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

Scheme 34.
2.26. Inhibitory effects on Fas
In 2013, Jung and colleagues [101] developed pharmacophore and 3D-QSAR models for several selected heterocycles, including three thiophene-3-carboxaletes (97-99, Fig. 11), as inhibitors of Fas-mediated cell death pathways. The predictive power of the synthesized compounds was 0.96 for the pharmacophore model, 0.58 for the comparative molecular field analysis (CoMFA) model, and 0.57 for the comparative molecular similarity analysis (CoMSIA) model. The pharmacophore model displayed good correspondence with experimental results and coherently explained the variance in biological activities with respect to the structure of the compounds.
Fig. 11.
2.27. 2-ATs as dyes
The synthesis and spectroscopic evaluation of representative self-calibrating dyes based on 2-N-substituted thiophenes was presented by Dakanali et al. in 2012 [102]. Modifications of the linker between the molecular rotor and the coumarin do not significantly affect the fluorescence profile of these dyes. 2-N-substituted thiophenes 100 and 101 (Fig. 12) show influential properties. For instance, the hydrophilic dye 100 is homogeneously distribution inside the cell and represents a suitable probe for viscosity measurements in the cytoplasm and hydrophobic dye 101 behaves as a membrane dye to some extent, although it also crosses the cell membrane and likely binds to intracellular proteins, from where additional fluorescence is derived.
Fig. 12.
3. Conclusions
In this review, we summarized recent advances in the use of 2-ATs and related compounds in medicinal chemistry. Likewise, we have focused on more promising 2-ATs through “hit to lead” approaches. In addition to their use as building blocks and synthons, 2-ATs are candidate protein/enzyme inhibitors (various kinase families), modulators of receptors involved in neurological disorders, perspective tools for molecular and cellular pharmacology (antimicrobial, antiviral and anticancer agents) and treatments for parasitic diseases. We postulate that further combinatorial investigations of 2-ATs based on SARs and HTS, as well as “hit to lead” optimization are needed to obtain optimum results in pre-clinical and clinical studies. This review shows that most of the promising results has been obtained in tandem 2-ATs (conjugates or hybrids), therefore further developments of the novel 2-AT-related conjugates seems more interesting direction. Moreover, some physical properties of 2-AT derivatives were not satisfactory studied, particularly their water solubility, which may hamper pre-clinical investigations. However, a large number of developments and structural modifications of 2-AT scaffolds by pharmacologists will likely resolve these challenges. Thus, based on the most recent reports, we believe that the chemistry and biology of 2-AT scaffolds will flourish.