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Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria
dc.creator | Videnović, Milica | |
dc.creator | Opsenica, Dejan M. | |
dc.creator | Burnett, James C. | |
dc.creator | Gomba, Laura | |
dc.creator | Nuss, Jonathan E. | |
dc.creator | Selaković, Života | |
dc.creator | Konstantinović, Jelena M. | |
dc.creator | Krstić-Ristivojević, Maja | |
dc.creator | Šegan, Sandra B. | |
dc.creator | Zlatović, Mario | |
dc.creator | Sciotti, Richard J. | |
dc.creator | Bavari, Sina | |
dc.creator | Šolaja, Bogdan A. | |
dc.date.accessioned | 2018-11-22T00:28:01Z | |
dc.date.available | 2018-11-22T00:28:01Z | |
dc.date.issued | 2014 | |
dc.identifier.issn | 0022-2623 | |
dc.identifier.uri | https://cherry.chem.bg.ac.rs/handle/123456789/1781 | |
dc.description.abstract | 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 mu M). 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 K-i of compound 67 is 0.10 mu M). 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. | en |
dc.publisher | Amer Chemical Soc, Washington | |
dc.relation | info:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172008/RS// | |
dc.relation | National Cancer Institute, National Institutes of Health (U.S.) [HHSN261200800001E] | |
dc.relation | National Institute of Allergy and Infectious Diseases (U.S.) [5-U01AI082051-02] | |
dc.rights | openAccess | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc/4.0/ | |
dc.source | Journal of Medicinal Chemistry | |
dc.title | Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria | en |
dc.type | article | |
dc.rights.license | BY-NC | |
dcterms.abstract | Опсеница, Дејан М.; Селаковић, Милица; Бурнетт, Јамес Ц.; Константиновић, Јелена; Крстић-Ристивојевић, Маја; Златовић, Марио; Шолаја, Богдан A.; Гомба, Лаура; Нусс, Јонатхан Е.; Сеган, Сандра; Сциотти, Рицхард Ј.; Бавари, Сина; Селаковић, Живота; | |
dc.citation.volume | 57 | |
dc.citation.issue | 10 | |
dc.citation.spage | 4134 | |
dc.citation.epage | 4153 | |
dc.identifier.wos | 000336510100017 | |
dc.identifier.doi | 10.1021/jm500033r | |
dc.citation.other | 57(10): 4134-4153 | |
dc.citation.rank | aM21 | |
dc.identifier.pmid | 24742203 | |
dc.type.version | publishedVersion | |
dc.identifier.scopus | 2-s2.0-84901253130 | |
dc.identifier.fulltext | https://cherry.chem.bg.ac.rs/bitstream/id/8841/1779.pdf |