Synthesis and Biological Evaluation of Botulinum Neurotoxin A Protease Inhibitors

Abstract

NSC 240898 was previously identified as a botulinum neurotoxin A light chain (BoNT/A LC) endopeptidase inhibitor by screening the National Cancer Institute Open Repository diversity set. Two types of analogs have been synthesized and shown to inhibit BoNT/A LC in a FRET-based enzyme assay, with confirmation in an HPLC-based assay. These two series of compounds have also been evaluated for inhibition of anthrax lethal factor (LF), an unrelated metalloprotease, to examine enzyme specificity of the BoNT/A LC inhibition. The most potent inhibitor against BoNT/A LC in these two series is compound 12 (IC 50 = 2.5 µM, FRET assay), which is 4.4-fold more potent than the lead structure, and 11.2-fold more selective for BoNT/A LC versus the anthrax LF metalloproteinase. Structure-activity relationship studies have revealed structural features important to potency and enzyme specificity.

Potent and broad-spectrum antibacterial activity of indole-based bisamidine antibiotics: Synthesis and SAR of novel analogs of MBX 1066 and MBX 1090

“…The Castro indole synthesis 22 (Path C) was considered, but the construction of acetylenic substrate 8 could not be accomplished under Sonogashira conditions 23,24 with the corresponding 4-bromo-3-nitrobenzonitrile. Although we could use Suzuki coupling reactions 25 (Path D) to join two preformed indole moieties to 1,4-dibromobenzene, 26,27 we expected the yield would be low due to deboronylation of the α-heteroatom boronic acid, 28 and the requisite boronic acid was expensive.…”

Development of a Comprehensive, Validated Pharmacophore Hypothesis for Anthrax Toxin Lethal Factor (LF) Inhibitors Using Genetic Algorithms, Pareto Scoring, and Structural Biology

“…6, 9, 14–31, 33–35 Each compound was individually sketched in MOE 2010.10 (Chemical Computing Group, Inc.) and was geometry optimized using the MMFF94s force field 68, 69 , applying a convergence criterion of 0.05 kcal/mol•Å. DB1 was divided into six total subsets, including training and test sets for nanomolar-level compounds, as described earlier.…”

Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E: Structure–activity relationship and a pharmacophore model

“…[12][13][14][15][16] Since the symptoms of botulism appear only after the toxin has been internalized by the neurons, and has started disrupting the SNARE complex, the endopeptidase activity of the catalytic domain is an ideal drug target. Towards this goal, a number of substrate-based peptide inhibitors [17][18][19][20][21][22][23] as well as small molecule non-peptide inhibitors [24][25][26][27][28][29][30][31][32] have been identified against BoNT/A. Similarly, a few inhibitors targeting BoNT/B have also been identified.…”