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

Scheme 29.
2.20. 2-ATs as aPKC inhibitors
Several series of substituted 2-ATs, including 2-amino-3-carboxy-4-phenylthiophenes, were reported as novel aPKC inhibitors by Titchenell et al. in 2013 [94]. These analogues were evaluated in models of bona fide aPKC-dependent signalling, including NFB driven-gene transcription as a marker of the inflammatory response and VEGF/TNF-induced vascular endothelial permeability. Among the 2-ATs, the benzodioxole-containing derivative 90, (Scheme 30), was in the low nanomolar range in these two cellular assays. A preliminary in silico calculation of the physicochemical parameters of compound 90, as well as other potential compounds, based on the results from cellular assays suggests that this class of compounds displays favourable biopharmaceutical properties. However, further stability, pharmacokinetic and toxicity analyses are clearly required. In addition, the clogP value and topological polar surface for compound 90 were 3.854 and 70.78, respectively.
Scheme 30.
2.21. 2-ATs as IKK- inhibitors
In 2011, Takahashi and co-workers presented urea-related thiophen-3-amides as IKK-β inhibitors [95]. The attractiveness of their research is the insertion of a tetrahydroindazolone fragment into 2-AT moiety. The primary enzymatic activity and cellular potency of various thiophene derivatives suggested that the N-benzyl group in the piperidin-3-yl-tetrahydroindazolone ring was a key fragment for increasing the potency, and the 2,4-difluoro-benzyl derivative (91, Scheme 31) offered the preferred overall profile for IKK-β potency, with more than 50-fold selectivity over IKK-α, as well as good cellular potency. Oral dosing at 10 mg/kg inhibited TNF-α production in a dose-dependent manner, when compound 91 was assessed in a mouse model of LPS-stimulated TNF-α production.
Scheme 31.
2.22. Effect on the diphenolase activity of mushroom tyrosinases
In 2016, Liu and colleagues reported an inhibitory effect of novel 2-AT derivatives containing N-substituted phenylthiourea fragments on the diphenolase activity of mushroom tyrosinases [96]. 4,5,6,7-Tetrahydro-2-[[(substitutedphenylamino)thioxomethyl]amino]-benzo[b]thiophene-3-carboxylate intermediates were not evaluated, because of their poor solubility in an aqueous buffer solution containing enzyme. The inhibitory effects of 2-(3-(3-fluorophenyl)thioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (92, Scheme 32) on the tyrosinase were investigated and compared with 75 µM kojic acid; however, the percent inhibition of compound 92 was less than kojic acid, although this compound exhibited higher activity than other compounds.