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 (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) – 0.889 μM (± 0.11 μM).

New 9-aminoacridine derivatives as inhibitors of Botulinum neurotoxins and P. falciparum malaria

“…N-[2-(1-Adamantyl)ethyl]-N'-(6-chloro-2-methoxyacridin-9-yl)ethane-1,2-diamine (22) Into stirred mixture of 2-(1-adamantyl)acetaldehyde (140 mg, 0.86 mmol) and 12 (260 mg, 0.86 mmol) in abs. EtOH (10 mL), Ti(OPr i ) 4 (381 µL, 1.29 mmol) was added dropwise.…”

Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria

“…19 In general, the most potent BoNT/A LC inhibitors reported to date possess K i values ranging from 0.1 to 10 μM and include hydroxamic acid based compounds 1 and 3 , 20 2,5-diphenylthiophene derivative 2 , 21 betulin derivative 4 , 22 naphthopyrone 5 , 23 and chrysene 6 (24) (Chart 1). …”

4-Amino-7-chloroquinolines: Probing Ligand Efficiency Provides Botulinum Neurotoxin Serotype A Light Chain Inhibitors with Significant Antiprotozoal Activity

“…11 As shown in Figure 2, 1 and 2 occupy pharmacophore zones 2 and 3. We deliberately did not explore increasing the size of the compounds to encompass pharmacophore zone 1 because we have found that compounds designed to occupy all three pharmacophore zones, although resulting in more potent BoNT/A LC inhibitors in vitro , 13 gravitate toward high MW and excessive flexibility 13 – both of which are factors that potentially drive synthetic compounds out of the sphere of druggability. When comparing 1 and 2 in pharmacophore zone 2, it is clear that possessing an N1-(7-chloroquinolin-4-yl)propane-1,3-diamine in this zone results in increased BoNT/A LC inhibition (versus an N1-(7-chloroquinolin-4-yl)ethane-1,2-diamine component ( i.e ., 1 versus 2 , respectively (Figure 2)), with the inclusion of an aliphatic ionizable nitrogen being tantamount for inhibitory activity.…”

“…6,10 As a part of the scientific effort to develop BoNT/A LC countermeasures, 4-amino-7-chloroquinoline (4,7-ACQ)-based compounds have, to date, been identified as some of the most potent, non-Zn 2+ chelating inhibitors of this LC serotype (Figure 1). 11,12,13,28 …”