Title |
A Chemotype That Inhibits Three Unrelated Pathogenic Targets: The Botulinum Neurotoxin Serotype A Light Chain, P. falciparum Malaria, and the Ebola Filovirus
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Published in |
Journal of Medicinal Chemistry, January 2011
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DOI | 10.1021/jm100938u |
Pubmed ID | |
Authors |
Igor Opsenica, James C. Burnett, Rick Gussio, Dejan Opsenica, Nina Todorović, Charlotte A. Lanteri, Richard J. Sciotti, Montip Gettayacamin, Nicoletta Basilico, Donatella Taramelli, Jonathan E. Nuss, Laura Wanner, Rekha G. Panchal, Bogdan A. Šolaja, Sina Bavari |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 1 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 2 | 3% |
United States | 1 | 1% |
Netherlands | 1 | 1% |
Pakistan | 1 | 1% |
Unknown | 65 | 93% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 17 | 24% |
Student > Ph. D. Student | 11 | 16% |
Other | 7 | 10% |
Professor | 5 | 7% |
Student > Bachelor | 4 | 6% |
Other | 14 | 20% |
Unknown | 12 | 17% |
Readers by discipline | Count | As % |
---|---|---|
Chemistry | 18 | 26% |
Agricultural and Biological Sciences | 17 | 24% |
Medicine and Dentistry | 7 | 10% |
Immunology and Microbiology | 4 | 6% |
Nursing and Health Professions | 3 | 4% |
Other | 8 | 11% |
Unknown | 13 | 19% |