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

Scheme 13.
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
In 2016, Bosc et al. reported the synthesis and biological evaluation of the novel imidazole-containing thiophenes against human and parasite farnesyltransferases, and their anti-parasitic activities were enhanced after the introduction of an N-benzylimidazole moiety on target inhibitors [63]. Based on an in vitro evaluation, compounds 40 and 41 (Scheme 14) displayed excellent inhibitory effects on recombinant human and T. brucei brucei FTases, with IC₅₀ values of 10 and 13 nM, respectively. In a subsequent investigation, all novel derivatives were evaluated to determine inhibitory activities on the growth of four protozoan parasites: the intraerythrocytic stage of P. falciparum (responsible for malaria), the bloodstream form of T. brucei brucei (the pathogenic agent of African sleeping sickness in cattle), the intracellular development of T. cruzi amastigotes (responsible for Chagas disease) and the intra-macrophage development of L. donovani amastigotes (the causative agent of visceral leishmaniasis). The best result of this study was the high activity of compound 40 toward T. cruzi, displaying a 30-fold increase in activity compared to the reference compound benznidazole on the Tulahuen strain and the same activity as nifurtimox on the Y strain. In addition, compound 42 (Scheme 14), which bears a Boc protecting group on the 2-C-N side of the thiophene ring, also was exhibited good activities toward all four parasites.
Scheme 14.
2.6. 2-ATs PTP1B inhibitors
A novel 2-N-amido-thiophene derivative were presented as a selective PTP1B inhibitor with cellular activity by Ye et al. in 2010 [64]. After measuring the percentage inhibitory rates of all prepared samples at concentrations of 100 and 10 µM, compounds with good inhibition rates (>50% at 10 µM) were selected for a further determination of the IC₅₀ values. Compound 43 displayed the highest activity (IC₅₀= 2.1 µM) among the prepared thiophene analogues, with 15-fold higher activity than the hit compound 2-[(3-carboxy-bicyclo[2,2,1]heptane-2-carbonyl)-amino]-4-naphthalen-2-yl-thiophene-3-carboxylic acid isopropyl ester. In addition, the authors studied the selectivity of four representative compounds (43-46, Scheme 15) toward other protein tyrosine phosphatases (TC PTP, CD45, PTPa, and LAR), and these selected samples displayed excellent selectivity for PTPa and LAR (>10-fold) and moderate selectivity for CD45 (3–5-fold). Notably, derivative 44, which contains a carboxyl substituent at the adamantyl ring, exhibited greater than 6-fold selectivity over TC PTP. Further studies on cellular activities revealed that compound 43 containing carboxyl substituent at phenyl ring was membrane-permeable and exerted extensive cellular effects on the activation of PI3K/AKT pathway in CHO-K1 cells.