Discovery of an orally bioavailable isoxazoline benzoxaborole ( AN8030 ) as a long acting animal ectoparasiticide

Zhang, Yongkang; Plattner, Jacob J.; Easom, Eric E.; Zhou, Yasheen; Akama, Tsutomu; Bu, Wei; White, W. Hunter; Defauw, Jean; Winkle, Joseph R.; Balko, T. W.; Guo, Shenghai; Xue, Jingchuan; Cao, Jianxin; Zou, Wenli

doi:10.1016/j.bmcl.2015.10.044

Cited by 28 publications

(17 citation statements)

References 22 publications

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“…Zhang et al. sought to develop new ectoparasitides through the incorporation of benzoxaboroles . Included in this study were MMV687775 ( 609 ) and MMV687776 ( 610 ), which both performed well in the tick LIM assay.…”

Section: Filariasis and Wolbachiamentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

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Section: Filariasis and Wolbachiamentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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“…Sarolaner provided >95% kill of fleas within 8 h of challenging dogs dosed with 2 mg/kg sarolaner for at least 35 days [ 307 ]. An oral dose of 50 mg/kg of an isoxazoline benzoxaborle (AN8030) to dogs provided 100% of fleas for 32 days [ 394 ]. A combination of selamectin/sarolaner applied to cats provided 72.5% kill within 12 h on day 1 and the kill increased to 93.8% when tested at 28 days.…”

Section: Pest Managementmentioning

confidence: 99%

The Biology and Ecology of Cat Fleas and Advancements in Their Pest Management: A Review

Rust

2017

Insects

114

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The cat flea Ctenocephalides felis felis (Bouché) is the most important ectoparasite of domestic cats and dogs worldwide. It has been two decades since the last comprehensive review concerning the biology and ecology of C. f. felis and its management. Since then there have been major advances in our understanding of the diseases associated with C. f. felis and their implications for humans and their pets. Two rickettsial diseases, flea-borne spotted fever and murine typhus, have been identified in domestic animal populations and cat fleas. Cat fleas are the primary vector of Bartonella henselae (cat scratch fever) with the spread of the bacteria when flea feces are scratched in to bites or wounds. Flea allergic dermatitis (FAD) common in dogs and cats has been successfully treated and tapeworm infestations prevented with a number of new products being used to control fleas. There has been a continuous development of new products with novel chemistries that have focused on increased convenience and the control of fleas and other arthropod ectoparasites. The possibility of feral animals serving as potential reservoirs for flea infestations has taken on additional importance because of the lack of effective environmental controls in recent years. Physiological insecticide resistance in C. f. felis continues to be of concern, especially because pyrethroid resistance now appears to be more widespread. In spite of their broad use since 1994, there is little evidence that resistance has developed to many of the on-animal or oral treatments such as fipronil, imidacloprid or lufenuron. Reports of the perceived lack of performance of some of the new on-animal therapies have been attributed to compliance issues and their misuse. Consequentially, there is a continuing need for consumer awareness of products registered for cats and dogs and their safety.

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“…An emerging class of boron-containing compounds known as benzoxaboroles have shown promise as therapies against a wide range of diseases including, but not limited to those caused by, viral [ 9 ], fungal [ 10 ], bacterial [ 11 , 12 ] and parasitic [ 13 ] infections and inflammation [ 14 ]. These compounds have been reported to act as inhibitors of kinases [ 15 ], tRNA synthetases [ 16 , 17 ], CPSF3 [ 18 , 19 ], phosphodiesterases [ 20 , 21 ], and carbonic anhydrases [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Benzoxaborole treatment perturbs S-adenosyl-L-methionine metabolism in Trypanosoma brucei

et al. 2018

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The parasitic protozoan Trypanosoma brucei causes Human African Trypanosomiasis and Nagana in other mammals. These diseases present a major socio-economic burden to large areas of sub-Saharan Africa. Current therapies involve complex and toxic regimens, which can lead to fatal side-effects. In addition, there is emerging evidence for drug resistance. AN5568 (SCYX-7158) is a novel benzoxaborole class compound that has been selected as a lead compound for the treatment of HAT, and has demonstrated effective clearance of both early and late stage trypanosomiasis in vivo. The compound is currently awaiting phase III clinical trials and could lead to a novel oral therapeutic for the treatment of HAT. However, the mode of action of AN5568 in T. brucei is unknown. This study aimed to investigate the mode of action of AN5568 against T. brucei, using a combination of molecular and metabolomics-based approaches.Treatment of blood-stage trypanosomes with AN5568 led to significant perturbations in parasite metabolism. In particular, elevated levels of metabolites involved in the metabolism of S-adenosyl-L-methionine, an essential methyl group donor, were found. Further comparative metabolomic analyses using an S-adenosyl-L-methionine-dependent methyltransferase inhibitor, sinefungin, showed the presence of several striking metabolic phenotypes common to both treatments. Furthermore, several metabolic changes in AN5568 treated parasites resemble those invoked in cells treated with a strong reducing agent, dithiothreitol, suggesting redox imbalances could be involved in the killing mechanism.

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Discovery of an orally bioavailable isoxazoline benzoxaborole ( AN8030 ) as a long acting animal ectoparasiticide

Cited by 28 publications

References 22 publications

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

The Biology and Ecology of Cat Fleas and Advancements in Their Pest Management: A Review

Benzoxaborole treatment perturbs S-adenosyl-L-methionine metabolism in Trypanosoma brucei

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