title: The synthesis of 2,5-bis(4-amidinophenyl)thiophene derivatives providing submicromolar-range inhibition of the botulinum neurotoxin serotype A metalloprotease.
abstract: 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).
authors.affiliation: Faculty of Chemistry, University of Belgrade, Studentski trg16, PO Box 51, Belgrade, Serbia.
authors.forename: Igor
authors.initials: I
authors.lastname: Opsenica
authors.forename: Vuk
authors.initials: V
authors.lastname: Filipovic
authors.forename: Jon E
authors.initials: JE
authors.lastname: Nuss
authors.forename: Laura M
authors.initials: LM
authors.lastname: Gomba
authors.forename: Dejan
authors.initials: D
authors.lastname: Opsenica
authors.forename: James C
authors.initials: JC
authors.lastname: Burnett
authors.forename: Rick
authors.initials: R
authors.lastname: Gussio
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Solaja
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
mesh_terms: D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011480:Protease Inhibitors; D013876:Thiophenes; D019274:Botulinum Toxins, Type A