Riluzole Series. Synthesis and in Vivo “Antiglutamate” Activity of 6-Substituted-2-benzothiazolamines and 3-Substituted-2-imino-benzothiazolines

Abstract

Two series of analogues of riluzole, a blocker of excitatory amino acid mediated neurotransmission, have been synthesized: monosubstituted 2-benzothiazolamines and 3-substituted derivatives. Of all the compounds prepared in the first series, only 2-benzothiazolamines bearing alkyl, polyfluoroalkyl, or polyfluoroalkoxy substituents in the 6-position showed potent anticonvulsant activity against administration of glutamic acid in rats. The most active compounds displaying in vivo "antiglutamate" activity were the 6-OCF(3) (riluzole), 6-OCF(2)CF(3), 6-CF(3), and 6-CF(2)CF(3) substituted derivatives with ED(50) values between 2.5 and 3.2 mg/kg i.p. Among the second series of variously substituted benzothiazolines, compounds as active as riluzole or up to 3 times more potent were identified in two series: benzothiazolines bearing a beta-dialkylaminoethyl moiety and compounds with an alkylthioalkyl chain and their corresponding sulfoxides and sulfones. The most potent derivatives were 2-imino-3-(2-methylthio)- and 2-imino-3-(2-methylsulfinyl)-ethyl-6-trifluoromethoxybenzothiazolines (61 and 64, ED(50) = 1.0 and 1.1 mg/kg i.p., respectively). In addition, intraperitoneal administration of some of the best benzothiazolines protected mice from mortality produced by hypobaric hypoxia.

Neuroprotective effect of naphtha[1,2-d]thiazol-2-amine in an animal model of Parkinson's disease

“…The thiazoles have emerged as important target molecules due to their pharmacological properties such as antioxidant [12], anti-inflammatory [13], antimicrobial [14] and noteworthy, as drugs for treating neurodegenerative disorders [15]. For example, Pramipexole (Figure 1), an aminobenzothiazole analogue is a dopamine D 2 /D 3 receptor agonist currently in clinical use for the treatment of PD [16].…”

Synthesis of some thiazolyl aminobenzothiazole derivatives as potential antibacterial, antifungal and anthelmintic agents

“…The synthetic route leading to the formation of 4-(6-substituted-1,3-benzothiazol- 9 15 21 39 28 81 72 10 12 13 21 18 41 52 11 22 16 27 23 63 34 12 27 29 18 12 29 32 13 37 26 53 62 57 44 14 28 21 39 42 35 32 15 44 33 51 54 48 61 16 59 54 32 38 26 22 17 13 15 28 21 14 12 18 6 8 18 11 9 4 2-yl)amino-2-(4-substitutedphenyl)amino-1,3-thiazole 9-24 is shown in Scheme 1. The compounds 6-substituted-1,3-benzothiazol-2-amines 1-4 were synthesised with an excellent yield following the methodology as described by Jimonet et al [25] from aryl amines. The compounds 1-4 on reaction with chloracetyl chloride afforded 2-chloro-N-(6-substituted-1,3-benzothiazol-2-yl)acetamide 5-8 on refluxing the reaction mixture at 120°C for 5h [26].…”

Reactivity and diverse synthetic applications of acyl isothiocyanates

“…Various compounds featuring this particular scaffold have been prepared, many exhibiting remarkable biological activities such as anticonvulsant activity against administration of glutamic acid in rat and in the design of active H 2 receptor histamine antagonists. 38,39 A single-pot three-component condensation of aroylisothiocyanates, amines and -halocarbonyls constitutes an excellent example of synthesizing the 3-alkyl-3H-thiazoline ring system. 40 Aroyl isothiocyanates 1 react smoothly with various amines in usual manner to afford acyl thioureas 54 (Scheme 21).…”