925922-75-4Relevant 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.
supporting information, p. 6085 - 6136 (2021/06/01)
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.
C?H Oxygenation Reactions Enabled by Dual Catalysis with Electrogenerated Hypervalent Iodine Species and Ruthenium Complexes
Massignan, Leonardo,Tan, Xuefeng,Meyer, Tjark H.,Kuniyil, Rositha,Messinis, Antonis M.,Ackermann, Lutz
supporting information, p. 3184 - 3189 (2020/01/24)
The catalytic generation of hypervalent iodine(III) reagents by anodic electrooxidation was orchestrated towards an unprecedented electrocatalytic C?H oxygenation of weakly coordinating aromatic amides and ketones. Thus, catalytic quantities of iodoarenes in concert with catalytic amounts of ruthenium(II) complexes set the stage for versatile C?H activations with ample scope and high functional group tolerance. Detailed mechanistic studies by experiment and computation substantiate the role of the iodoarene as the electrochemically relevant species towards C?H oxygenations with electricity as a sustainable oxidant and molecular hydrogen as the sole by-product. para-Selective C?H oxygenations likewise proved viable in the absence of directing groups.
PYRIDYLPHENOL COMPOUND AND USE THEREOF
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Page/Page column 73, (2008/12/05)
The present invention provides a compound which has metastin receptor antagonist activity and is useful for preventing and treating hormone-dependent cancer, benign prostatomegaly, endometriosis, precocious puberty, uterine myoma or the like. More specifically, the present invention provides a compound, represented by the formula: or a salt thereof, a prodrug thereof, and a pharmaceutical agent containing the same; wherein Ring A represents a 5- to 8-membered homocyclic or heterocyclic group optionally having a substituent other than formula -X-R1 wherein X represents a bond or a spacer, and R1 represents optionally substituted amino or an optionally substituted nitrogen-containing heterocyclic group; Ring B represents an optionally substituted benzene ring; R2 represents an optionally substituted homocyclic or heterocyclic group; and R3 and R4 independently represent a hydrogen atom, cyano, acyl or an optionally substituted hydrocarbon group.
