Potent and specific inhibitors of trypanothione reductase from Trypanosoma cruzi

Síntese, avaliação biológica e modelagem molecular de arilfuranos como inibidores da enzima tripanotiona redutase

“…As principais diferenças entre a TR e a GR estão relacionadas ao tamanho, carga e distribuição dos bolsões hidrofílicos/hidrofóbicos. Estas diferenças fazem com que o sítio ativo da TR, em comparação com o da GR, seja capaz de acomodar facilmente substratos apresentando grupos mais volumosos 7 . Além disso, a TR apresenta resíduos carregados negativamente e regiões hidrofóbicas em seu sítio ativo que são capazes de interagir, via interações eletrostáticas e de van der Waals, respectivamente, com seu substrato.…”

Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity

“…Aminodiphenyl sulfides are structurally related to the phenothiazine-based neuroleptics and have been found to retain TR activity while losing the undesired neuroleptic activity displayed in the tricylic compounds. Dimerization and the introduction of additional hydrophobic side chains have been shown to increase the potency of aminodiphenyl sulfides but also to introduce undesirable ADME (absorption, distribution, metabolism, and excretion) properties (20). A number of irreversible inhibitors, such as carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea], ajoene, and various platinum complexes, have been found to be good inhibitors of TR, yet their activity is often nonselective (18,40).…”

Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal–antiplasmodial activity

“…20,46,48,49 In these compounds the presence of a protonatable nitrogen atom seems to be crucial for the TryR inhibitory activity because it mimics the positively charged substrate, trypanothione disulfide. Interestingly, it has been reported that dimerization of several classes of compounds with known TryR inhibitory activity leads to increased potency, [50][51][52] which might be related to the presence of two interacting binding sites in the large active site of TryR. 49 These precedents prompted us to determine whether TryR was a biological target for aminoquinoline-based heterodimers of series I-III.…”