A Chemotype That Inhibits Three Unrelated Pathogenic Targets: The Botulinum Neurotoxin Serotype A Light Chain, P. falciparum Malaria, and the Ebola Filovirus

Abstract

A 1,7-bis(alkylamino)diazachrysene-based small molecule was previously identified as an inhibitor of the botulinum neurotoxin serotype A light chain metalloprotease. Subsequently, a variety of derivatives of this chemotype were synthesized to develop structure-activity relationships, and all are inhibitors of the BoNT/A LC. Three-dimensional analyses indicated that half of the originally discovered 1,7-DAAC structure superimposed well with 4-amino-7-chloroquinoline-based antimalarial agents. This observation led to the discovery that several of the 1,7-DAAC derivatives are potent in vitro inhibitors of Plasmodium falciparum, and in general, are more efficacious against CQ-resistant strains than against CQ-susceptible strains. In addition, by inhibiting β-hematin formation, the most efficacious 1,7-DAAC-based antimalarials employ a mechanism of action analogous to that of 4,7-ACQ-based antimalarials, and are well tolerated by normal cells. One candidate was also effective when administered orally in a rodent-based malaria model. Finally, the 1,7-DAAC-based derivatives were examined for Ebola filovirus inhibition in an assay employing Vero76 cells, and three provided promising antiviral activities and acceptably low toxicities.

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

“…24 Under both treatments mice died on day 13 postinfection. All mice died of malaria, and no signs of tissue damage caused by compound toxicity were observed upon necropsy.…”

“…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). …”

Ebola Virus Potential Drug Targets and Prospects for Small Molecule Drug Discovery

“…In animal model of EBOV, FGI-106 provided protection from lethal infection when administered IP as a prophylactic (2 h before and then 2 days and 5 days after infection) or therapeutic agent (1, 2 or 3 days after infection) (Aman et al, 2009). Many other 1,7-DAAC derivatives (23) were synthesized and tested for activity against Ebola virus in a cell-based assay (Opsenica and Burnett, 2011). Most of these compounds were toxic at 20 M and only three of the compounds showed potent antiviral activity (96-100% in vitro viral inhibition) with toxicity < 20% at 20 M (Opsenica and Burnett, 2011).…”

“…Many other 1,7-DAAC derivatives (23) were synthesized and tested for activity against Ebola virus in a cell-based assay (Opsenica and Burnett, 2011). Most of these compounds were toxic at 20 M and only three of the compounds showed potent antiviral activity (96-100% in vitro viral inhibition) with toxicity < 20% at 20 M (Opsenica and Burnett, 2011). In another study, a limited structureactivity and structure-toxicity relationship studies on 1,7-DAAC analogs indicated that structural modifications may result in increased antiviral activity and decreased toxicity (Selaković et al, 2012).…”

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

“…We have previously reported the discovery of a variety of non-Zn 2+ chelating BoNT/A LC lead inhibitor chemotypes [10–15], many of which possess terminal di-cationic moieties [11–14]. With respect to di-cationic inhibitors, the synthesis of more potent derivatives of leads possessing bis-amidine and bis-imidazoline functional groups has been described [16–19].…”