Synthesis of 2H‐ and 14C‐labeled fexinidazole and its primary metabolites labeled with 2H

Fontana, E.; Pignatti, A.; Venegoni, Serena; Bray, M.A.

doi:10.1002/jlcr.1914

Cited by 5 publications

(6 citation statements)

References 9 publications

(11 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fexinidazole sulfone was prepared either by oxidation of fexinidazole [33], or by modification of a published method [34]. DNDI-VL-2098 was prepared by adapting the reported syntheses of related compounds [35].…”

Section: Methodsmentioning

confidence: 99%

Activation of Bicyclic Nitro-drugs by a Novel Nitroreductase (NTR2) in Leishmania

et al. 2016

View full text Add to dashboard Cite

Drug discovery pipelines for the “neglected diseases” are now heavily populated with nitroheterocyclic compounds. Recently, the bicyclic nitro-compounds (R)-PA-824, DNDI-VL-2098 and delamanid have been identified as potential candidates for the treatment of visceral leishmaniasis. Using a combination of quantitative proteomics and whole genome sequencing of susceptible and drug-resistant parasites we identified a putative NAD(P)H oxidase as the activating nitroreductase (NTR2). Whole genome sequencing revealed that deletion of a single cytosine in the gene for NTR2 that is likely to result in the expression of a non-functional truncated protein. Susceptibility of leishmania was restored by reintroduction of the wild-type gene into the resistant line, which was accompanied by the ability to metabolise these compounds. Overexpression of NTR2 in wild-type parasites rendered cells hyper-sensitive to bicyclic nitro-compounds, but only marginally to the monocyclic nitro-drugs, nifurtimox and fexinidazole sulfone, known to be activated by a mitochondrial oxygen-insensitive nitroreductase (NTR1). Conversely, a double knockout NTR2 null cell line was completely resistant to bicyclic nitro-compounds and only marginally resistant to nifurtimox. Sensitivity was fully restored on expression of NTR2 in the null background. Thus, NTR2 is necessary and sufficient for activation of these bicyclic nitro-drugs. Recombinant NTR2 was capable of reducing bicyclic nitro-compounds in the same rank order as drug sensitivity in vitro. These findings may aid the future development of better, novel anti-leishmanial drugs. Moreover, the discovery of anti-leishmanial nitro-drugs with independent modes of activation and independent mechanisms of resistance alleviates many of the concerns over the continued development of these compound series.

show abstract

Section: Methodsmentioning

confidence: 99%

Activation of Bicyclic Nitro-drugs by a Novel Nitroreductase (NTR2) in Leishmania

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Thus, a precursor suitable for late‐stage introduction of the tritium label as well as well‐defined high specific activity was desired. Fontana and coworkers described a strategy for the synthesis of a deuterium‐labeled methyl‐phenyl‐sulfide containing active pharmaceutical ingredient . These authors methylated a volatile, thus easily dimerizing thiol using a low‐boiling deuterated methylating agent followed by sulfur oxidation.…”

Section: Introductionmentioning

confidence: 99%

“…Fontana and coworkers described a strategy for the synthesis of a deuterium-labeled methyl-phenyl-sulfide containing active pharmaceutical ingredient. 16 These authors methylated a volatile, thus easily dimerizing thiol using a low-boiling deuterated methylating agent followed by sulfur oxidation. As such, we speculated if this strategy can be applied to prepare tritiated isotopomers of prostaglandin D 2 receptor antagonists, which are structurally related to fevipiprant.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a high specific activity methyl sulfone tritium isotopologue of fevipiprant (NVP‐QAW039)

Luu

Goujon

Meisterhans³

et al. 2015

Labelled Comp Radiopharmac

View full text Add to dashboard Cite

The synthesis of a triple tritiated isotopologue of the CRTh2 antagonist NVP-QAW039 (fevipiprant) with a specific activity >3 TBq/mmol is described. Key to the high specific activity is the methylation of a bench-stable dimeric disulfide precursor that is in situ reduced to the corresponding thiol monomer and methylated with [(3)H3]MeONos having per se a high specific activity. The high specific activity of the tritiated active pharmaceutical ingredient obtained by a build-up approach is discussed in the light of the specific activity usually to be expected if hydrogen tritium exchange methods were applied.

show abstract

“…In this pathway, 2-(chloromethyl)-1-methyl-5-nitro-1H-imidazole was treated with 4-methyl mercaptophenol in acetonitrile under argon atmosphere to furnish Fexinidazole 14 in 60% yield [ 140 ]. In 2011, Fexinidazole 14 was synthesized by Fontana et al (route B), wherein 4-methyl mercaptophenol was first treated with methyl iodide in the presence of trimethylamine in dry THF to obtain 4-(methylthio)phenol, which upon further treatment with 2-(chloromethyl)-1-methyl-5-nitro-1 H -imidazole in dimethyl formamide, produced deuterium-labeled Fexinidazole 14 [ 141 ]. In 2014, Zsolt et al from Drugs for Neglected Diseases Initiative (DNDI) (CH) patented another route (route C) for the synthesis of Fexinidazole 14 .…”

Section: Activity Profile and Synthetic Pathways Developed To Constru...mentioning

confidence: 99%

Functionalized Nitroimidazole Scaffold Construction and Their Pharmaceutical Applications: A 1950–2021 Comprehensive Overview

et al. 2022

View full text Add to dashboard Cite

Nitroimidazole represents one of the most essential and unique scaffolds in drug discovery since its discovery in the 1950s. It was K. Maeda in Japan who reported in 1953 the first nitroimidazole as a natural product from Nocardia mesenterica with antibacterial activity, which was later identified as Azomycin 1 (2-nitroimidazole) and remained in focus until now. This natural antibiotic was the starting point for synthesizing numerous analogs and regio-isomers, leading to several life-saving drugs and clinical candidates against a number of diseases, including infections (bacterial, viral, parasitic) and cancers, as well as imaging agents in medicine/diagnosis. In the present decade, the nitroimidazole scaffold has again been given two life-saving drugs (Delamanid and Pretomanid) used to treat MDR (multi-drug resistant) tuberculosis. Keeping in view the highly successful track-record of the nitroimidazole scaffold in providing breakthrough therapeutic drugs, this comprehensive review focuses explicitly on presenting the activity profile and synthetic chemistry of functionalized nitroimidazole (2-, 4- and 5-nitroimidazoles as well as the fused nitroimidazoles) based drugs and leads published from 1950 to 2021. The present review also presents the miscellaneous examples in each class. In addition, the mutagenic profile of nitroimidazole-based drugs and leads and derivatives is also discussed.

show abstract

Synthesis of ²H‐ and ¹⁴C‐labeled fexinidazole and its primary metabolites labeled with ²H

Cited by 5 publications

References 9 publications

Activation of Bicyclic Nitro-drugs by a Novel Nitroreductase (NTR2) in Leishmania

Activation of Bicyclic Nitro-drugs by a Novel Nitroreductase (NTR2) in Leishmania

Synthesis of a high specific activity methyl sulfone tritium isotopologue of fevipiprant (NVP‐QAW039)

Functionalized Nitroimidazole Scaffold Construction and Their Pharmaceutical Applications: A 1950–2021 Comprehensive Overview

Contact Info

Product

Resources

About