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

Scheme 32.
2.23. 2-ATs as CB2 receptor ligands
2-(Acylamino)thiophene derivatives were presented as CB2 receptor ligands by Osman et al. in 2016 [97]. Moreover, target derivatives were tested in radio ligand binding studies and functionally characterized in adenylate cyclase assays. Among the prepared samples, compound 93 (Scheme 33) was the most potent and selective, showing a remarkably high affinity for the CB2 receptor (K_i=2.15 nM) and a CB2 receptor subtype selectivity reaching up to 500-fold over CB1. Obviously, the adamantyl substituent of the amide fragment influenced the selectivity. A subsequent in vitro pharmacological evaluation of compound 93 revealed that this compound reduced the cAMP levels induced by the NKH-477 stimulus for an orthosteric Gi agonist, but compound 93 showed no activity in presence of the EC₈₀ ligand challenge.
Scheme 33.
2.24. Antagonistic activity
Regarding the antagonistic activity of small molecule conjugates and hybrids, thiophenes and thiazoles will be good ring equivalents to benzene (e.g., in guanidinium systems targeting α₂-adrenoceptors) [98]. In 2010, Briel and co-workers studied the antagonistic activities of 2-ATs towards the kainate receptor subtypes GluR5 and GluR6 [99]. The authors used a luminescence reporter assay to determine the antagonistic effect of the prepared compounds on kainate receptors. Although a large number of synthesis reactions were conducted to prepare 2-AT derivatives and their analogues, only the lead compound ethyl 2-amino-4-methyl-5-phenylthiophene-3-carboxylate (94, Fig. 10) showed high activity toward the GluR6 receptor, with an IC₅₀=0.75 µM. Notably, in the MTT assay, toxic effects of the selected compounds were only observed at high concentrations and long incubation times.
Fig. 10.
2.25. 2-ATs as PDE4 inhibitors
In 2014, Kolli et al. developed a ligand/additive-free Pd-catalysed C-N cross-coupling/cyclization of 2-chloro-3-alkynylquinoxalines with ethyl 2-aminothiophene-3-carboxylate derivatives and synthesized novel 1-thienyl pyrroloquinoxaline-containing thiophenes as potential PDE4 inhibitors [100]. PDE4B isolated from Sf9 cells was used to assess these compounds along with a reference compound, rolipram (in this study inhibition rate was 89%), a well-known inhibitor of PDE4. The compounds that significantly inhibited PDE4B at 30 µM include compounds 95 (85%) and 96 (78%) (Scheme 34). Based on the results of the hepatotoxicity assay, compound 96 showed toxicity at 30 µM, but was non-toxic at 1, 3 and 10 µM. Accordingly, compound 95 was not toxic at 1 and 3 µM, although the toxicity increased significantly at 10 and 30 µM. In addition, the apoptotic activities of these PDE4 inhibitors were then tested in Zebrafish embryos, along with the well-known drug methotrexate, and compound 96 showed increased apoptotic activities at 3, 10 and 30 µM. Regarding the second target compound, compound 95 showed a consistent increase in apoptotic activities as the concentration increased to 10 µM, although the activity was not increased further at 30 µM.