal of Medicinal Chemistry, 62(5), 2521-2540. Advance online publication. https://doi.org/10.1021/acs.jmedchem.8b01854

@article{ce10ecf13daa43ee9543fe10aefc076d,

title = "Boron-Pleuromutilins as Anti-Wolbachia Agents with Potential for Treatment of Onchocerciasis and Lymphatic Filariasis.",

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 Onchocherca 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 (NTDs) disproportionately impact patients in the developing world. The lead preclinical candidate compound containing a 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.",

author = "Jacobs, \{Robert T.\} and Lunde, \{Christopher S.\} and Freund, \{Yvonne R.\} and Vincent Hernandez and Xianfeng Li and Yi Xia and Carter, \{David S.\} and Berry, \{Pamela W.\} and Jason Halladay and Fernando Rock and Rianna Stefanakis and Eric Easom and Plattner, \{Jacob J.\} and Louise Ford and Kelly Johnston and Cook, \{Darren A.N.\} and Rachel Clare and Andrew Cassidy and Laura Myhill and Hayley Tyrer and Joanne Gamble and Guimaraes, \{Ana F.\} and Andrew Steven and Franziska Lenz and Alexandra Ehrens and Frohberger, \{Stefan J.\} and Marianne Koschel and Achim Hoerauf and H{\"u}bner, \{Marc P.\} and McNamara, \{Case W.\} and Bakowski, \{Malina A.\} and Joseph Turner and Mark Taylor and Steve Ward",

year = "2019",

month = feb,

day = "7",

doi = "10.1021/acs.jmedchem.8b01854",

language = "English",

volume = "62",

pages = "2521--2540",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "5",

}

Jacobs, RT, Lunde, CS, Freund, YR, Hernandez, V, Li, X, Xia, Y, Carter, DS, Berry, PW, Halladay, J, Rock, F, Stefanakis, R, Easom, E, Plattner, JJ, Ford, L , Johnston, K, Cook, DAN, Clare, R, Cassidy, A, Myhill, L, Tyrer, H, Gamble, J, Guimaraes, AF, Steven, A, Lenz, F, Ehrens, A, Frohberger, SJ, Koschel, M, Hoerauf, A, Hübner, MP, McNamara, CW, Bakowski, MA, Turner, J , Taylor, M & Ward, S 2019, 'Boron-Pleuromutilins as Anti-Wolbachia Agents with Potential for Treatment of Onchocerciasis and Lymphatic Filariasis.', Journal of Medicinal Chemistry, vol. 62, no. 5, pp. 2521-2540. https://doi.org/10.1021/acs.jmedchem.8b01854

TY - JOUR

T1 - Boron-Pleuromutilins as Anti-Wolbachia Agents with Potential for Treatment of Onchocerciasis and Lymphatic Filariasis.

AU - Jacobs, Robert T.

AU - Lunde, Christopher S.

AU - Freund, Yvonne R.

AU - Hernandez, Vincent

AU - Li, Xianfeng

AU - Xia, Yi

AU - Carter, David S.

AU - Berry, Pamela W.

AU - Halladay, Jason

AU - Rock, Fernando

AU - Stefanakis, Rianna

AU - Easom, Eric

AU - Plattner, Jacob J.

AU - Ford, Louise

AU - Johnston, Kelly

AU - Cook, Darren A.N.

AU - Clare, Rachel

AU - Cassidy, Andrew

AU - Myhill, Laura

AU - Tyrer, Hayley

AU - Gamble, Joanne

AU - Guimaraes, Ana F.

AU - Steven, Andrew

AU - Lenz, Franziska

AU - Ehrens, Alexandra

AU - Frohberger, Stefan J.

AU - Koschel, Marianne

AU - Hoerauf, Achim

AU - Hübner, Marc P.

AU - McNamara, Case W.

AU - Bakowski, Malina A.

AU - Turner, Joseph

AU - Taylor, Mark

AU - Ward, Steve

PY - 2019/2/7

Y1 - 2019/2/7

N2 - 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 Onchocherca 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 (NTDs) disproportionately impact patients in the developing world. The lead preclinical candidate compound containing a 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.

AB - 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 Onchocherca 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 (NTDs) disproportionately impact patients in the developing world. The lead preclinical candidate compound containing a 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.

U2 - 10.1021/acs.jmedchem.8b01854

DO - 10.1021/acs.jmedchem.8b01854

M3 - Article

SN - 0022-2623

VL - 62

SP - 2521

EP - 2540

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 5

ER -

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

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