Second generation steroidal 4-aminoquinolines are potent, dual-target inhibitors of the botulinum neurotoxin serotype A metalloprotease and P. falciparum malaria.
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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DOI：
10.1021/jm500033r
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发表时间：
2014-05-22
影响因子：
7.3
通讯作者：
Solaja BA
中科院分区：
文献类型：
--
作者：
Videnović M;Opsenica DM;Burnett JC;Gomba L;Nuss JE;Selaković Z;Konstantinović J;Krstić M;Segan S;Zlatović M;Sciotti RJ;Bavari S;Solaja BA
合成了明显更有效的第二代基于4-氨基-7-氯喹啉（4，7-ACQ）的肉毒杆菌神经毒素血清型A（BoNT/A）轻链抑制剂。在胆酸盐组分的C（3）位引入氨基显著增加了效力（此类衍生物的IC 50值范围为0.81 - 2.27 μM）。制备了另外两个亚类：双（甾体）-4，7-ACQ衍生物和双（4，7-ACQ）胆酸盐衍生物;两个类别都提供了具有纳摩尔范围效力的抑制剂（例如，化合物67的Ki为0.10 μM）。在使用原代神经元的BoNT/A攻击期间，选择的衍生物保护SNAP-25高达89%。进行对接模拟以使化合物的体外效力合理化。除了特定的残基接触，酶的催化锌的协调和酶的催化水的驱逐是一个一致的主题。关于抗疟活性，化合物提供了比CQ更好的抗氯喹抗性（CQR）疟疾的IC 90活性，并且七种化合物比甲氟喹对CQR菌株W2更有活性。
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 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 Ki 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 IC90 activities against chloroquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2.
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影响因子：
5
作者：
Capek, Petr;Zhang, Yan;Dickerson, Tobin J.
通讯作者：
Dickerson, Tobin J.
影响因子：
4.2
作者：
Cardellina, John H., II;Roxas-Duncan, Virginia I.;Smith, Leonard A.
通讯作者：
Smith, Leonard A.
影响因子：
2.7
作者：
Burnett, J. C.;Wang, C.;Bavari, S.
通讯作者：
Bavari, S.
DOI：
10.1016/j.bbrc.2003.08.112
发表时间：
2003-10-10
影响因子：
3.1
作者：
Burnett, JC;Schmidt, JJ;Bavari, S
通讯作者：
Bavari, S
DOI：
10.1038/nrd1694
发表时间：
2005-04
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Burnett JC;Henchal EA;Schmaljohn AL;Bavari S
通讯作者：
Bavari S