Benznidazole

• CAT Number: R056701
• CAS Number: 22994-85-0
• Molecular Formula: C12H12N4O3
• Molecular Weight: 260.253
• Purity: ≥95%
• Solubility: >39 [ug/mL]
• Storage: -20°C
• IUPAC Name: N-benzyl-2-(2-nitroimidazol-1-yl)acetamide
• InChI: InChI=1S/C12H12N4O3/c17-11(14-8-10-4-2-1-3-5-10)9-15-7-6-13-12(15)16(18)19/h1-7H,8-9H2,(H,14,17)
• InChIKey: CULUWZNBISUWAS-UHFFFAOYSA-N
• SMILES: C1=CC=C(C=C1)CNC(=O)CN2C=CN=C2[N+](=O)[O-]

Benznidazole(CAS: 22994-85-0） is a nitroimidazole derivative having an antiprotozoal activity by interfering with parasite protein biosynthesis, influencing cytokines production and stimulating host phagocytosis. (NCI)
Benznidazole is an orally available, broad spectrum antimicrobial agent used in the treatment of Chagas disease. Benznidazole is a nitroimidazole similar to metronidazole and is associated with serum enzyme elevations during therapy in up to 10% of patients but has not linked to cases of clinically apparent acute liver injury.
Benznidazole is a monocarboxylic acid amide obtained by formal condensation of the carboxy group of (2-nitroimidazol-1-yl)acetic acid with the aromatic amino group of benzylamine. Used for treatment of Chagas disease. It has a role as an antiprotozoal drug. It is a member of imidazoles, a C-nitro compound and a monocarboxylic acid amide.

Overview of Clinical Research

Originator： Chemo Group
Developer： Drugs for Neglected Diseases Initiative Foundation; Exeltis France; Exeltis USA; Insud Pharma; Mundo Sano
Class：Acetamides; Antiprotozoals; Imidazoles
Mechanism of Action： Free radical stimulants
Orphan Drug Status： Yes – Chagas disease
New Molecular Entity： No

Reference

[1]. Benznidazole.
Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006–. 2021 Jun 21.
Benznidazole is excreted into milk in dosages much lower than the treatment dosage for infants. Because of the low levels of benznidazole in breastmilk and safety when given directly to infants, its use is acceptable in nursing mothers.
PMID: 29999711

[2]. Drugs Today (Barc). 2018 Jan;54(1):15-23. doi: 10.1358/dot.2018.54.1.2753402.
An update on benznidazole for the treatment of patients with Chagas disease.
Thakare R(1), Dasgupta A(1), Chopra S(2).
Author information: (1)Division of Microbiology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India. (2)Division of Microbiology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India. .
Chagas disease is a vector-borne, systemic and chronic parasitic infection caused by Trypanosoma cruzi with approximately 8 million cases worldwide. The treatment for acute phase of Chagas disease consists of benznidazole and nifurtimox, although this treatment combination falls short in terms of efficacy against chronic phases of infection. This review provides an update on benznidazole progress and approval by the U.S. Food and Drug Administration in 2017 for the treatment of Chagas disease along with its lacunae.
DOI: 10.1358/dot.2018.54.1.2753402 PMID: 29569658 [Indexed for MEDLINE]

[3]. J Antimicrob Chemother. 2020 Aug 1;75(8):2213-2221. doi: 10.1093/jac/dkaa130.
Population pharmacokinetics and biodistribution of benznidazole in mice.
Perin L(1), Pinto L(1), Balthazar Nardotto GH(2), da Silva Fonseca K(1), Oliveira Paiva B(1), Fernanda Rodrigues Bastos Mendes T(1), Molina I(1)(3), Correa-Oliveira R(1)(4), Melo de Abreu Vieira P(1)(5), Martins Carneiro C(1)(6).
Author information: (1)Laboratory of Immunopathology, Nucleus of Biological Sciences Research, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil. (2)Laboratory of Clinical Pharmacokinetics, Department of Clinical, Toxicological and Bromatological Analyses, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. (3)Tropical Medicine and International Health Unit, Department of Infectious Diseases, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain, PROSICS Barcelona. (4)Laboratory of Cellular and Molecular Immunology, René Rachou Research Center, Oswaldo Cruz Foundation, Belo Horizonte, Minas Gerais, Brazil. (5)Laboratory of Morphopathology, Department of Biological Sciences, Nucleus of Biological Sciences Research, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil. (6)Department of Clinical Analysis, School of Pharmacy, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
OBJECTIVES: To evaluate the population pharmacokinetics of different benznidazole treatment regimens and the drug's biodistribution in mice. METHODS: Two hundred mice were divided into five groups according to benznidazole dosing regimens: (1) 100 mg/kg/day for 20 days; (2) 100 mg/kg/day for 40 days; (3) 200 mg/kg/day for 20 days; (4) 40 mg/kg/day for 20 days; or (5) 40 mg/kg/day for 40 days. The mice were euthanized and blood, heart, liver, colon and brain were collected. Samples were prepared by liquid-liquid extraction and analysed by HPLC-diode-array detection. The pharmacokinetic analysis of benznidazole was evaluated via non-linear mixed-effects modelling using the NONMEN program. RESULTS: Our results demonstrate that mouse weight allometrically influences benznidazole clearance; the AUC curve and the highest plasma concentration are dose proportional; benznidazole does not influence its own metabolism; its tissue distribution is limited; and the standard treatment regimen for Chagas' disease in mice (100 mg/kg/day for 20 days) is inadequate from a pharmacokinetic standpoint, as are the other regimens tested in this study (100 mg/kg/day for 40 days, 200 mg/kg/day for 20 days and 40 mg/kg/day for 20 or 40 days). CONCLUSIONS: Benznidazole reformulations that allow better tissue penetration and plasma and tissue exposure should be evaluated to enable higher cure rates in both animals and patients. The population pharmacokinetic model developed here can allow optimization of the dosing regimen of benznidazole to treat experimental Chagas' disease. Determining appropriate treatment regimens in animals allows translation of these to clinical studies.
DOI: 10.1093/jac/dkaa130 PMID: 32356873 [Indexed for MEDLINE]

[4]. Expert Opin Pharmacother. 2019 Oct;20(15):1797-1807. doi: 10.1080/14656566.2019.1650915. Epub 2019 Aug 28.
An evaluation of benznidazole as a Chagas disease therapeutic.
Caldas IS(1), Santos EG(2), Novaes RD(2).
Author information: (1)Department of Pathology and Parasitology, Institute of Biomedical Sciences, Universidade Federal de Alfenas (UNIFAL-MG) , Alfenas , Minas Gerais , Brazil. (2)Department of Structural Biology, Institute of Biomedical Sciences, Universidade Federal de Alfenas (UNIFAL-MG) , Alfenas , Minas Gerais , Brazil.
Introduction: As benznidazole is the first-line treatment for patients with Chagas disease, rational chemotherapy strategies are required based on the critical analysis of the evidence on the relevance and applicability of this drug at different disease stages. Areas covered: The authors discuss the current understanding of benznidazole-based chemotherapy for Chagas disease, focusing specifically on epidemiology, pharmacokinetics, mechanism of action, clinical recommendations, cure criteria, and therapeutic efficacy in different phases of the disease. Expert opinion: Benznidazole shows high bioavailability after oral administration. Benznidazole at 5-8 mg/kg/day and 5-10 mg/kg/day for 30-60 days are consistent clinical recommendations for children and adults, respectively. A high correlation between negative parasitological, serological, and polymerase chain reaction (PCR) assays in long-term post-therapeutic follow-up has been consistently used to evaluate therapeutic efficacy. These methods support the evidence that the success of benznidazole-based chemotherapy is closely correlated with the phase of infection in which the treatment is administered. The greater therapeutic efficacy is obtained in acute infections, gradually worsening as the infection becomes chronic. When therapeutic failure is confirmed by any diagnostic assay, benznidazole treatment does not always ensure better long-term prognosis, and Chagas cardiomyopathy may develop as well as in untreated patients.
DOI: 10.1080/14656566.2019.1650915 PMID: 31456439 [Indexed for MEDLINE]

[5]. Acta Trop. 2020 Jan;201:105218. doi: 10.1016/j.actatropica.2019.105218. Epub 2019 Oct 11.
The effect of benznidazole dose among the efficacy outcome in the murine animal model. A quantitative integration of the literature.
Molina I(1), Perin L(2), Aviles AS(3), de Abreu Vieira PM(4), da Silva Fonseca K(2), Cunha LM(2), Carneiro CM(2).
Author information: (1)Tropical Medicine Unit, Infectious Disease Department. PROSICS (International Health Program of the Catalan Health Institute), Hospital Universitario Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas, Instituto de Ciências Exatas e Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil. Electronic address: . (2)Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas, Instituto de Ciências Exatas e Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil. (3)Tropical Medicine Unit, Infectious Disease Department. PROSICS (International Health Program of the Catalan Health Institute), Hospital Universitario Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. (4)Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas, Instituto de Ciências Exatas e Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil; Laboratório de Morfopatologia, Departamento de Ciências Biológicas, Núcleo de Pesquisas em Ciências Biológicas, Instituto de Ciências Exatas e Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
Despite more than 100 years since it was firstly described Chagas disease, only two drugs are available to treat Chagas disease: Nifurtimox launched by Bayer in 1965 and benznidazole launched by Roche in 1971. Drug discovery initiatives have been looking for new compounds as an alternative to these old drugs. Although new platforms have been used with the latest technologies, a critical step on that process still relies on the in vivo model. Unfortunately, to date, available animal models have limited predictive value and there is no standardization. With the aim to better understand the role of benznidazole, the current standard of care of Chagas disease, we performed this review. We intend to analyze the influence of the experimental design of the most used animal model, the murine model, in the assessment of the efficacy endpoint.
DOI: 10.1016/j.actatropica.2019.105218 PMID: 31610148 [Indexed for MEDLINE]