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

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.

Riluzole–Rasagiline Hybrids: Toward the Development of Multi-Target-Directed Ligands for Amyotrophic Lateral Sclerosis

“…By exploiting the existing structural similarities between the 1,3-benzothiazol-2-amine core of 1 and the benzene core of 2 , we designed hybrids 3 – 6 . Similarly, partially saturated analogues 7 and 8 were designed on the basis of the neuroprotective activity of pifithrin-α and dexpramipexole (Figure S1B), an investigational drug for ALS . The resulting high level of structural integration should ensure that 3 – 8 maintain the fragment-like properties of their parent compounds while potentially expanding their pharmacodynamic profile.…”

“…Similarly, partially saturated analogues 7 and 8 were designed on the basis of the neuroprotective activity of pifithrin-α 13 and dexpramipexole (Figure S1B), an investigational drug for ALS. 14 The resulting high level of structural integration should ensure that 3−8 maintain the fragment-like properties of their parent compounds while potentially expanding their pharmacodynamic profile. It should be noted that the propargylamine moiety of 2 is essential not only for the MAO-B inhibitory activity but also for its neuroprotective/antioxidant and antiapoptotic effects.…”

Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis

“…An alternative synthetic route for riluzole is the reaction of 4-(trifluoromethoxy)aniline with ammonium thiocyanate in the presence of acetonitrile (71%) ( Figure 8 ) [ 105 ]. Riluzole ( Figure 9 ) has been reported to exhibit neuroprotective effects in several animal models of PD, Huntington’s disease and cerebral ischemia [ 106 ]. Moreover, two large randomized placebo-controlled clinical trials were carried out to investigate the potency of riluzole in ALS treatment [ 107 ].…”

Synthesis, spectral characterization and biological activities of Ag(I), Pt(IV) and Au(III) complexes with novel azo dye ligand (N, N, O) derived from 2-amino-6-methoxy benzothiazole

“…In the manufacturing of such dispersed azo coloring 2-aminobenzothiazole is used. For the prevention of amyotrophic lateral sclerosis (Mignani et al 2020) and 2-(4aminophenyl)benzothiazole proof of antitumor properties (Mavroidi et al 2016), riluzole (2-amino-6-tri uoromethoxybenzothiazole) is sold as an anti-tumour (Araki et al 2001). The benzothiazole derivative catalyzes the formation of sul de links (reticulation) among unsaturated elastomeric polymers to obtain a exible and elastic crosslinking material (Ibrahim, Arafa, and Behbehani 2018).…”

“…Rogers 1966; Turan et al 2021; Ammar et al 2018; Al-Maydama et al 2006; Sabir, Malik b, and Iftikhar 1994) are given in Table7.The TGA curve of the ligand (6-MBTAMB) shows three steps of weight loss within the temperature range of 31 70. 837.95°C.…”