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

Jacobs, Robert Toms, Lunde, Christopher S, Freund, Yvonne R, Hernandez, Vincent, Li, Xianfeng, Xia, Yi, Carter, David S, Berry, Pamela, Halladay, Jason, Rock, Fernando, Stefanakis, Rianna, Easom, Eric E, Plattner, Jacob J, Ford, Louise, Johnston, Kelly L, Cook, Darren A N, Clare, Rachel ORCID: https://orcid.org/0000-0002-3945-0530, Cassidy, Andrew, Myhill, Laura, Tyrer, Hayley, Gamble, Joanne, Guimaraes, Ana F, Steven, Andrew, Lenz, Franziska, Ehrens, Alexandra, Frohberger, Stefan J, Koschel, Marianne, Hoerauf, Achim, Hübner, Marc P, McNamara, Case, Bakowski, Malina A, Turner, Joseph D ORCID: https://orcid.org/0000-0002-2185-5476, Taylor, Mark J ORCID: https://orcid.org/0000-0003-3396-9275 and Ward, Stephen A ORCID: https://orcid.org/0000-0003-2331-3192 (2019) 'Boron-Pleuromutilins as Anti-Wolbachia Agents with Potential for Treatment of Onchocerciasis and Lymphatic Filariasis.'. Journal of medicinal chemistry.

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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.

Item Type:	Article
Subjects:	QV Pharmacology > Local Anti-Infective Agents. Dyes. Tars > QV 220 Local anti-infective agents. Disinfectants QW Microbiology and Immunology > Bacteria > QW 150 Proteobacteria. Rickettsiaceae, Wolbachia WC Communicable Diseases > Tropical and Parasitic Diseases > WC 880 Filariasis and related conditions (General) WC Communicable Diseases > Tropical and Parasitic Diseases > WC 885 Onchocerciasis
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1021/acs.jmedchem.8b01854
Depositing User:	Stacy Murtagh
Date Deposited:	26 Feb 2019 17:07
Last Modified:	15 Mar 2019 09:08
URI:	https://archive.lstmed.ac.uk/id/eprint/10251

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