Synthesis and Anti-Chagas Activity Profile of a Redox-Active Lead 3-Benzylmenadione Revealed by High-Content Imaging DOI

Nathan Trometer,

Jéremy Pecourneau,

Liwen Feng

et al.

ACS Infectious Diseases, Journal Year: 2024, Volume and Issue: 10(5), P. 1808 - 1838

Published: April 12, 2024

Chagas disease, or American trypanosomiasis, is a neglected tropical disease which top priority target of the World Health Organization. The endemic mainly in Latin America, caused by protozoan Trypanosoma cruzi and has spread around globe due to human migration. There are multiple transmission routes, including vectorial, congenital, oral, iatrogenic. Less than 1% patients have access treatment, relying on two old redox-active drugs that show poor pharmacokinetics severe adverse effects. Hence, priorities for next steps R&D include (i) discovery novel drugs/chemical classes, (ii) filling pipeline with drug candidates new mechanisms action, (iii) pressing need more research chemical entities. In present work, we first identified hit (4a) potent anti-T. activity from library 3-benzylmenadiones. We then designed synthetic strategy build 49 3-(4-monoamino)benzylmenadione derivatives via reductive amination obtain diazacyclic benz(o)ylmenadiones. Among them, high content imaging an anti-amastigote "early lead" 11b (henceforth called cruzidione) revealing optimized pharmacokinetic properties enhanced specificity. Studies yeast model revealed cruzidione metabolite, 3-benzoylmenadione (cruzidione oxide), enters redox cycling NADH-dehydrogenase, generating reactive oxygen species, as hypothesized early (4a).

Language: Английский

Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases DOI Open Access
Britney N. Lizama, Jennifer Kahle, Susan M. Catalano

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(7), P. 6251 - 6251

Published: March 26, 2023

There is a large unmet medical need to develop disease-modifying treatment options for individuals with age-related degenerative diseases of the central nervous system. The sigma-2 receptor (S2R), encoded by TMEM97, expressed in brain and retinal cells, regulates cell functions via its co-receptor progesterone membrane component 1 (PGRMC1), through other protein–protein interactions. Studies describing S2R involve manipulation expression or pharmacological modulation using exogenous small-molecule ligands. These studies demonstrate that modulates key pathways involved including autophagy, trafficking, oxidative stress, amyloid-β α-synuclein toxicity. Furthermore, can ameliorate functional deficits cell-based animal models disease. This review summarizes current evidence-based understanding biology function, potential as therapeutic target system, Alzheimer’s disease, α-synucleinopathies, dry macular degeneration.

Language: Английский

Citations

25
Computational Chemistry for the Identification of Lead Compounds for Radiotracer Development DOI Creative Commons
Chia‐Ju Hsieh, Sam Giannakoulias, E. James Petersson

et al.

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(2), P. 317 - 317

Published: Feb. 18, 2023

The use of computer-aided drug design (CADD) for the identification lead compounds in radiotracer development is steadily increasing. Traditional CADD methods, such as structure-based and ligand-based virtual screening optimization, have been successfully utilized many discovery programs are highlighted throughout this review. First, we discuss hit at beginning programs. This followed by an analysis how hits derived from can be filtered culled to highly probable candidates test vitro assays. We then illustrate used optimize potency experimentally validated positron emission tomography (PET). Finally, conclude with a survey newest techniques employing machine learning (ML).

Language: Английский

Citations

19
A Novel Brain PET Radiotracer for Imaging Alpha Synuclein Fibrils in Multiple System Atrophy DOI
Ho Young Kim,

Wai Kit Chia,

Chia‐Ju Hsieh

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(17), P. 12185 - 12202

Published: Aug. 31, 2023

Abnormal α-synuclein (α-syn) aggregation characterizes α-synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy (MSA). However, no suitable positron emission tomography (PET) radiotracer for imaging α-syn in PD MSA exists currently. Our structure–activity relationship studies identified 4-methoxy-N-(4-(3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)benzamide (4i) as a PET candidate α-syn. In vitro assays revealed high binding of 4i to recombinant fibrils (inhibition constant (Ki) = 6.1 nM) low affinity amyloid beta (Aβ) Alzheimer's (AD) homogenates. [3H]4i also exhibited specific AD, progressive supranuclear palsy, corticobasal degeneration tissues well tissues, suggesting notable tau. Nevertheless, the pathologic aggregates post-mortem brain was significantly higher than tissues. This finding demonstrated potential use [11C]4i tracer patients. Nonhuman primate confirmed good uptake rapid washout [11C]4i.

Language: Английский

Citations

12
Structure-Affinity relationships of novel σ2R/TMEM97 ligands DOI
Grant D. Walby, Qi Gu, Hongfen Yang

et al.

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 145, P. 107191 - 107191

Published: Feb. 10, 2024

Language: Английский

Citations

2
Structure-affinity relationships of stereoisomers of norbenzomorphan-derived σ2R/TMEM97 modulators DOI

Yan Lu,

Qi Gu, Stephen F. Martin

et al.

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 257, P. 115488 - 115488

Published: May 23, 2023

Language: Английский

Citations

6
Development of a Highly Specific 18F-Labeled Radioligand for Imaging of the Sigma-2 Receptor in Brain Tumors DOI
Tao Wang, Jingqi Wang, Leyuan Chen

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(18), P. 12840 - 12857

Published: Sept. 13, 2023

Novel ligands with the 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or 5,6-dimethoxyisoindoline pharmacophore were designed and synthesized for evaluation of their structure-activity relationship to sigma-2 (σ2) receptor developed as suitable PET radioligands. Compound 1 was found possess nanomolar affinity (Ki(σ1) = 2.57 nM) σ2 receptor, high subtype selectivity (>2000-fold), over 40 other receptors transporters. Radioligand [18F]1 prepared radiochemical yield 37-54%, > 99% purity, molar activity 107-189 GBq/μmol. Biodistribution blocking studies in mice micro-PET/CT imaging rats indicated excellent binding specificity vivo. Micro-PET/CT U87MG glioma xenograft model demonstrated clear tumor visualization uptake tumor-to-background ratio. Co-injection CM398 (5 μmol/kg) led a remarkable reduction (80%, 60-70 min), indicating specific xenografts.

Language: Английский

Citations

5
Synthesis and anti-Chagas activity profile of a novel redox-active lead 3-benzylmenadione revealed by high-content imaging DOI Creative Commons

Nathan Trometer,

Jéremy Pecourneau,

Liwen Feng

et al.

Published: Feb. 8, 2024

Chagas’ disease or American trypanosomiasis is a neglected tropical disease, which top priority target of the World Health Organization. The caused by protozoan Trypanosoma cruzi, endemic in Latin America and has spread around globe due to human migration. There are multiple transmission routes, from vectorial, congenital, oral iatrogenic. Less than 1% patients have access treatment, limited two old redox-active drugs, but these poor pharmacokinetics severe adverse effects. Hence, priorities for next steps R&D include i) discovery new drugs/chemical classes clinical trials; ii) filling pipeline with drug candidates that mechanisms action, iii) need more research chemical entities. In present work, we first identified hit (4a), library 3-benzylmenadiones, had potent anti-T.cruzi activity. We then designed synthetic strategy build 49 3-(4-mono-amino)benzylmenadione derivatives, via reductive amination obtain diazacyclic benz(o)ylmenadiones. Among them, an anti-amastigote “early lead” 11b (henceforth called cruzidione) high content imaging optimized pharmacokinetic properties better specificity. Studies yeast model revealed cruzidione metabolite, 3-benzoylmenadione (cruzidione oxide), enters redox-cycling NADH-dehydrogenase, generating reactive oxygen species, as hypothesized early (4a).

Language: Английский

Citations

1
Synthesis and Anti-Chagas Activity Profile of a Redox-Active Lead 3-Benzylmenadione Revealed by High-Content Imaging DOI

Nathan Trometer,

Jéremy Pecourneau,

Liwen Feng

et al.

ACS Infectious Diseases, Journal Year: 2024, Volume and Issue: 10(5), P. 1808 - 1838

Published: April 12, 2024

Chagas disease, or American trypanosomiasis, is a neglected tropical disease which top priority target of the World Health Organization. The endemic mainly in Latin America, caused by protozoan Trypanosoma cruzi and has spread around globe due to human migration. There are multiple transmission routes, including vectorial, congenital, oral, iatrogenic. Less than 1% patients have access treatment, relying on two old redox-active drugs that show poor pharmacokinetics severe adverse effects. Hence, priorities for next steps R&D include (i) discovery novel drugs/chemical classes, (ii) filling pipeline with drug candidates new mechanisms action, (iii) pressing need more research chemical entities. In present work, we first identified hit (4a) potent anti-T. activity from library 3-benzylmenadiones. We then designed synthetic strategy build 49 3-(4-monoamino)benzylmenadione derivatives via reductive amination obtain diazacyclic benz(o)ylmenadiones. Among them, high content imaging an anti-amastigote "early lead" 11b (henceforth called cruzidione) revealing optimized pharmacokinetic properties enhanced specificity. Studies yeast model revealed cruzidione metabolite, 3-benzoylmenadione (cruzidione oxide), enters redox cycling NADH-dehydrogenase, generating reactive oxygen species, as hypothesized early (4a).

Language: Английский

Citations

0