Ring Distortion of Vincamine Leads to the Identification of Re-Engineered Antiplasmodial Agents.
Ring Distortion of Vincamine Leads to the Identification of Re-Engineered Antiplasmodial Agents.
复制标题
长春胺环畸变导致重新设计的抗疟原虫药物的鉴定。
DOI：
10.1021/acsomega.1c02480
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发表时间：
2021-08-10
期刊：
影响因子：
4.1
通讯作者：
Huigens RW 3rd
中科院分区：
文献类型：
--
作者：
Norwood VM 4th;Murillo-Solano C;Goertzen MG 2nd;Brummel BR;Perry DL;Rocca JR;Chakrabarti D;Huigens RW 3rd
非常需要新的药物来抗击疟疾，疟疾在2019年导致全球∼409,000人死亡。我们利用环扭曲策略从长春花碱中创造出复杂多样的化合物，目的是发现具有重新设计的生物活性的分子。我们发现化合物8(V3b)针对抗氯喹恶性疟原虫DD2寄生虫(EC_(50)=1.81±0.09μM，EC_(50)=40μM)，并建立了25个相关类似物的构效关系。新类似物30(V3ss，Dd2，EC_(50)=0.25±0.004μM；HepG_2，EC_(50)>；25μM)显示出最强的活性，能阻止原虫脱离红细胞内分裂体期，并需要24小时才能杀死恶性疟原虫DD2细胞。这些发现表明，长春花环扭曲有可能发现新的抗疟疾药物和其他对人类健康重要的治疗方法。
There is a significant need for new agents to combat malaria, which resulted in ∼409,000 deaths globally in 2019. We utilized a ring distortion strategy to create complex and diverse compounds from vincamine with the goal of discovering molecules with re-engineered biological activities. We found compound 8 (V3b) to target chloroquine-resistant Plasmodium falciparum Dd2 parasites (EC50 = 1.81 ± 0.09 μM against Dd2 parasites; EC50 > 40 μM against HepG2 cells) and established structure–activity relationships for 25 related analogues. New analogue 30 (V3ss, Dd2, EC50 = 0.25 ± 0.004 μM; HepG2, EC50 > 25 μM) was found to demonstrate the most potent activity, which prevents exit on the parasite from the schizont stage of intraerythrocytic development and requires >24 h to kill P. falciparum Dd2 cells. These findings demonstrate the potential that vincamine ring distortion has toward the discovery of novel antimalarial agents and other therapies significant to human health.
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影响因子：
16.6
作者：
Charaschanya M;Aubé J
通讯作者：
Aubé J
DOI：
10.1038/nrmicro3138
发表时间：
2013-12
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
Kato N;Comer E;Sakata-Kato T;Sharma A;Sharma M;Maetani M;Bastien J;Brancucci NM;Bittker JA;Corey V;Clarke D;Derbyshire ER;Dornan GL;Duffy S;Eckley S;Itoe MA;Koolen KM;Lewis TA;Lui PS;Lukens AK;Lund E;March S;Meibalan E;Meier BC;McPhail JA;Mitasev B;Moss EL;Sayes M;Van Gessel Y;Wawer MJ;Yoshinaga T;Zeeman AM;Avery VM;Bhatia SN;Burke JE;Catteruccia F;Clardy JC;Clemons PA;Dechering KJ;Duvall JR;Foley MA;Gusovsky F;Kocken CH;Marti M;Morningstar ML;Munoz B;Neafsey DE;Sharma A;Winzeler EA;Wirth DF;Scherer CA;Schreiber SL
通讯作者：
Schreiber SL
μ阿片受体：新型拮抗剂和结构建模。
影响因子：
4.6
作者：
Kaserer T;Lantero A;Schmidhammer H;Spetea M;Schuster D
通讯作者：
Schuster D
影响因子：
4.2
作者：
Heidebrecht, Richard W., Jr.;Mulrooney, Carol;Austin, Christopher P.;Barker, Robert H., Jr.;Beaudoin, Jennifer A.;Cheng, Ken Chih-Chien;Comer, Eamon;Dandapani, Sivaraman;Dick, Justin;Duvall, Jeremy R.;Ekland, Eric H.;Fidock, David A.;Fitzgerald, Mark E.;Foley, Michael;Guha, Rajarshi;Hinkson, Paul;Kramer, Martin;Lukens, Amanda K.;Masi, Daniela;Marcaurelle, Lisa A.;Su, Xin-Zhuan;Thomas, Craig J.;Weiwer, Michel;Wiegand, Roger C.;Wirth, Dyann;Xia, Menghang;Yuan, Jing;Zhao, Jinghua;Palmer, Michelle;Munoz, Benito;Schreiber, Stuart
通讯作者：
Schreiber, Stuart