1360611-42-2Relevant articles and documents
Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series
Palmer, Michael J.,Deng, Xiaoyi,Watts, Shawn,Krilov, Goran,Gerasyuto, Aleksey,Kokkonda, Sreekanth,El Mazouni, Farah,White, John,White, Karen L.,Striepen, Josefine,Bath, Jade,Schindler, Kyra A.,Yeo, Tomas,Shackleford, David M.,Mok, Sachel,Deni, Ioanna,Lawong, Aloysus,Huang, Ann,Chen, Gong,Wang, Wen,Jayaseelan, Jaya,Katneni, Kasiram,Patil, Rahul,Saunders, Jessica,Shahi, Shatrughan P.,Chittimalla, Rajesh,Angulo-Barturen, I?igo,Jiménez-Díaz, María Belén,Wittlin, Sergio,Tumwebaze, Patrick K.,Rosenthal, Philip J.,Cooper, Roland A.,Aguiar, Anna Caroline Campos,Guido, Rafael V. C.,Pereira, Dhelio B.,Mittal, Nimisha,Winzeler, Elizabeth A.,Tomchick, Diana R.,Laleu, Beno?t,Burrows, Jeremy N.,Rathod, Pradipsinh K.,Fidock, David A.,Charman, Susan A.,Phillips, Margaret A.
, p. 6085 - 6136 (2021)
Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes.
Rhodium-Catalyzed C?H Activation/Annulation Cascade of Aryl Oximes and Propargyl Alcohols to Isoquinoline N-Oxides
Li, Yuan,Fang, Feifei,Zhou, Jianhui,Li, Jiyuan,Wang, Run,Liu, Hong,Zhou, Yu
supporting information, p. 3305 - 3310 (2021/05/17)
A β-hydroxy elimination instead of common oxidization to carbonyl group in secondary propargyl alcohols was successfully developed to form 2-benzyl substituted isoquinoline N-oxides by a Rhodium-catalyzed C?H activation and annulation cascade, in which moderate to excellent yields (up to 92%) could be obtained under mild reaction conditions, along with good regioselectivity, broad generality and applicability. (Figure presented.).
Metal-Free CH-CH-Type Cross-Coupling of Arenes and Alkynes Directed by a Multifunctional Sulfoxide Group
Fernández-Salas, José A.,Eberhart, Andrew J.,Procter, David J.
supporting information, p. 790 - 793 (2016/02/05)
A metal-free CH-CH-type coupling of arenes and alkynes, mediated by a multifunctional sulfoxide directing group, exploits nonprefunctionalized coupling partners, proceeds under mild conditions, is operationally simple, and exhibits high functional group t
