2-Aminothiophene scaffolds: Diverse biological and pharmacological attributes in medicinal chemistry

Fig. 8.
Scheme 24.
2.14. Anticonvulsant activity
The anticonvulsant activity of Schiff Bases of 2-ATs against maximum electroshock-induced seizure and pentylenetetrazole-induced seizure was screened by Kunda et al. in 2013; phenytoin and diazepam were selected as reference drugs [86]. In general, the synthesized derivatives showed modest activity. The introduction of an indole linker at the 2-amino position of 2-AT core led to the production of hybrid compound 80 (Scheme 25), which was synthesized via the Gewald reaction. Hybrid 80 exhibited good activity compared with other synthesized samples and standards. Notably, further prospective developments in the evaluation of the anticonvulsant activity of 2-AT-related hybrids may be reported in the future.
Scheme 25.
2.15. 2-ATs as positive AMPA receptor modulators
In 2010, Jamieson and co-workers described a novel series of positive modulators of the AMPA receptor based on substituted 2-ATs [87, 88]. The authors focused on identifying a novel series of positive modulators of the AMPA receptor, which are of potential utility in the treatment of neurological disorders, such as schizophrenia, Alzheimer’s disease, Parkinson’s disease and attention deficit hyperactivity disorder. The most potent compound 81 (GluR1 pEC₅₀ = 6.6, Scheme 26) displayed both reasonable solubility and microsomal stability. In addition, based on the in vivo pharmacokinetics in rat (2 mg/kg iv, 10 mg/kg po), compound 81 has low clearance rate, a reasonable half-life (Clp = 2.3 mL/min/kg, T_1/2 = 3.8 h, V_ss= 0.5 L/kg) and significantly improved brain exposure (brain:plasma ratio = 1.03). However, the measured oral bioavailability was low (3.8%), indicating that the conformational constraint alone was not sufficient to enhance this important parameter. Therefore, the authors decided to introduce a polar functional group in the pyrazole region based on SARs and a modelling analysis of the crystal structure to improve improvement oral bioavailability. Next, secondary amine derivative 82 (GluR1 pEC₅₀ = 6.1, Scheme 26) displayed a good overall balance of potency, solubility and microsomal stability (5 rat Cli < 19 µL/min/mg protein, human Cli < 12 µL/min/mg protein, solubility = 107 mg/L). Compound 82 was suggested as a candidate positive modulator of AMPA receptors in patients with neurological disorders.