The synthesis of 2,5-bis(4-amidinophenyl)thiophene derivatives providing submicromolar-range inhibition of the botulinum neurotoxin serotype A metalloprotease

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 (Ki = 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 Ki values ranging from 0.302 μM (±0.03 μM) to 0.889 μM (±0.11 μM).

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► The discovery of a novel BoNT A inhibitor chemotype.
► The synthesis of submicromolar-range derivatives of a novel lead inhibitor.
► Replacing terminal amidines with secondary amines facilitates syntheses.