- Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy
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The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90 values below 1 mg/kg when dosed orally for 4 days. The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498) to preclinical development.
- Baragana, Beatriz,Norcross, Neil R.,Wilson, Caroline,Porzelle, Achim,Hallyburton, Irene,Grimaldi, Raffaella,Osuna-Cabello, Maria,Norval, Suzanne,Riley, Jennifer,Stojanovski, Laste,Simeons, Frederick R. C.,Wyatt, Paul G.,Delves, Michael J.,Meister, Stephan,Duffy, Sandra,Avery, Vicky M.,Winzeler, Elizabeth A.,Sinden, Robert E.,Wittlin, Sergio,Frearson, Julie A.,Gray, David W.,Fairlamb, Alan H.,Waterson, David,Campbell, Simon F.,Willis, Paul,Read, Kevin D.,Gilbert, Ian H.
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p. 9672 - 9685
(2016/11/19)
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- A novel multiple-stage antimalarial agent that inhibits protein synthesis
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There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a po
- Baraga?a, Beatriz,Hallyburton, Irene,Lee, Marcus C.S.,Norcross, Neil R.,Grimaldi, Raffaella,Otto, Thomas D.,Proto, William R.,Blagborough, Andrew M.,Meister, Stephan,Wirjanata, Grennady,Ruecker, Andrea,Upton, Leanna M.,Abraham, Tara S.,Almeida, Mariana J.,Pradhan, Anupam,Porzelle, Achim,Martínez, María Santos,Bolscher, Judith M.,Woodland, Andrew,Norval, Suzanne,Zuccotto, Fabio,Thomas, John,Simeons, Frederick,Stojanovski, Laste,Osuna-Cabello, Maria,Brock, Paddy M.,Churcher, Tom S.,Sala, Katarzyna A.,Zakutansky, Sara E.,Jiménez-Díaz, María Belén,Sanz, Laura Maria,Riley, Jennifer,Basak, Rajshekhar,Campbell, Michael,Avery, Vicky M.,Sauerwein, Robert W.,Dechering, Koen J.,Noviyanti, Rintis,Campo, Brice,Frearson, Julie A.,Angulo-Barturen, I?igo,Ferrer-Bazaga, Santiago,Gamo, Francisco Javier,Wyatt, Paul G.,Leroy, Didier,Siegl, Peter,Delves, Michael J.,Kyle, Dennis E.,Wittlin, Sergio,Marfurt, Jutta,Price, Ric N.,Sinden, Robert E.,Winzeler, Elizabeth A.,Charman, Susan A.,Bebrevska, Lidiya,Gray, David W.,Campbell, Simon,Fairlamb, Alan H.,Willis, Paul A.,Rayner, Julian C.,Fidock, David A.,Read, Kevin D.,Gilbert, Ian H.
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p. 315 - 320
(2015/06/25)
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- Design, synthesis and antitumour activity of bisquinoline derivatives connected by 4-oxy-3-fluoroaniline moiety
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A series of novel bisquinoline derivatives connected by a 4-oxy-3-fluoroaniline moiety were synthesized and evaluated for their in vitro antitumour activities against a panel of five cancer cell lines (H460, HT-29, MKN-45, U87MG, and SMMC-7721). Most of compounds tested showed a potent activity and high selectivity towards the H460 and MKN-45 cell lines. Among the compounds tested, six (15d, 15e, 15m, 15n, 16a, and 16i) were further examined for their c-Met kinase activity; the compounds showed high efficacy with IC 50 values in the single-digit nM range. An analysis of structure-activity relationships indicated that an unsubstituted or a halogen-substituted phenyl ring on the 2-arylquinoline-4-carboxamide moiety was favourable for antitumour activity.
- Li, Sai,Huang, Qiang,Liu, Yajing,Zhang, Xiaolong,Liu, Shuang,He, Chao,Gong, Ping
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