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

Scheme 4.
2.2. Antimicrobial activity
The potential antimicrobial effects of the pyrazolone linker-containing 2-ATs were screened by Aly and co-workers in 2011 [48]. As shown in Scheme 5, the ester fragment of the 4-acetamide pyrazolone interacts in the Gewald reaction by assuming the role of a ketone. Among the prepared hybrids, compounds 13 and 14 (Scheme 5) displayed good activity toward selected microorganisms (A. fumigatus (RCMB 002003), G. candidum (RCMB 052006), C. albicans (RCMB 005002) and S. racemosum (RCMB 005003)) and the inhibitory zones ranged from 16.4-24.3 millimeters (mm).
Scheme 5.
In 2014, Nasr and co-workers presented an in vitro antimicrobial evaluation of the novel hybrid thiophene derivatives [49]. All hybrid thiophenes were generated by reacting sulphisoxazole with 1-cyanoacetyl-3,5-dimethylpyrazole. Notably, the synergistic effect of combining the sulphonamide and biologically active heterocyclic rings in one molecule usually produces promising results in medicinal chemistry. The 2-adamantylamino-thiophene 15 (Scheme 6) exhibited more potent activity against E. coli than gentamycin (Inhibition zone, 29.9 mm vs 19.9 mm and MIC, 0.007 µg/mL vs 1.95 µg/mL) and an equipotent minimal inhibitory concentration toward B. subtilis as ampicillin (MIC, 0.24 µg/mL).
Scheme 6.
Most antifungal compounds contain an azole linker. In 2012, Tani and co-workers investigated several hits using molecular modelling and a screen of a virtual compound database to examine potential non-azole antifungal compounds [50]. The antifungal activity of the hit compounds was tested against S. cerevisiae and C. albicans, and two novel potent non-azole antifungal compounds (16 and 17, Fig. 5) were also identified. These compounds markedly inhibited the growth of C. albicans in the agar plate bioassay, with MIC values of 12 µM and 8 µM, respectively. Analogous to the activation mechanism of aflatoxin B1, the compounds were designed to fit the active site of the yeast CYP51 enzyme and to contain functional groups that would produce reactive intermediates, inducing yeast cell death.
Fig. 5.
Hrast et al. reported a new series of cyanothiophene-based inhibitors of MurF enzymes from various pathogens (S. pneumoniae, E. coli and S. aureus) [51, 52]. All synthesized thiophene derivatives were tested for their inhibitory activities on MurF_Sp, MurF_Ec and MurF_Sa using the Malachite green assay. Based on the two structures (18 and 19, Scheme 7), authors reported information for the future structure-based design of improved inhibitors. This information was important, because most compounds are inactive antibacterial compounds and only a few samples show moderate antibacterial activity toward S. pneumoniae. In general, the benzyl-substituted derivatives with electron-donating groups (EDG) improve the inhibitory activity more than 2_–3-fold compared with benzyl-substituted derivatives with electron-withdrawing groups (EWG) at para or meta positions of the benzyl ring. Another target compound (20, Scheme 7) in which the p-hydroxyphenyl group is attached to the saturated ring inhibits MurF_Sp and MurF_Ec with IC₅₀ values of 20 µM and 25 µM, respectively. Eventually, these thiophene derivatives were thought to be unlikely to be developed into antibacterial drug candidates until the non-specific effect of damaging the bacterial cytoplasmic membrane is diminished without compromising their inhibitory effects on MurF.