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

Keywords: 2-aminothiophene, inhibitor, receptor, modulator, in vitro, in vivo, drugs

Contents
1. Introduction
2. Biological and pharmacological properties of 2-ATs
2.1. Anticancer activity
2.2. Antimicrobial activity
2.3. Antiviral activity
2.4. Anti-tubercular activity
2.5. Anti-parasitic activity
2.5.1. Antimalarial activity
2.5.2. Anti-T. cruzi activity
2.5.3. Antileishmanial activity
2.5.4. Multi-target investigation of the anti-parasitic activities (antimalarial, anti-T. cruzi, antileishmanial and anti-T. brucei brucei activities) of 2-ATs
2.6. 2-ATs PTP1B inhibitors
2.7. Multi-target investigation of the anticancer, antimicrobial, antiviral and anti-diabetic activities of 2-ATs
2.8. 2-ATs as allosteric modulators of A₁, A₁, A_2A and A₃ adenosine receptors
2.9. 2-ATs as SARMs
2.10. 2-ATs as allosteric EP2 receptor potentiators
2.11. 2-ATs as retinoid X receptor α agonists
2.12. 2-ATs as tau fibrillization inhibitors
2.13. Effect on the GABA_B receptor
2.14. Anticonvulsant activity
2.15. 2-ATs as positive AMPA receptor modulators
2.16. 2-ATs as negative NMDA receptor modulators
2.17. 2-ATs as JNK inhibitors
2.18. 2-ATs as JAK2 inhibitors
2.19. 2-ATs as p38 kinase inhibitors
2.20. 2-ATs as aPKC inhibitors
2.21. 2-ATs as IKK-β inhibitors
2.22. Effect on the diphenolase activity of mushroom tyrosinases
2.23. 2-ATs as CB2 receptor ligand
2.24. Antagonistic activity
2.25. 2-ATs as PDE4 inhibitors
2.26. Inhibitory effects on Fas
2.27. 2-ATs as dyes
3. Conclusions
Acknowledgments
Abbreviations
References

1. Introduction
Over the past few years, leading small molecule compounds have become attractive to researchers studying multiple aspects of medicinal chemistry due to their excellent properties [1, 2]. 2-Aminothiophenes (2-ATs) are five-membered small molecule heterocycles, for which various synthesis pathway (Fig. 1) were suggested by Gewald in the 1960s [3-5]. Other scientists have developed diverse methods for optimizing the Gewald reaction to derive their substituted analogues [6-14].
Fig. 1.
2-ATs are used as building blocks and synthons in organic synthesis. Currently, 2-AT analogues (e.g., 2-N-substituted thiophenes) attract special attention because of their diverse biological and pharmacological attributes. Among the known biological functions of 2-ATs, we can enumerate anticancer [15-17], antiviral [17, 18], antimicrobial [16, 19-22], and anti-tubercular activities [23, 24], as well as allosteric ligands for the adenosine A₁ receptors (e.g., PD 81,723, Fig. 2) [25, 26], kinase inhibitors (e.g., 2-TCU, Fig. 2) [27], antioxidants [28, 29] and various positive effects on neurological disorders (e.g., ATPZ 15, Fig. 2) [30]. A large number of thiophene- or aminothiophene-containing drugs (e.g., Zyprexa, Fig. 2) [31] and discovered drug candidates that have shown promising pharmacological effects in initial pre-clinical trials [32] have again justified positive perspectives of the 2-AT scaffold; therefore, 2-AT fragment-derived compounds remain an active area of research and clinical development.
Fig. 2.
The chemistry of the 2-ATs and their 2-N-substituted derivatives has been reported in several reviews [33-36]; however, no reviews have solely focused on their pharmacological applications, advances in medicinal chemistry and perspectives, although attention and inquiries into 2-ATs have greatly increased in the last few decades (Fig. 3) [37].
Fig. 3.
Thus, these important features of 2-ATs attracted our attention and we aim to discuss recent advances in this small molecule scaffold. Likewise, over the past few years, our scientific group has investigated the base 2-ATs and its cyclic derivatives, such as bioactive thieno[2,3-d]pyrimidines [38]. In this review, we will discuss and summarize major reports of the biological and pharmacological functions of 2-ATs and related compounds, together their possible synthetic pathways.