Enantiomers of Nifurtimox Do Not Exhibit Stereoselective Anti-Trypanosoma cruzi Activity, Toxicity, or Pharmacokinetic Properties

Moraes, Carolina Borsoi; White, Karen L.; Braillard, Stéphanie; Perez, Catherine; Goo, Junghyun; Gaspar, Luís; Shackleford, David M.; Cordeiro-da-Silva, Anabela; Thompson, R.C.A.; Freitas‐Junior, Lúcio H.; Charman, Susan A.; Chatelain, Eric

doi:10.1128/aac.05139-14

Cited by 6 publications

(3 citation statements)

References 5 publications

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“… 62 A study published in 2015 concluded that it was unlikely that a single enantiomer of nifurtimox would have a therapeutic advantage over the racemate ( 19 and 20 , Figure 10 ). 63 This conclusion was based on an observed lack of stereoselectivity in the toxicity, pharmacokinetics, and activity of nifurtimox against T. cruzi .…”

Section: Resultsmentioning

confidence: 99%

Chirality of New Drug Approvals (2013–2022): Trends and Perspectives

McVicker,

O’Boyle

2024

J. Med. Chem.

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Many drugs are chiral with their chirality determining their biological interactions, safety, and efficacy. Since the 1980s, there has been a regulatory preference to bring single enantiomer to market. This perspective discusses trends related to chirality that have developed in the past decade (2013−2022) of new drug approvals. The EMA has not approved a racemate since 2016, while the average for the FDA is one per year from 2013 to 2022. These 10 include drugs which have been previously marketed elsewhere for several decades, analogues of pre-existing drugs, or drugs where the undefined stereocenter does not play a role in therapeutic activity. Two chiral switches were identified which were both combined with drug repurposing. This combination strategy has the potential to produce therapeutically valuable drugs in a faster time frame. Two class III atropisomers displaying axial chirality were approved between 2013 and 2022, one as a racemate and one as a single enantiomer. ■ SIGNIFICANCE• An awareness and understanding of recent trends in new drug approvals has the potential to inform and promote innovation in new drug discovery. • Making the correct choices regarding drug chirality early in the development process can lead to a substantial cost saving given the cost of the drug approval. • Determining the impact on patients of practices such as chiral switching and drug repurposing requires data on how often such practices are leveraged.

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Section: Resultsmentioning

confidence: 99%

Chirality of New Drug Approvals (2013–2022): Trends and Perspectives

McVicker,

O’Boyle

2024

J. Med. Chem.

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“…The current chagas disease treatment, which has been in use for over 40 years, is centered on the nitro heterocyclic drugs nifurtimox and benznidazole (Figure 1), both of which exhibit trypanosomicidal action against all parasite forms. Nifurtimox is a racemic mixture which is as effective and safe as its individual enantiomers (Moraes et al., 2015). They are deemed far from optimal due to the adverse effects that can disrupt the therapeutic procedure and the low curative efficacy (Castro et al., 2006; Coura & de Castro, 2002; Jannin & Villa, 2007; Rocha et al., 2007).…”

Section: Introductionmentioning

confidence: 99%

A comprehensive review on potential candidates for the treatment of chagas disease

et al. 2023

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Twenty different infectious disorders induced by bacteria, viruses, and parasites are categorized as neglected tropical diseases (NTDs) by WHO. The severity of chagas disease remains a major concern in endemic areas and an emerging public health hazard in nonendemic countries. Trypanosoma cruzi, the etiological agent of this NTD, is mostly transmitted by triatomine vectors and comprises a range of epidemiologically significant variants. Current chemotherapeutics are obsolete, and one of the primary reasons for treatment cessation is their poor safety and effectiveness. Due to the aforementioned challenges, researchers are now focusing on discovering alternative novel safe, and economically reachable therapies for the treatment of trypanosomiasis. Certain target‐based drugs that target specific biochemical processes of the causative parasites have been described as potential antichagasic agents that possesses various types of heterocyclic scaffolds. These flexible molecules have a wide range of biological actions, and various synthesized compounds with strong activity have been documented. This review aims to discuss the available literature on synthetic anti‐T. cruzi drugs that will give a food for thought to medicinal chemists thriving to design and develop such drugs. Furthermore, some of the studies discussed herein are concerned with the potential of novel drugs to block new viable sites in T. cruzi.

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“…However, the use of genetically unmodified parasites has always been an attractive pursuit, made available only recently due to technologic advancements. Such cell-based assays were developed by researchers at Institut Pasteur Korea and have met widespread use [15][16][17][18]. This assay employed the use of wild type parasites of T. cruzi infecting a non-modified cell line and the imaging of the resulting infection (in the amastigote stage) by high-content analysis (HCA) microscopy.…”

Section: Introductionmentioning

confidence: 99%

Silent Information Regulator 2 from Trypanosoma cruzi Is a Potential Target to Infection Control

Gaspar¹,

Smith²,

Moretti³

et al. 2018

Chagas Disease - Basic Investigations and Challenges

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Human trypanosomiasis is a neglected tropical disease caused by protozoan parasites of the genus Trypanosoma. Trypanosoma brucei is responsible for sleeping sickness, also called African trypanosomiasis, while Trypanosoma cruzi causes Chagas disease, or American trypanosomiasis. Together, these diseases are responsible for significant mortality, morbidity and lost productivity in the endemic regions. There are no vaccines and treatments rely on drugs with limited efficacy, high cost, serious side effects and long administration periods. Since these diseases affect mostly the poor, there is no economic interest in the development of new drugs by pharmaceutical companies, and hopes for new treatments rely on public initiatives, public-private partnerships or philanthropic programs. The first step in the discovery of new drugs involves the identification of active molecules as starting points for further development, by either employing whole cells or by specific molecular target screenings. Research efforts undertaken by the authors' groups have focused on exploiting both strategies in the search for new molecules for trypanosomiasis drug discovery. In this chapter, we focus on Chagas disease and the recently uncovered potential of using sirtuins as targets for infection control.

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Enantiomers of Nifurtimox Do Not Exhibit Stereoselective Anti-Trypanosoma cruzi Activity, Toxicity, or Pharmacokinetic Properties

Cited by 6 publications

References 5 publications

Chirality of New Drug Approvals (2013–2022): Trends and Perspectives

Chirality of New Drug Approvals (2013–2022): Trends and Perspectives

A comprehensive review on potential candidates for the treatment of chagas disease

Silent Information Regulator 2 from Trypanosoma cruzi Is a Potential Target to Infection Control

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