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

Scheme 3.
In the same year, Balzarini and co-workers developed 2-AT-3-nitrile (compound 4 described above, Scheme 3); in this report, the authors discovered that 2-AT-3-carboxylates acted as novel and highly selective cytostatic agents. In particular, compound 5 (Fig. 4) showed better cytostatic activity in over twenty of tumour cell types [42]. 2-AT-3-carboxylates display an unusual cytostatic selectivity for several T-cell (but not B-cell) lymphoma, prostate cancer, kidney carcinoma and hepatoma cell lines. These tumour-selective compounds preferentially suppressed protein synthesis rather than DNA or RNA synthesis, and the promising compound 5 resulted in an accumulation of prostate cancer cells in G1 phase of the cell cycle and induced apoptosis. Furthermore, according to Thomas et al., the antiproliferative potency and selectivity of compound 5 is preserved when the ethyl linker between the 2-amino-3-carboxymethylthiophene moiety is replaced and the aryl group is substituted for a thioalkyl analogue. The 5-((4-ethylphenylthio)- (6) and 5-((4-isopropylphenylthio) (7, Fig. 4) analogues were more potent (IC₅₀=0.3–0.4 µM) and selective (TS=100–144) anti-T-lymphoma/leukaemia agents than compound 5 [43]. In 2017, the authors reported another novel prototype compound 8 (containing a 5-heptyl chain, Fig. 4), which elicited cytotoxicity, rather than cytostatic activity [44]. Compound 8 inhibited the growth of 15 cancer cell lines at nanomolar concentrations in the NCI-60 anticancer drug screen of US NIH. In addition, compound 8 was not comparable to any known antitumor drug present in the NIH database, suggesting a likely novel molecular mechanism of action of 8.
Fig. 4.
TP53 plays an important role in regulating the cell cycle, apoptosis, and DNA repair via a complex network of proteins known as the p53 pathway. In 2013, Wang and colleagues investigated the synthesis and antitumor activities of novel 3,4,5-trisubstituted ATs by measuring the inhibition of the p53–MDM2 interaction [45-47]. After identifying the lead compound MCL0527 (Scheme 4) using a pharmacophore-based virtual screening strategy combined with molecular docking studies, the authors investigated several new series of p53–MDM2 binding inhibitors based on substituted 2-ATs. Some prepared samples displayed appreciably improved MDM2 binding affinities compared with MCL0527 and showed comparable activities to Nutlin-3 (Chart 1). Moreover, several compounds showed at least 3-fold inhibitory selectivity for A549 cells expressing wild-type p53 compared with p53-null PC-3 cells. Three amides (9, 10 and 11, Scheme 4) displayed 22-, 6- and 22-fold selectivity for the p53 status, respectively, which was much better than Nutlin-3 (4-fold). Thioamide derivative 12 (Scheme 4) exhibited the most potent MDM2 binding affinity, with a K_i value of 0.086 µM. In addition, based on the docking models, thioamide derivative 12 mimicked the p53 peptide and interacted with the MDM2 protein, confirming the binding mode of compound 12 with MDM2.