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

Scheme 18.
In 2015, Pandya and colleagues reported novel thiazole–thiophene conjugates as adenosine receptor antagonists [76]. Several synthesized conjugates interacted with the A₁, A_2A and A₃ adenosine receptor subtypes with good affinity values; however, among these conjugates, compound 71 (Scheme 19) showed an A3 K_i value of 0.33 µM, with selectivity ratios of >90 for the A₁ subtype and >30 for the A₂ subtype. According to the docking studies, compound 71 interacts with the amino acid ASN250 through hydrogen bonding, which is reported to be responsible for antagonist interaction. For example, in the most potent molecule 71, the carbonyl oxygen of the CONH₂ group present on the 3-position of the thiophene ring interacts with a hydrogen of the ASN250 amido group. The carbonyl oxygen of the amide linker present between the thiazole and thiophene participates in three interactions, namely with the second amido hydrogen of ASN250 and with the two amido hydrogens of GLN167.
Scheme 19.
2.9. 2-ATs as SARMs
SARMs display activity in the brain and are capable of simultaneously improving the symptoms of various diseases, including osteoporosis, sarcopenia, and neural-based cognitive diseases, such as Alzheimer’s disease. In 2013, Akita and co-workers presented the pharmacological effects of 3-bromo-5-[(propyl) (2,2,2-trifluoroethyl)amino]thiophene-2-carbonitrile (72 (NEP28), Scheme 20) as a non-steroidal SARM with highly effective activity on muscle and brain and a safer pharmacological effect on prostate growth than 5α-dihydrotestosterone or methyltestosterone [77]. Compound 72 increased the activity of neprilysin, a known Aβ-degrading enzyme. Thus, the combination of androgen therapy with SARMs might be a very promising treatment for not only diseases that are mainly targeted by current androgen therapy but also neural diseases. Compound 72 is synthesized when 3-bromo-5-(propylamino)thiophene-2-carbonitrile reacts with trifluoroacetic acid and sodium borohydride in substitution/reduction reaction.