AN7973
目录号 : GC35336
AN7973 是 6-甲酰胺苯并氧杂硼杂环戊烯，阻止细胞内寄生虫 (parasite) 发育并抑制隐孢子虫生长。 AN7973 具有良好的安全性，稳定性和 PK 参数，是治疗隐孢子虫病的一种良好候选药物。
Cas No.:1620899-32-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
AN7973 is the 6-carboxamide benzoxaborole, blocks intracellular parasite development and inhibits Cryptosporidium growth. AN7973 is orally active, possesses favorable safety, stability, and PK parameters, and is an exciting drug candidate for treating cryptosporidiosis.
AN7973 (oral gavage; 5-25 mg/kg; once daily) is efficacious in murine models of both acute and chronic infection by rapidly eliminating C.parvum in vivo[1].AN7973 (oral gavage; 5 mg/kg, 10 mg/kg, 6.67 mg/kg; once daily, twice daily, three times daily) reduces C.parvum fecal shedding, diarrhea, and dehydration in a neonatal calf model (closely mimics that seen in infants) of cryptosporidiosis[1].AN7973 possesses favorable safety, stability, and PK parameters as an exciting drug candidate for treating cryptosporidiosis[1]. Animal Model: Four to five weeks NOD scid gamma mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ)(NSG) with chronic Cryptosporidium infection[1]
[1]. 1.Lunde CS, et al. Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis. Nat Commun. 2019 Jun 27; 10(1):2816.
| Cas No. | 1620899-32-2 | SDF | |
| Canonical SMILES | ClC1=CC(N2C=CC=N2)=CC=C1C(NC3=CC=C(C(C)(C)OB4O)C4=C3)=O | ||
| 分子式 | C19H17BClN3O3 | 分子量 | 381.62 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.6204 mL | 13.102 mL | 26.2041 mL |
| 5 mM | 0.5241 mL | 2.6204 mL | 5.2408 mL |
| 10 mM | 0.262 mL | 1.3102 mL | 2.6204 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
The trypanocidal benzoxaborole AN7973 inhibits trypanosome mRNA processing
PLoS Pathog 2018 Sep 25;14(9):e1007315.PMID:30252911DOI:10.1371/journal.ppat.1007315.
Kinetoplastid parasites-trypanosomes and leishmanias-infect millions of humans and cause economically devastating diseases of livestock, and the few existing drugs have serious deficiencies. Benzoxaborole-based compounds are very promising potential novel anti-trypanosomal therapies, with candidates already in human and animal clinical trials. We investigated the mechanism of action of several benzoxaboroles, including AN7973, an early candidate for veterinary trypanosomosis. In all kinetoplastids, transcription is polycistronic. Individual mRNA 5'-ends are created by trans splicing of a short leader sequence, with coupled polyadenylation of the preceding mRNA. Treatment of Trypanosoma brucei with AN7973 inhibited trans splicing within 1h, as judged by loss of the Y-structure splicing intermediate, reduced levels of mRNA, and accumulation of peri-nuclear granules. Methylation of the spliced leader precursor RNA was not affected, but more prolonged AN7973 treatment caused an increase in S-adenosyl methionine and methylated lysine. Together, the results indicate that mRNA processing is a primary target of AN7973. Polyadenylation is required for kinetoplastid trans splicing, and the EC50 for AN7973 in T. brucei was increased three-fold by over-expression of the T. brucei cleavage and polyadenylation factor CPSF3, identifying CPSF3 as a potential molecular target. Molecular modeling results suggested that inhibition of CPSF3 by AN7973 is feasible. Our results thus chemically validate mRNA processing as a viable drug target in trypanosomes. Several other benzoxaboroles showed metabolomic and splicing effects that were similar to those of AN7973, identifying splicing inhibition as a common mode of action and suggesting that it might be linked to subsequent changes in methylated metabolites. Granule formation, splicing inhibition and resistance after CPSF3 expression did not, however, always correlate and prolonged selection of trypanosomes in AN7973 resulted in only 1.5-fold resistance. It is therefore possible that the modes of action of oxaboroles that target trypanosome mRNA processing might extend beyond CPSF3 inhibition.
Emerging treatment options for cryptosporidiosis
Curr Opin Infect Dis 2021 Oct 1;34(5):455-462.PMID:34261904DOI:10.1097/QCO.0000000000000761.
Purpose of review: Substantial progress has been made recently on the development of new therapeutics for cryptosporidiosis, an infection by the protozoan parasite Cryptosporidium that is associated with diarrhea, malnutrition, growth stunting, cognitive deficits, and oral vaccine failure in children living in low-resource settings. Recent findings: Various drug discovery approaches have generated promising lead candidates. The repurposed antimycobacterial drug clofazimine was tested in Malawian HIV patients with cryptosporidiosis but was ineffective. Target-based screens identified inhibitors of lysyl-tRNA synthetase, phenylalanyl-tRNA synthetase, methionyl-tRNA synthetase, and calcium-dependent protein kinase 1. Phenotypic screens led to discovery of a phosphatidylinositol 4-kinase inhibitor, the piperazine MMV665917, and the benzoxaborole AN7973. The relationship between pharmacokinetic properties and in-vivo efficacy is gradually emerging. A pathway to clinical trials, regulatory approval, and introduction has been proposed but additional work is needed to strengthen the route. Summary: Several lead compounds with potent activity in animal models and a favorable safety profile have been identified. A sustained effort will be required to advance at least one to clinical proof-of-concept studies. The demonstrated risk of resistance indicates multiple candidates should be advanced as potential components of a combination therapy.
Clinically relevant benzoxaboroles inhibit mRNA processing in Trypanosoma brucei
BMC Res Notes 2022 Dec 17;15(1):371.PMID:36528767DOI:10.1186/s13104-022-06258-y.
Objective: The cleavage and polyadenylation endonuclease CPSF73 is thought to be the target of the anti-trypanosomal benzoxaboroles AN7973, acoziborole and AN11736. We previously showed that AN7973 inhibits mRNA processing. We here investigated whether the drug candidates acoziborole (for human sleeping sickness) and AN11736 (for nagana in cattle) have the same effect. We also affinity purified tagged CPSF73 from parasites without, or after, AN7973 treatment, and analysed differentially co-purified proteins by mass spectrometry. Results: AN11736 and acoziborole both inhibited mRNA processing, as demonstrated by decreased levels of spliced mRNAs and accumulation of di- and tri-cistronic mRNAs from the alpha-beta tubulin locus. Treating the cells with AN7973 for 30 min. did not significantly affect the proteins that copurified with CPSF73.
Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis
Nat Commun 2019 Jun 27;10(1):2816.PMID:31249291DOI:10.1038/s41467-019-10687-y.
Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children and causes chronic diarrhea in AIDS patients, but the only approved treatment is ineffective in malnourished children and immunocompromised people. We here use a drug repositioning strategy and identify a promising anticryptosporidial drug candidate. Screening a library of benzoxaboroles comprised of analogs to four antiprotozoal chemical scaffolds under pre-clinical development for neglected tropical diseases for Cryptosporidium growth inhibitors identifies the 6-carboxamide benzoxaborole AN7973. AN7973 blocks intracellular parasite development, appears to be parasiticidal, and potently inhibits the two Cryptosporidium species most relevant to human health, C. parvum and C. hominis. It is efficacious in murine models of both acute and established infection, and in a neonatal dairy calf model of cryptosporidiosis. AN7973 also possesses favorable safety, stability, and PK parameters, and therefore, is an exciting drug candidate for treating cryptosporidiosis.
Diminazene resistance in Trypanosoma congolense is not caused by reduced transport capacity but associated with reduced mitochondrial membrane potential
Mol Microbiol 2021 Aug;116(2):564-588.PMID:33932053DOI:10.1111/mmi.14733.
Trypanosoma congolense is a principal agent causing livestock trypanosomiasis in Africa, costing developing economies billions of dollars and undermining food security. Only the diamidine diminazene and the phenanthridine isometamidium are regularly used, and resistance is widespread but poorly understood. We induced stable diminazene resistance in T. congolense strain IL3000 in vitro. There was no cross-resistance with the phenanthridine drugs, melaminophenyl arsenicals, oxaborole trypanocides, or with diamidine trypanocides, except the close analogs DB829 and DB75. Fluorescence microscopy showed that accumulation of DB75 was inhibited by folate. Uptake of [3 H]-diminazene was slow with low affinity and partly but reciprocally inhibited by folate and by competing diamidines. Expression of T. congolense folate transporters in diminazene-resistant Trypanosoma brucei brucei significantly sensitized the cells to diminazene and DB829, but not to oxaborole AN7973. However, [3 H]-diminazene transport studies, whole-genome sequencing, and RNA-seq found no major changes in diminazene uptake, folate transporter sequence, or expression. Instead, all resistant clones displayed a moderate reduction in the mitochondrial membrane potential Ψm. We conclude that diminazene uptake in T. congolense proceed via multiple low affinity mechanisms including folate transporters; while resistance is associated with a reduction in Ψm it is unclear whether this is the primary cause of the resistance.