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

Scheme 7.
2.3. Antiviral activity
In 2013, Massari et al. reported a structural investigation of cycloheptathiophene-3-carboxamide derivatives targeting influenza virus polymerase assembly [53]. The previously synthesized 2-(2-fluorobenzamido)-N-(pyridin-3-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (Scheme 8) [54] was able to disrupt the PA−PB1 interaction in vitro, with an IC₅₀ of 90.7 µM, although it exhibited antiviral activity against FluA in infected cells with EC₅₀ values slightly higher than 100 μM. Likewise, its peculiar mechanism of action, coupled with the lack of cytotoxicity (CC₅₀ > 250 μM) evaluated in MDCK and HEK 293T cell lines, made this compound a valid starting point. Therefore, the authors synthesized a series of analogues of this cycloheptathiophene-3-carboxamide for structural optimization study. Among the obtained compound, and the unsubstituted AT 21 and 2-(4-chlorobenzamido) derivative 22 (Scheme 8) emerged as the most potent inhibitors of the physical interaction between the two viral subunits, with IC₅₀ values of 35 and 32 μM, respectively, which were better than the hit compound and comparable to the reference peptide. The antiviral effects of these two potent derivatives were further investigated against a number of clinical isolates of FluA in addition to PR8. PRAs were performed using influenza strains A/Parma/24/09 (H1N1), A/Wisconsin/67/05 (H3N2), and several pandemic swine-originated influenza virus (S-OIV) clinical isolates (H1N1). These derivatives effectively inhibited all FluA strains tested of both H1N1 and H3N2 subtypes, including the oseltamivir-resistant clinical isolate (A/Parma/24/09). Compound 22 was slightly more potent than compound 21, with EC₅₀ values ranging from 15 to 23 μM.
Scheme 8.
2.4. Anti-tubercular activity
2-Amino-5-(4-(2,6-dichlorobenzyloxy)phenyl)thiophene-3-carboxylic acid derivatives were presented as promising anti-tubercular agents by Lu and colleagues in 2011 [55]. The anti-tubercular activity of target samples toward the MTB strain H37Rv (ATCC #27294) and the in vitro cytotoxicity toward VERO cells were evaluated. In general, the four most active compounds (23-26, Scheme 9) showed excellent MICs against clinical MDR-TB and XDR-TB strains. The introduction of a hydroxyl or 4-chlorophenyl group to the amide linker produced an interesting behaviour. For example, compounds 23 and 26 exhibited good activity against XDR-TB strain, with MICs of 12.0 µM and 16.0 µM, respectively, suggesting that this compound class holds promise as lead compounds for the treatment of drug-resistant TB. Moreover, based on preliminary molecular modelling results, the target of this 2-amino-5-(4-(benzyloxy)phenyl)thiophene-3-carboxylic acid series might be associated with mtFabH.