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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 \u03bcM). 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 \u03bcM). During BoNT\/A challenge using primary neurons, select derivatives protected SNAP-25 by up to 89%. Docking simulations were performed to rationalize the compounds\u2019 in vitro potencies. In addition to specific residue contacts, coordination of the enzyme\u2019s catalytic zinc and expulsion of the enzyme\u2019s 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.<\/jats:p>","DOI":"10.1021\/jm500033r","type":"journal-article","created":{"date-parts":[[2014,4,17]],"date-time":"2014-04-17T16:05:19Z","timestamp":1397750719000},"page":"4134-4153","source":"Crossref","is-referenced-by-count":28,"title":["Second Generation Steroidal\n4-Aminoquinolines\nAre Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype\nA Metalloprotease and\n                    <i>P. falciparum<\/i>\n                    Malaria"],"prefix":"10.1021","volume":"57","author":[{"given":"Milica","family":"Videnovic\u0301","sequence":"first","affiliation":[{"name":"University of Belgrade , , Studentski trg 16 , P.O. Box 51, , ,","place":["Belgrade, Serbia, 11158"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dejan M.","family":"Opsenica","sequence":"additional","affiliation":[{"name":"University of Belgrade , , Njegoseva 12 , ,","place":["Belgrade, Serbia, 11000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James C.","family":"Burnett","sequence":"additional","affiliation":[{"name":"Leidos Biomedical Research, Inc. , , FNLCR at Frederick, P.O. Box B, , ,","place":["Frederick, Maryland, United States, 21701"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Gomba","sequence":"additional","affiliation":[{"name":"United States Army Medical Research Institute of Infectious Diseases , , 1425 Porter Street , , ,","place":["Frederick, Maryland, United States, 21702"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan E.","family":"Nuss","sequence":"additional","affiliation":[{"name":"United States Army Medical Research Institute of Infectious Diseases , , 1425 Porter Street , , ,","place":["Frederick, Maryland, United States, 21702"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z\u030civota","family":"Selakovic\u0301","sequence":"additional","affiliation":[{"name":"University of Belgrade , , Studentski trg 16 , P.O. Box 51, , ,","place":["Belgrade, Serbia, 11158"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelena","family":"Konstantinovic\u0301","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry Innovative Centre , Studentski trg 12-16 , ,","place":["Belgrade, Serbia, 11158"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Krstic\u0301","sequence":"additional","affiliation":[{"name":"University of Belgrade , , Studentski trg 16 , P.O. Box 51, , ,","place":["Belgrade, Serbia, 11158"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"S\u030cegan","sequence":"additional","affiliation":[{"name":"University of Belgrade , , Njegoseva 12 , ,","place":["Belgrade, Serbia, 11000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Zlatovic\u0301","sequence":"additional","affiliation":[{"name":"University of Belgrade , , Studentski trg 16 , P.O. Box 51, , ,","place":["Belgrade, Serbia, 11158"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Sciotti","sequence":"additional","affiliation":[{"name":"Walter Reed Army Institute of Research , , , ,","place":["Silver Spring, Maryland, United States, 20910"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sina","family":"Bavari","sequence":"additional","affiliation":[{"name":"United States Army Medical Research Institute of Infectious Diseases , , 1425 Porter Street , , ,","place":["Frederick, Maryland, United States, 21702"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogdan A.","family":"S\u030colaja","sequence":"additional","affiliation":[{"name":"University of Belgrade , , Studentski trg 16 , P.O. 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