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

Scheme 16.
In 2016, Elgaher et al. discovered and developed 2-ureidothiophene-3-carboxylic acids as dual bacterial RNAP and HIV-1 RT inhibitors for the treatment of MRSA/HIV-1 co-infections [65]. Using structure-based optimization, the authors identified the privileged structure for RT inhibition by screening four regioisomeric classes of “switch region”-binding RNAP inhibitors and then explored the steric volume allowed in the NNRTI binding pocket by enlarging the bulkiness of the ureido moiety. SAR studies revealed the importance of non-bulky hydrophilic substituents at the ureido side chain for RT inhibition. The new modifications improved the activity up to 12-fold (compound 49, Scheme 17). The RT inhibitory activity of compound 49 is comparable to NVP and significantly higher than AZT-TP. Thus, an inspection of the substituent constants and molecular properties of the new compounds revealed that hydrophilic and hydrogen bond donor/acceptor substituents at the N-phenyl group are important for activity. In addition, novel RNAP/RT inhibitors displayed high potency against S. aureus and high cellular antiretroviral activity, accompanied by marginal or no cytotoxicity.
Scheme 17.
2.8. 2-ATs as allosteric modulators of A₁, A₁, A_2A and A₃ adenosine receptors
2-ATs have been reported to act as allosteric modulators of A₁AR [66-68]. The pharmacological properties of 2-Amino-4,5-dimethylthien-3-yl)-[3-(trifluoromethyl)phenyl]-methanone (PD 81,723, Fig. 2) were studied and this compound was recognized as the first specific and selective AEs of the A₁AR among the library of 2-ATs. Subsequently, in 2012, Romagnoli et al. investigated 2-amino-3-aroyl-4-[(4-arylpiperazin-1-yl)methyl]thiophenes as potent AEs of the A₁AR and studied the structural modification of the phenyl piperazine moiety at the 4-position of the 2-amino-3-(4-chlorobenzoyl)-thiophene scaffold by synthesizing a wide series of compounds with one or more electron-withdrawing substituents in all five positions of the phenyl ring linked to the piperazine moiety [69]. In general, among the more than forty novel synthesized samples, only nine compounds showed AE activity less than PD 81,723, seven derivatives showed activity at least as high as PD 81,723 and approximately thirty analogues exhibited substantially higher activity. Compounds such as 3,4-difluoro, 3-chloro, 4-fluoro, and 4-(trifluoromethoxy) derivatives (50-52, Fig. 7) were the most active compounds in binding (saturation and competition experiments) and functional cAMP studies.
One year later, the same group [70] again confirmed that among the series of 2-amino-3-aroyl thiophenes, the tetrahydropyrazino[1,2-a]indole nucleus of conformationally constrained arylpiperazine analogues (in this case, compounds 53 and 54, Fig. 7) appeared to be significantly more active than PD 81,723 in the functional assay. Furthermore, the A₁AR was hypothesized to contain an allosteric binding site that is able to accommodate the phenylpiperazine moiety, and appropriate substituents on the phenyl ring influence this interaction and contribute importantly to increase AE activity. Likewise, the same group [71] reported other active AEs for the A₁AR by refining the SAR around this class of compounds through the synthesis and biological evaluation of a new series of 2-amino-3-(4-chlorobenzoyl)-4-[(arylpiperazinyl)methyl]-thiophene derivatives, which are characterized by the insertion of methyl, ethyl, bromine, and aryl moieties at the 5-position. In this case, several derivatives (55-57, Fig. 7) were the most active compounds in binding and functional cAMP assays. In competition binding experiments, the K_i values for CCPA in the presence of these samples were decreased approximately 13.3-, 10.5-, and 13.0-fold, respectively, and these compounds were almost 2-fold more active at 10 μM than their 5-H-substituted or 5-unsubstituted (2-amino-3-aroyl-4-[(4-arylpiperazin-1-yl)methyl]thiophenes) derivatives.
In 2014 and 2015, Romagnoli et al. [72-74] again presented another novel series of 2-amino-3-benzoyl-4-neopentyl thiophene derivatives as AEs for the A₁AR. If we compare this report with previous investigations, small differences and advances included the presence of a neopentyl at the 4-position and a heteroaryl or variably substituted phenyl group at the 5-position of 2-amino-3-aroyl-thiophene skeleton, which represent the best combination to yield a series of compounds with improved AE activity (compounds 58-62, Fig. 7). After optimization and a position-dependent effect study, the presence of EDGs or EWGs on the phenyl ring at the 4- and 5-positions of the thiophene ring produced positive AEs for the A₁AR in the binding and functional assays (compounds 63-67, Fig. 7). In general, instead of the neopentyl fragment at the 4-position, the regioisomeric substituted or unsubstituted benzyl fragments were selected as lead compounds in this study.
Fig. 7.
Allosteric ligand activities of 2-aminocycloalkyl[b]thiophenes were investigated by Aurelio et al. in 2011 [75]. The ability of the novel series of ATs to act as allosteric modulators of the A₁AR was screened using a plate-based assay of A₁-AR-mediated ERK1/2 phosphorylation (pERK1/2) in intact CHO cells. Two concentrations of all target 2-ATs were investigate to evaluate intrinsic agonism, the EC₅₀ concentration of the orthosteric agonist R-PIA, and enhancement or inhibition of the A1-AR agonist activity, and derivatives 68-70 (Scheme 18) functioned as strong allosteric agonists among the synthesized 2-ATs. Notably, the authors tried to increase size of the 2-AT core at the expense of the number methylene groups in the cycloalkane ring to improve their bio-attributes. However, neither the type of substituent on the 3-benzoyl group nor the size of the cycloalkyl ring are required to engender affinity for the allosteric site, but rather these modifications influence the cooperative effects of these compounds on R-PIA.