Nitroheterocyclic derivatives: privileged scaffold for drug development against Chagas disease

Scarim, Cauê Benito; Chin, Chung Man

doi:10.1007/s00044-019-02453-y

Cited by 15 publications

(13 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, NFOH produces fewer side effects, is less genotoxic, inhibits parasite replication by a different downstream mechanism, and as shown here, is considerably more active against the infectious trypomastigote form of the parasite. The reduced toxicity of NFOH, curative activity and potential for flexibility in terms of dosing regimens, also identifies it as an attractive partner for other anti-chagasic candidates in combination therapy [15,24,25,[27][28][29]40,42].…”

Section: Discussionmentioning

confidence: 99%

“…CD treatment is limited to two nitroheterocyclic drugs, nifurtimox and benznidazole (BZN), both of which have been in use for more than 50 years. These drugs are effective against T. cruzi [15] during the acute stage of infection [16]. However, there is a limited cure rate during the chronic stage in both adults and children [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Image-Based In Vitro Screening Reveals the Trypanostatic Activity of Hydroxymethylnitrofurazone against Trypanosoma cruzi

Scarim

Olmo

Ferreira

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Hydroxymethylnitrofurazone (NFOH) is a therapeutic candidate for Chagas disease (CD). It has negligible hepatotoxicity in a murine model compared to the front-line drug benznidazole (BZN). Here, using Trypanosoma cruzi strains that express bioluminescent and/or fluorescent reporter proteins, we further investigated the in vitro and in vivo activity of NFOH to define whether the compound is trypanocidal or trypanostatic. The in vitro activity was assessed by exploiting the fluorescent reporter strain using wash-out assays and real-time microscopy. For animal experimentation, BALB/c mice were inoculated with the bioluminescent reporter strain and assessed by highly sensitive in vivo and ex vivo imaging. Cyclophosphamide treatment was used to promote parasite relapse in the chronic stage of infection. Our data show that NFOH acts by a trypanostatic mechanism, and that it is more active than BZN in vitro against the infectious trypomastigote form of Trypanosoma cruzi. We also found that it is more effective at curing experimental infections in the chronic stage, compared with the acute stage, a feature that it shares with BZN. Therefore, given its reduced toxicity, enhanced anti-trypomastigote activity, and curative properties, NFOH can be considered as a potential therapeutic option for Chagas disease, perhaps in combination with other trypanocidal agents.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Image-Based In Vitro Screening Reveals the Trypanostatic Activity of Hydroxymethylnitrofurazone against Trypanosoma cruzi

Scarim

Olmo

Ferreira

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Hence, among the 5-nitrofuran-acyl hydrazones scaffolds, nitrofurazone 2, hydroxymethyl nitrofurazone 5, [14] and nifuroxazide 6, underscore relevant antitrypanosomal activity, as shown in Figure 1. [13,15] Despite the efforts aiming at effective, safe, and affordable antichagasic agents, just a few candidates advanced into clinical trials in the CD drug discovery pipeline. Thus, the intrinsic aspects of the chemical scaffold of classical nitro-containing drugs somewhat play a relevant role in the response toward CD.…”

Section: Chagas Disease (Cd) Is a Neglected Tropical Disease Caused Bymentioning

confidence: 99%

“…and13 C NMR spectra were recorded in CDCl 3 solutions using a Bruker75-or 300-MHz spectrometer. Chemical shifts (δ) are indicated in parts per million (ppm) downfield from tetramethylsilane or deuterated solvent (CDCl 3 27 and 13 C δ 77.0 ppm; dimethyl sulfoxide (DMSO)-d 6 δ 2.5 and 13 C δ 39.51 ppm; as the internal standard.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Repurposing of 5‐nitrofuran‐3,5‐disubstituted isoxazoles: A thriving scaffold to antitrypanosomal agents

Carvalho

Neves

Portapilla

et al. 2022

Archiv der Pharmazie

View full text Add to dashboard Cite

Chagas disease (CD) is a neglected disease caused by the protozoan Trypanosoma cruzi. The two drugs used in the treatment schedules exhibit adverse effects and severe toxicity. Thus, searching for new antitrypanosomal agents is urgent to provide improved treatments to those affected by this disease. 5-Nitrofuran-isoxazole analogs were synthesized by cycloaddition reactions [3+2] between chloro-oximes and acetylenes in satisfactory yields. We analyzed the structure-activity relationship of the analogs based on Hammett's and Hansch's parameters. The 5-nitrofuran-isoxazole analogs exhibited relevant in vitro antitrypanosomal activity against the amastigote forms of T. cruzi. Analog 7s was the trending hit of the series, showing an IC 50 value of 40 nM and a selectivity index of 132.50. A possible explanation for this result may be the presence of an electrophile near the isoxazole core. Moreover, the most active analogs proved to act as an in vitro substrate of type I nitroreductase rather than the cruzain, enzymes commonly investigated in molecular target studies of CD drug discovery. These findings suggest that 5-nitrofuran-isoxazole analogs are promising in the studies of agents for CD treatment.

show abstract

Recent advancement in drug development of nitro(NO₂)‐heterocyclic compounds as lead scaffolds for the treatment of Mycobacterium tuberculosis

Scarim

Pavan

2022

Drug Development Research

Self Cite

View full text Add to dashboard Cite

Tuberculosis (TB) is an infectious disease caused predominantly by Mycobacterium tuberculosis (Mtb). It was responsible for approximately 1.4 million deaths worldwide in 2019. The lack of new drugs to treat drug-resistant strains is a principal factor for the slow rise in TB infections. Our aim is to aid the development of new TB treatments by describing improvements (last decade, 2011-2021) to nitro(NO 2 )-based compounds that have shown activity or pharmacological properties (e.g., anti-proliferative, anti-kinetoplastid) against Mtb. For all compounds, we have included final correlations of minimum inhibitory concentrations against Mtb (H 37 Rv).

show abstract

Nitroheterocyclic derivatives: privileged scaffold for drug development against Chagas disease

Cited by 15 publications

References 52 publications

Image-Based In Vitro Screening Reveals the Trypanostatic Activity of Hydroxymethylnitrofurazone against Trypanosoma cruzi

Image-Based In Vitro Screening Reveals the Trypanostatic Activity of Hydroxymethylnitrofurazone against Trypanosoma cruzi

Repurposing of 5‐nitrofuran‐3,5‐disubstituted isoxazoles: A thriving scaffold to antitrypanosomal agents

Recent advancement in drug development of nitro(NO₂)‐heterocyclic compounds as lead scaffolds for the treatment of Mycobacterium tuberculosis

Contact Info

Product

Resources

About

Nitroheterocyclic derivatives: privileged scaffold for drug development against Chagas disease

Cited by 15 publications

References 52 publications

Image-Based In Vitro Screening Reveals the Trypanostatic Activity of Hydroxymethylnitrofurazone against Trypanosoma cruzi

Image-Based In Vitro Screening Reveals the Trypanostatic Activity of Hydroxymethylnitrofurazone against Trypanosoma cruzi

Repurposing of 5‐nitrofuran‐3,5‐disubstituted isoxazoles: A thriving scaffold to antitrypanosomal agents

Recent advancement in drug development of nitro(NO2)‐heterocyclic compounds as lead scaffolds for the treatment of Mycobacterium tuberculosis

Contact Info

Product

Resources

About

Recent advancement in drug development of nitro(NO₂)‐heterocyclic compounds as lead scaffolds for the treatment of Mycobacterium tuberculosis