A chemotype that inhibits three unrelated pathogenic targets: the botulinum neurotoxin serotype A light chain, P. falciparum malaria, and the Ebola filovirus
Articolo
Data di Pubblicazione:
2011
Citazione:
A chemotype that inhibits three unrelated pathogenic targets: the botulinum neurotoxin serotype A light chain, P. falciparum malaria, and the Ebola filovirus / I. Opsenica, J.C. Burnett, R. Gussio, D. Opsenica, N. Todorović, C.A. Lanteri, R.J. Sciotti, M. Gettayacamin, N. Basilico, D. Taramelli, J.E. Nuss, L. Wanner, R.G. Panchal, B.A. Solaja, S. Bavari. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 54:5(2011 Mar), pp. 1157-1169. [10.1021/jm100938u]
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
in-vitro; antimalarial-drugs; proteolytic activity; virus; chloroquine; toxin; 4-aminoquinoline; metalloprotease; pharmacophore; mechanisms
Elenco autori:
I. Opsenica, J.C. Burnett, R. Gussio, D. Opsenica, N. Todorović, C.A. Lanteri, R.J. Sciotti, M. Gettayacamin, N. Basilico, D. Taramelli, J.E. Nuss, L. Wanner, R.G. Panchal, B.A. Solaja, S. Bavari
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