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Design, synthesis, and biological evaluation of novel substituted benzamide derivatives bearing a 1,2,3-triazole moiety as potent human dihydroorotate dehydrogenase inhibitors. 2018

Kuan Lu, and Lude Cai, and Xue Zhang, and Guodong Wu, and Congjun Xu, and Yanfang Zhao, and Ping Gong
Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenyang 110016, PR China.

A novel series of substituted benzamide derivatives bearing a 1,2,3-triazole moiety were designed and synthesized by click chemistry. Human dihydroorotate dehydrogenase inhibition assay was used to evaluate the synthesized compounds as potent hDHODH inhibitors. Most compounds showed moderate to significant potency, accompanied with a suitable clogD7.4 value and compounds 4d, 4o, and 5j effectively inhibited the activity of hDHODH with IC50 values of 2.1, 2.1 and 1.5 μM, respectively. Compound 4o also effectively suppressed proliferation of the activated PBMCs. The study of structure-activity relationships also revealed that a suitable substitution on para-position of terminal phenyl ring was crucial for high activity. Together, the most promising compound 4o might serve as a novel hDHODH inhibitors for further investigation.

UI MeSH Term Description Entries
D007166 Immunosuppressive Agents Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging. Immunosuppressant,Immunosuppressive Agent,Immunosuppressants,Agent, Immunosuppressive,Agents, Immunosuppressive
D007963 Leukocytes, Mononuclear Mature LYMPHOCYTES and MONOCYTES transported by the blood to the body's extravascular space. They are morphologically distinguishable from mature granulocytic leukocytes by their large, non-lobed nuclei and lack of coarse, heavily stained cytoplasmic granules. Mononuclear Leukocyte,Mononuclear Leukocytes,PBMC Peripheral Blood Mononuclear Cells,Peripheral Blood Human Mononuclear Cells,Peripheral Blood Mononuclear Cell,Peripheral Blood Mononuclear Cells,Leukocyte, Mononuclear
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D009570 Nitriles Organic compounds containing the -CN radical. The concept is distinguished from CYANIDES, which denotes inorganic salts of HYDROGEN CYANIDE. Nitrile
D003437 Crotonates Derivatives of BUTYRIC ACID that include a double bond between carbon 2 and 3 of the aliphatic structure. Included under this heading are a broad variety of acid forms, salts, esters, and amides that include the aminobutryrate structure. 2-Butenoic Acids,Crotonic Acids,2 Butenoic Acids,Acids, 2-Butenoic,Acids, Crotonic
D004355 Drug Stability The chemical and physical integrity of a pharmaceutical product. Drug Shelf Life,Drugs Shelf Lives,Shelf Life, Drugs,Drug Stabilities,Drugs Shelf Life,Drugs Shelf Live,Life, Drugs Shelf,Shelf Life, Drug,Shelf Live, Drugs,Shelf Lives, Drugs
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006885 Hydroxybutyrates Salts and esters of hydroxybutyric acid. Hydroxybutyric Acid Derivatives,Hydroxybutyric Acids,Acid Derivatives, Hydroxybutyric
D000090722 Dihydroorotate Dehydrogenase An oxidoreductase that catalyzes the conversion of DIHYDROOROTATE to orotate with QUINONE as an electron acceptor in the biosynthesis of PYRIMIDINES. DHODH,DHOO-Dehydrogenase-U,Dihydro-Orotate Dehydrogenase,Dihydro-Orotate-Cytochrome C Reductase,Dihydroorotate Dehydrogenase (Ubiquinone),Dihydroorotate Dehydrogenase Type A,Dihydroorotate Dehydrogenase Type B,Dihydroorotate Dehydrogenase Type C,Dihydroorotate-Ubiquinone Oxidoreductase,DHODase A,DHODase B,A, DHODase,B, DHODase,C Reductase, Dihydro-Orotate-Cytochrome,DHOO Dehydrogenase U,Dehydrogenase, Dihydro-Orotate,Dehydrogenase, Dihydroorotate,Dihydro Orotate Cytochrome C Reductase,Oxidoreductase, Dihydroorotate-Ubiquinone,Reductase, Dihydro-Orotate-Cytochrome C

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