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

Scheme 11.
2.5.2. Anti-T. cruzi activity
The synthesis of novel thiophene-thiazolidine hybrid derivatives bearing various groups at the thiazolidine ring was presented by Silva-Júnior et al. in 2016 [60]. All prepared hybrids containing an imine linker between the thiophene and thiazolidine rings were tested for their ability to inhibit the in vitro growth of amastigote and trypomastigote forms of T. cruzi and the activity of the enzyme cruzain. Thiophene-thiourea hybrid 32 and thiophene-thiazolidine hybrids 33-35 (Scheme 12) were the most active derivatives against the amastigote form, with significant IC₅₀ values ranging from 9.7 to 6.03 μM. A specific combination of groups, such as ethyl at R and allyl at R1, leads to lower activity. Therefore, these chemical groups are considered as unfavourable in relation to activity against these evolutionary forms. Additionally, the combination of an i-propyl group at R and phenyl group at R1 seems to be the best combination and increased the activity. This increased activity is related to the hydrophobicity of the compounds, which increases the activity toward evolutionary forms of the T. cruzi parasite. However, compound 35, which contains an allyl group at R1 (unfavourable), showed a similar IC₅₀ value to compound 32.
Scheme 12.
2.5.3. Antileishmanial activity
Rodrigues, Félix and colleagues investigated the antileishmanial activity of new hybrid compounds containing a combination of 2-AT and indole cores in 2015 and 2016, respectively [61, 62]. Antileishmanial activity is mediated by apoptosis and immunomodulatory activity against L. amazonensis promastigote and axenic amastigote forms in vitro. In addition, the authors studied the cytotoxicity of the prepared samples toward blood cells. The effects of the selected compounds 36-38 (Scheme 13) on the promastigote forms are associated with apoptosis involving phosphatidylserine externalization and DNA fragmentation, accompanied by secondary necrotic cell death. These three compounds are also effective against macrophage infection, and the anti-amastigote activities of compounds 36 and 38 are associated with the modulation of the host immune response. Another 2-N-substituted thiophene derivative, 2-[(1H-indol-3-ilmethylene)-amino]-4,5,6,7,8,9-hexahydro-cycloocta[b]thiophene-3-carbonitrile, exhibits a promising result (39, Scheme 13), with an IC₅₀ value of 2.1 µg/mL, and thus compound 39 was logically selected for subsequent studies. Promastigotes treated with compound 39 exhibited DNA fragmentation, and samples exposed to 1×, 2×, and 4× the IC₅₀ showed DNA bands that were fragmented in three portions compared to the control. Furthermore, an increase in the intensity of the last band was observed with increasing drug concentrations, suggesting a higher fragmentation rate in promastigotes treated with a concentration four times the IC₅₀.