- Synthesis, design, and structure–activity relationship of the pyrimidone derivatives as novel selective inhibitors of plasmodium falciparum dihydroorotate dehydrogenase
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The inhibition of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) potentially represents a new treatment option for malaria, as P. falciparum relies entirely on a de novo pyrimidine biosynthetic pathway for survival. Herein, we report a series of pyrimidone derivatives as novel inhibitors of PfDHODH. The most potent compound, 26, showed high inhibition activity against PfDHODH (IC50 = 23 nM), with >400-fold species selectivity over human dihydroorotate dehydrogenase (hDHODH). The brand-new inhibitor scaffold targeting PfDHODH reported in this work may lead to the discovery of new antimalarial agents.
- Xu, Le,Li, Wenjie,Diao, Yanyan,Sun, Hongxia,Li, Honglin,Zhu, Lili,Zhou, Hongchang,Zhao, Zhenjiang
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- Discovery of AS-0141, a Potent and Selective Inhibitor of CDC7 Kinase for the Treatment of Solid Cancers
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CDC7, a serine-threonine kinase, plays conserved and important roles in regulation of DNA replication and has been recognized as a potential anticancer target. We report here the optimization of a series of furanone analogues starting from compound 1 with a focus on ADME properties suitable for clinical development. By replacing the 2-chlorobenzene moiety in 1 with various aliphatic groups, we identified compound 24 as a potent CDC7 inhibitor with excellent kinase selectivity and favorable oral bioavailability in multiple species. Oral administration of 24 demonstrated robust in vivo antitumor efficacy in a colorectal cancer xenograft model. Compound 24 (AS-0141) is currently in phase I clinical trials for the treatment of solid cancers.
- Asami, Tokiko,Funakoshi, Yoko,Irie, Takayuki,Masai, Hisao,Sawa, Ayako,Sawa, Masaaki,Taniyama, Chika,Uno, Yuko
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p. 14153 - 14164
(2021/10/20)
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- Pyrimidone derivative and application thereof
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The invention relates to a pyrimidone derivative and application thereof. The pyrimidone derivative is a compound shown as a formula I or pharmaceutically-acceptable salt thereof. An activity inhibition experiment discovers that the pyrimidone derivative provided by the invention has a significant activity inhibition effect on dihydroorotate dehydrogenase of plasmodium falciparum. The invention lays a foundation for the preparation of a novel anti-malarial drug. In the formula I, R1 is a straight chain and a branched chain of C1-C6 or cyclic alkyl or amino; and A is a 5 to 6-membered saturatedor unsaturated carbocyclic group.
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Paragraph 0028; 0032; 0033
(2018/07/06)
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- NOVEL FURANONE DERIVATIVE
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To provide a novel furanone derivative, and a medicine including the same. The furanone derivative is represented by the formula (I): wherein A represents —COOR1 or a hydrogen atom; R1 represents a hydrogen atom, an optionally substituted hydrocarbon grou
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Paragraph 0311; 0312
(2014/02/16)
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- Novel selective and potent inhibitors of malaria parasite dihydroorotate dehydrogenase: Discovery and optimization of dihydrothiophenone derivatives
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Taking the emergence of drug resistance and lack of effective antimalarial vaccines into consideration, it is of significant importance to develop novel antimalarial agents for the treatment of malaria. Herein, we elucidated the discovery and structure-activity relationships of a series of dihydrothiophenone derivatives as novel specific inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). The most promising compound, 50, selectively inhibited PfDHODH (IC50 = 6 nM, with >14 000-fold species-selectivity over hDHODH) and parasite growth in vitro (IC50 = 15 and 18 nM against 3D7 and Dd2 cells, respectively). Moreover, an oral bioavailability of 40% for compound 50 was determined from in vivo pharmacokinetic studies. These results further indicate that PfDHODH is an effective target for antimalarial chemotherapy, and the novel scaffolds reported in this work might lead to the discovery of new antimalarial agents.
- Xu, Minghao,Zhu, Junsheng,Diao, Yanyan,Zhou, Hongchang,Ren, Xiaoli,Sun, Deheng,Huang, Jin,Han, Dongmei,Zhao, Zhenjiang,Zhu, Lili,Xu, Yufang,Li, Honglin
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p. 7911 - 7924
(2013/11/06)
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