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

Scheme 15.
2.7. Multi-target investigation of the anticancer, antimicrobial, antiviral and anti-diabetic activities of 2-ATs
Recently, our group studied the multi-target biological properties of the novel Schiff bases, based on 2,5-diaminothiophene-3,4-dicarboxylate (DDTD) [16]. First, all synthesized compounds were screened for anticancer and antimicrobial activities in vitro. The Schiff base containing the 5-nitro furfuryl fragment (47, Scheme 16) showed potent activity toward three cancer cell lines (T47D, MCF-7, and Hela), and the IC₅₀ values were considerably lower than the positive control doxorubicin. These compounds also exhibited the greatest inhibitory effects on three species of microbial pathogens (S. aureus ATCC 6538, E. coli ATCC 11229 and C. albicans ATCC 10231). Likewise, we also determined the inhibitory effects of the corresponding compounds on the enzyme PTP-1B in vitro. Several compounds, including compound 47 (7.12 µM), inhibited the PTP-1B enzyme in a concentration-dependent manner. Furthermore, in a continuation of our research on DDTD, we investigated the antiproliferative activities of novel Schiff bases (mainly selected aldehydes with di- and poly-substituents at the aromatic portion) and mono- and bis-amides of DDTD in cancer cell lines (PC-3, A549, HCT-15 and T47D cells, which are considered appropriate and relevant cell models in drug discovery), and the most active samples were selected for a selectivity screen using normal human embryonic kidney (HEK-293) cells and an evaluation of their antiviral properties against influenza A and B viruses [17]. Interestingly, the best result was obtained with derivative 48 (Scheme 16). By inserting a 5-nitro-2-thienyl fragment in DDTD core, compound 48 exhibited excellent inhibitory effects on all tumour cell lines, which resulted in high antiproliferative activity. Moreover, the SARs of selected compounds in inhibiting influenza A and B viruses suggest that the introduction of diverse pharmacophore substituents, such as nitro-furfuryl and fluorine, significantly increased the inhibitory activity. Notably, building blocks such as DDTD may represent the best synthon for the production of a symmetrical thienopyrimidin-di-one scaffold.