RESUMO
Botulinum neurotoxins (BoNTs), composed of a family of seven serotypes (categorized A-G), are the deadliest of known biological toxins. The activity of the metalloprotease, light chain (LC) component of the toxins is responsible for causing the life-threatening paralysis associated with the disease botulism. Herein we report significantly more potent analogs of novel, lead BoNT serotype A LC inhibitor 2,5-bis(4-amidinophenyl)thiophene (K(i) = 10.88 µM ± 0.90 µM). Specifically, synthetic modifications involved simultaneously replacing the lead inhibitor's terminal bis-amidines with secondary amines and the systematic tethering of 4-amino-7-chloroquinoline substituents to provide derivatives with K(i) values ranging from 0.302 µM (± 0.03 µM) to 0.889µM (± 0.11 µM).
Assuntos
Toxinas Botulínicas Tipo A/antagonistas & inibidores , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Tiofenos/síntese química , Tiofenos/farmacologia , Toxinas Botulínicas Tipo A/química , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Inibidores de Proteases/química , Tiofenos/químicaRESUMO
We report on the initial result of the coupling of 4-amino-7-chloroquinoline with steroidal and adamantane constituents to provide small molecules with excellent in vitro antimalarial activities (IC90 (W2) down to 6.74 nM). The same entities also inhibit the botulinum neurotoxin serotype A light chain metalloprotease at low micromolar levels (7-31 microM). Interestingly, structural features imparting increased antimalarial activity also provide increased metalloprotease inhibition, thus allowing for simultaneous compound optimizations against distinct targets.