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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

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          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 (IC 50 values for such derivatives ranged from 0.81 to 2.27 μM). 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 μM). 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 IC 90 activities against chloroquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2.

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          Most cited references 43

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          Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique.

          A rapid, semiautomated microdilution method was developed for measuring the activity of potential antimalarial drugs against cultured intraerythrocytic asexual forms of the human malaria parasite Plasmodium falciparum. Microtitration plates were used to prepare serial dilutions of the compounds to be tested. Parasites, obtained from continuous stock cultures, were subcultured in these plates for 42 h. Inhibition of uptake of a radiolabeled nucleic acid precursor by the parasites served as the indicator of antimalarial activity. Results of repeated measurements of activity with chloroquine, quinine, and the investigational new drug mefloquine demonstrated that the method is sensitive and precise. Several additional antimalarial drugs and compounds of interest were tested in vitro, and the results were consistent with available in vivo data. The use of P. falciparum isolates with known susceptibility to antimalarial drugs also permitted evaluation of the cross-resistance potential of each compound tested. The applications and expectations of this new test system within a drug development program are discussed.
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            Crystal structure of botulinum neurotoxin type A and implications for toxicity.

            Botulinum neurotoxin type A (BoNT/A) is the potent disease agent in botulism, a potential biological weapon and an effective therapeutic drug for involuntary muscle disorders. The crystal structure of the entire 1,285 amino acid di-chain neurotoxin was determined at 3.3 A resolution. The structure reveals that the translocation domain contains a central pair of alpha-helices 105 A long and a approximately 50 residue loop or belt that wraps around the catalytic domain. This belt partially occludes a large channel leading to a buried, negative active site--a feature that calls for radically different inhibitor design strategies from those currently used. The fold of the translocation domain suggests a mechanism of pore formation different from other toxins. Lastly, the toxin appears as a hybrid of varied structural motifs and suggests a modular assembly of functional subunits to yield pathogenesis.
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              Analyzing a bioterror attack on the food supply: the case of botulinum toxin in milk.

              We developed a mathematical model of a cows-to-consumers supply chain associated with a single milk-processing facility that is the victim of a deliberate release of botulinum toxin. Because centralized storage and processing lead to substantial dilution of the toxin, a minimum amount of toxin is required for the release to do damage. Irreducible uncertainties regarding the dose-response curve prevent us from quantifying the minimum effective release. However, if terrorists can obtain enough toxin, and this may well be possible, then rapid distribution and consumption result in several hundred thousand poisoned individuals if detection from early symptomatics is not timely. Timely and specific in-process testing has the potential to eliminate the threat of this scenario at a cost of <1 cent per gallon and should be pursued aggressively. Investigation of improving the toxin inactivation rate of heat pasteurization without sacrificing taste or nutrition is warranted.
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                Author and article information

                Journal
                J Med Chem
                J. Med. Chem
                jm
                jmcmar
                Journal of Medicinal Chemistry
                American Chemical Society
                0022-2623
                1520-4804
                17 April 2015
                17 April 2014
                22 May 2014
                : 57
                : 10
                : 4134-4153
                Affiliations
                []Faculty of Chemistry, University of Belgrade , Studentski trg 16, P.O. Box 51, 11158, Belgrade, Serbia
                []Institute of Chemistry, Technology, and Metallurgy, University of Belgrade , Njegoseva 12, 11000 Belgrade, Serbia
                [§ ]Computational Drug Development Group, Leidos Biomedical Research, Inc. , FNLCR at Frederick, P.O. Box B, Frederick, Maryland 21701, United States
                []Department of Bacteriology, United States Army Medical Research Institute of Infectious Diseases , 1425 Porter Street, Frederick, Maryland 21702, United States
                []Faculty of Chemistry Innovative Centre , Studentski trg 12-16, 11158 Belgrade, Serbia
                [# ]Division of Experimental Therapeutics, Walter Reed Army Institute of Research , Silver Spring, Maryland 20910, United States
                []Target Discovery and Experimental Microbiology, United States Army Medical Research Institute of Infectious Diseases , 1425 Porter Street, Frederick, Maryland 21702, United States
                Author notes
                [* ]D.M.O.: phone, +381-11-333-66-81; fax, +381-11-263-60-61; e-mail, dopsen@ 123456chem.bg.ac.rs .
                [* ]S.B.: phone, 1-301-619-4246; fax, 1-301-619-2348; e-mail, sina.bavari.civ@ 123456mail.mil .
                [* ]B.A.S.: phone, +381-11-263-86-06; fax, +381-11-218-43-30; e-mail, bsolaja@ 123456chem.bg.ac.rs .
                Article
                10.1021/jm500033r
                4032193
                24742203
                Copyright © 2014 American Chemical Society
                Funding
                National Institutes of Health, United States
                Categories
                Article
                Custom metadata
                jm500033r
                jm-2014-00033r

                Pharmaceutical chemistry

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