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

Scheme 9.
In 2014, Samala et al. reported the synthesis and anti-tubercular properties of 2,6-disubstituted 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamides using inhibition of MTB PS; in this case, in vitro activities against MTB and cytotoxicity toward the RAW 264.7 cell line were evaluated [56]. The compound 6-(4-nitrophenylsulfonyl)-2-(5-nitrothiophene-2-carboxamido)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (27, Scheme 10) was the most active compound, with an IC₅₀ of 5.87 µM against MTB PS, it inhibited MTB with an MIC of 9.28 µM and it was non-cytotoxic at 50 µM when tested against RAW 264.7 cells in vitro.
Scheme 10.
One year later, the same authors [57] used the crystal structure of the MTB L-AlaDH protein in complex with N₆-methyl adenosine for a structure-based virtual screen of an in house database to identify new small molecule (in this case, 2,6-disubstituted 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamides) inhibitors for MTB-L-AlaDH. Derivatives 28 and 29 (Fig. 6) displayed better activity (IC₅₀ of 0.58 and 0.64 µM, respectively) when phenyl or butoxy groups were inserted into the amide liner at position 6. In addition, DSF experiments were used to explore the thermal stability and binding affinity of the most active compounds from these series for the MTB L-AlaDH protein.
Fig. 6.
2.5. Anti-parasitic activity
2.5.1. Antimalarial activity
P. falciparum is the causative agent of the most deadly form of human malaria, and in this case, it only relies on de novo biosynthesis for survival. As shown in the 2010 study by Booker and co-workers, treatment of infected mice in the acute P. berghei efficacy model with N-cyclopropyl-5-(2-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)thiophene-2-carboxamide (30, Scheme 11) resulted in a sterile cure. Likewise, in vitro activity ADME dates (11% free fraction of drug in human plasma, no P450 inhibition IC₅₀ >10 μM, hERG IC₅₀ of 53 μM) for 5-(4-cyano-2-methyl- analogue (31, Scheme 11) were presented [58]. One year later, Skerlj and colleagues [59] optimized this research and reported that the efficacy of compound 31 was evaluated by PO dosing in two additional mouse models of malaria: the P. berghei ANKA and P. falciparum 3D7^0087/N9 models. The ED₅₀, ED₉₀, and ED₉₉ values ranged from 13 to 62 mg/kg/day, revealing the predicted potency. Based on these results and the favourable drug-like properties, 2-N-benzoimidazole- and 5-propanamide-containing thiophene 31 has been chosen as a potential drug development candidate for the treatment of malaria.