Significantly
more potent second generation 4-amino-7-chloroquinoline
(4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A
(BoNT/A) light chain were synthesized. Introducing an amino group
at the C(3) position of the cholate component markedly increased potency
(IC50 values for such derivatives ranged from 0.81 to 2.27
μM). Two additional subclasses were prepared: bis(steroidal)-4,7-ACQ
derivatives and bis(4,7-ACQ)cholate derivatives; both classes provided
inhibitors with nanomolar-range potencies (e.g., the Ki of compound 67 is 0.10 μM). During
BoNT/A challenge using primary neurons, select derivatives protected
SNAP-25 by up to 89%. Docking simulations were performed to rationalize
the compounds’ in vitro potencies. In addition to specific
residue contacts, coordination of the enzyme’s catalytic zinc
and expulsion of the enzyme’s catalytic water were a consistent
theme. With respect to antimalarial activity, the compounds provided
better IC90 activities against chloroquine resistant (CQR)
malaria than CQ, and seven compounds were more active than mefloquine
against CQR strain W2.
Ebola (EBOV) and Marburg (MARV) filoviruses are highly infectious pathogens causing deadly hemorrhagic fever in humans and non-human primates. Promising vaccine candidates providing immunity against filoviruses have been reported. However, the sporadic nature and swift progression of filovirus disease underlines the need for the development of small molecule therapeutics providing immediate antiviral effects. Herein we describe a brief structural exploration of two previously reported diazachrysene (DAAC)-based EBOV inhibitors. Specifically, three analogs were prepared to examine how slight substituent modifications would affect inhibitory efficacy and inhibitor-mediated toxicity during not only EBOV, but also MARV cellular infection. Of the three analogs, one was highly efficacious, providing IC50 values of 0.696 µM ± 0.13 µM and 2.76 µM ± 0.21 µM against EBOV and MARV infection, respectively, with little or no associated cellular toxicity. Overall, the structure-activity and structure-toxicity results from this study provide a framework for the future development of DAAC-based filovirus inhibitors that will be both active and non-toxic in vivo.
Herein we report on a diazachrysene class of small molecules that exhibit potent antiviral activity against the Ebola (EBOV) virus. The antiviral compounds are easily synthesized, and the most active compounds have excellent in vitro activity (0.34-0.70 μM) and are significantly less lipophilic than their predecessors. The three most potent diazachrysene antivirals do not exhibit any toxicity in vivo and protected 70-90% of the mice at 10 mg/kg following EBOV challenge. Together, these studies suggest that diazachrysenes are a promising class of compounds for hit to lead optimization and as potential Ebola therapeutics.
An efficient one‐pot, two step method for fusing two biologically active motifs, CF3‐substituted pyrazoles and isochromenes, was developed. Selective O‐benzylation of CF3‐substituted pyrazolones and subsequent Pd‐catalyzed direct C–H arylation generate a fused tricycle. For the synthesized compounds through‐space 13C–19F spin–spin coupling was revealed. In addition, the synthesis of three thioisochromene analogues, and one isocoumarin derivative, was accomplished.
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