Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Jul 22;25(15):3320.
doi: 10.3390/molecules25153320.

From Riluzole to Dexpramipexole via Substituted-Benzothiazole Derivatives for Amyotrophic Lateral Sclerosis Disease Treatment: Case Studies

Serge Mignani  1   2 , Jean-Pierre Majoral  3   4 , Jean-François Desaphy  5 , Giovanni Lentini  6
Affiliations
Review

From Riluzole to Dexpramipexole via Substituted-Benzothiazole Derivatives for Amyotrophic Lateral Sclerosis Disease Treatment: Case Studies

Serge Mignani et al. Molecules. .

Abstract

The 1,3-benzothiazole (BTZ) ring may offer a valid option for scaffold-hopping from indole derivatives. Several BTZs have clinically relevant roles, mainly as CNS medicines and diagnostic agents, with riluzole being one of the most famous examples. Riluzole is currently the only approved drug to treat amyotrophic lateral sclerosis (ALS) but its efficacy is marginal. Several clinical studies have demonstrated only limited improvements in survival, without benefits to motor function in patients with ALS. Despite significant clinical trial efforts to understand the genetic, epigenetic, and molecular pathways linked to ALS pathophysiology, therapeutic translation has remained disappointingly slow, probably due to the complexity and the heterogeneity of this disease. Many other drugs to tackle ALS have been tested for 20 years without any success. Dexpramipexole is a BTZ structural analog of riluzole and was a great hope for the treatment of ALS. In this review, as an interesting case study in the development of a new medicine to treat ALS, we present the strategy of the development of dexpramipexole, which was one of the most promising drugs against ALS.

Keywords: 1,3-benzothiazole (BTZ); DrugBank; amyotrophic lateral sclerosis (ALS); chronic neurodegenerative disorders; dexpramipexole; indoles; riluzole.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Common names and therapeutic applications of the 1,3-benzothiazole drugs included in DrugBank [3]; A: approved, I: investigational, E: experimental, W: withdrawn; each drug has been color-coded as follows: yellow = etiotropic agent, magenta = drugs acting on CNS, white = diagnostic, and blue = pharmacodynamic agent (see text for details).
Figure 2
Figure 2
Structures and classes of the 1,3-benzothiazole drugs included in DrugBank3; A: approved, I: investigational, E: experimental, W: withdrawn; each therapeutic class has been color-coded as follows: yellow = etiotropic agent, magenta = drugs acting on CNS, white = diagnostic, and blue = pharmacodynamic agent (see text for details).
Figure 3
Figure 3
Patterns of substitution displayed by the 1,3-benzothiazole drugs included in DrugBank [3]; A: approved, I: investigational, E: experimental, W: withdrawn; each therapeutic class has been color-coded as follows: yellow = etiotropic agent, magenta = drugs acting on CNS, white = diagnostic, and blue = pharmacodynamic agent (see text for details).
Figure 4
Figure 4
Substituents displayed by the approved 1,3-benzothiazole drugs included in DrugBank [3]; dexpramipexole (E1) was included.
Figure 5
Figure 5
Substituents displayed by the investigational 1,3-benzothiazole drugs included in DrugBank [3].
Figure 6
Figure 6
Chemical structure of riluzole (Rilutek®) and edaravone (Radicava®).
Figure 7
Figure 7
Chemical structure of 6-substituted-2-benzothiazolamines and 3-substituted-2-iminobenzothiazolines.
Scheme 1
Scheme 1
Synthesis of 6-substituted 2-benzothiazolamines.
Scheme 2
Scheme 2
3-Substituted 2-iminobenzothiazolines.
Figure 8
Figure 8
Simultaneous modifications in positions 3 and 6, and 2 and 3.
Figure 9
Figure 9
Chemical structures of the most potent hybrids of riluzole (VI, VII, VIII, IX and X).
Scheme 3
Scheme 3
Chemical structures of pifithrin-α, XI, XII, XII and their synthetic pathway.
Figure 10
Figure 10
Chemical structures of riluzole, dexpramipexole, and (−)-pramipexole.
Scheme 4
Scheme 4
Synthesis of (S)-pramipexole and dexpramipexole using the optical resolution strategy.
Scheme 5
Scheme 5
Synthesis of (–)-pramipexole and dexpramipexole using the biocatalyst strategy.
Figure 11
Figure 11
Chemical structures of modified benzothiazolamines.
See this image and copyright information in PMC

References

    1. Garg V., Maurya R.K., Thanikachalam P.V., Bansal G., Monga V. An insight into the medicinal perspective of synthetic analogs of indole: A review. Eur. J. Med. Chem. 2019;180:562–612. - PubMed
    1. Kumari A., Singh R.K. Medicinal chemistry of indole derivatives: Current to future therapeutic prospectives. Bioorg. Chem. 2019;89:103021. doi: 10.1016/j.bioorg.2019.103021. - DOI - PubMed
    1. Wishart D.S., Feunang Y.D., Guo A.C., Lo E.J., Marcu A., Grant J.R., Sajed T., Johnson D., Li C., Sayeeda Z., et al. DrugBank 5.0: A major update to the DrugBank database for 2018. Nucleic Acids Res. 2018;46:D1074–D1082. doi: 10.1093/nar/gkx1037. - DOI - PMC - PubMed
    1. Cerveri A., Bandini M. Recent advances in the catalytic functionalization of “electrophilic” indoles. Chin. J. Chem. 2020;38:287–294. doi: 10.1002/cjoc.201900446. - DOI
    1. Troy D., Hubbard T.D., Murray I.A., Perdew G.H. Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation. Drug Metab. Dispos. 2015;43:1522–1535. - PMC - PubMed

MeSH terms