Benzoxaborole antimalarial agents. Part 2: Discovery of fluoro-substituted 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles

Zhang, Yongkang; Plattner, Jacob J.; Freund, Yvonne R.; Easom, Eric E.; Zhou, Yasheen; Ye, Long; Zhou, Huchen; Waterson, David; Gamo, Francisco‐Javier; Sanz, Laura M.; Ge, Ming; Li, Zhiya; Li, Lingchao; Wang, Hailong; Cui, H.

doi:10.1016/j.bmcl.2011.12.096

Cited by 49 publications

(35 citation statements)

References 13 publications

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“…An in vitro screen of a benzoxaborole library1920 against the multidrug-resistant P. falciparum W2 strain identified the 7-[(2′-carboxylic acid) ethyl] benzoxaborole AN3661 (Fig. 1a).…”

Section: Resultsmentioning

confidence: 99%

“…Our docking model of AN3661 at the PfCPSF3 binding site is consistent with the structure-activity relationships established for this series of compounds as antimalarial agents. First, the oxaborole group is essential for activity, as replacement of a carbon atom for the boron resulted in an inactive compound20. Second, the carboxylic acid group is important for activity, although it can be replaced by other acidic groups such as a tetrazole19.…”

Section: Discussionmentioning

confidence: 99%

“…This manuscript reports the antimalarial profile and mechanism of action of another benzoxaborole, AN3661, which was identified from a screen of a benzoxaborole library against cultured P. falciparum asexual blood stage parasites1920. AN3661 demonstrated potent antimalarial activity, and genetic and biochemical studies identified its target as a homologue of mammalian cleavage and polyadenylation specificity factor (CPSF) subunit 3.…”

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confidence: 99%

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A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue

et al. 2017

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Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratory-adapted strains (mean IC50 32 nM), Ugandan field isolates (mean ex vivo IC50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED90 0.34 and 0.57 mg kg−1, respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf3, which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). CRISPR-Cas9-mediated introduction of pfcpsf3 mutations into parental lines recapitulated AN3661 resistance. PfCPSF3 homology models placed these mutations in the active site, where AN3661 is predicted to bind. Transcripts for three trophozoite-expressed genes were lost in AN3661-treated trophozoites, which was not observed in parasites selected or engineered for AN3661 resistance. Our results identify the pre-mRNA processing factor PfCPSF3 as a promising antimalarial drug target.

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“…An in vitro screen of a benzoxaborole library1920 against the multidrug-resistant P. falciparum W2 strain identified the 7-[(2′-carboxylic acid) ethyl] benzoxaborole AN3661 (Fig. 1a).…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue

et al. 2017

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“…Of the boron-containing compounds that are currently in pharmaceutical development programs, boronic acids [1,2], boronate esters [3,4], benzoxaboroles [5,6], and oxazaborolidines [7,8] are frequently used boron functional groups. Having an empty p-orbital on the trivalent boron atom, these analogs interact with their targets to form tetrahedral intermediates.…”

Section: Abstract: Peptide; Organotrifluoroborate; Potassium Trifluormentioning

confidence: 99%

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Potassium {4-[(3S,6S,9S)-3,6-dibenzyl-9-isopropyl-4,7,10-trioxo-11–oxa-2,5,8-triazadodecyl]phenyl}trifluoroborate

Tsai

Lin

Hsieh

et al. 2014

Molbank

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[5,6], and oxazaborolidines [7,8] are frequently used boron functional groups. Having an empty p-orbital on the trivalent boron atom, these analogs interact with their targets to form tetrahedral intermediates. Organotrifluoroborates, on the other hand, are seldom considered in biological applications due to their lack of an empty p-orbital. Srebnik and coworkers, the first group to investigate the biological activity of a series of aryl organotrifluoroborates in enzyme-inhibition assays, reported that aryl potassium trifluoroborates were much more potent than the corresponding boronic acids against α-chymotrypsin and trypsin [9,10]. The toxicological profile of organotrifluoroborates were also investigated by Oliveira and co-workers, who showed that thiophene-3-trifluoroborate exhibits minimal toxicity in a mouse model, and concluded that this class of compounds is suitable for further development as pharmacologically active agents [11]. Despite their promising biological studies, the reported studies of organotrifluoroborates OPEN ACCESS

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Methods for the Introduction of the Phosphonate Moiety into Complex Organic Molecules

2019

Organophosphorus Chemistry

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Benzoxaborole antimalarial agents. Part 2: Discovery of fluoro-substituted 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles

Cited by 49 publications

References 13 publications

A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue

A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue

Potassium {4-[(3S,6S,9S)-3,6-dibenzyl-9-isopropyl-4,7,10-trioxo-11–oxa-2,5,8-triazadodecyl]phenyl}trifluoroborate

Methods for the Introduction of the Phosphonate Moiety into Complex Organic Molecules

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