3-NITROPROPIONIC ACID IS A SUICIDE INHIBITOR OF MITOCHONDRIAL RESPIRATION THAT, UPON OXIDATION BY COMPLEX II, FORMS A COVALENT ADDUCT WITH A CATALYTIC-BASE ARGININE IN THE ACTIVE SITE OF THE ENZYME*. Li-shar Huang 1 , Gang Sun 2± , David Cobessi 1§ , Andy Wang 1 , John T. Shen 1 , Eric Y. Tung 1 , Vernon E. Anderson 2 , and Edward A. Berry 1 From Lawrence Berkeley National Laboratory, Berkeley, CA; and , 2 Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH Running title: Structure of 3-nitropropionate - inactivated Complex II Address correspondence regarding the crystallographic work to EAB (EABerry@LBL.gov; telephone 1-510-486-4335), and correspondence regarding characterization of the tryptic fragments and 3-NP adduct to VEA (vea@cwru.edu). Current address: Div. of Bioorganic Chemistry and Mol. Pharm., Dept. of Int. Medicine, Wash. Univ. School of Medicine, Campus Box 8020, 660 South Euclid Avenue, St. Louis, MO 63110 Current address: Ecole Superieure de Biotechnologie de Strasbourg, UMR7100 CNRS, Boulevard Sebastien Brant, BP 10413, 67412 Illkirch, France We report three new structures of mitochondrial respiratory Complex II (succinate ubiquinone oxidoreductase, E.C. 1.3.5.1) at up to 2.1 A resolution, with various inhibitors. The structures define the conformation of the bound inhibitors and suggest the residues involved in substrate binding and catalysis at the dicarboxylate site. In particular they support the role of Arg297 as a general base catalyst accepting a proton in the dehydrogenation of succinate. The dicarboxylate ligand in oxaloacetate-containing crystals appears to be the same as that reported for Shewanella flavocytochrome c treated with fumarate. The plant and fungal toxin 3-nitropropionic acid, an irreversible inactivator of succinate dehydrogenase, forms a covalent adduct with the side chain of Arg297. The modification eliminates a trypsin cleavage site in the flavoprotein, and tandem mass spectroscopic analysis of the new fragment shows the mass of Arg 297 to be increased by 83 Da and to have potential of losing 44 Da, consistent with decarboxylation, during fragmentation. The toxin 3-nitropropionic acid (3-NP 1 ) is produced by certain plants and fungi. It is a specific inhibitor of mitochondrial respiratory complex II. Fatalities after eating moldy sugarcane have been linked to 3-NP toxicity(1,2). Ruminants grazing in regions with 3-NP-producing plants acquire resistance due to reduction of the nitro group to an amine by ruminal bacteria(3). The effectiveness of 3-NP in vivo after injection or oral administration has made it useful in studies involving tissues or whole animals. Ingestion of 3-NP results in neurodegeneration with symptoms resembling those of Huntington's disease(4), and conversely Huntington's disease results in loss of complex II activity(5), thus 3-NP has been used to produce an animal model for study of Huntington's(6,7). Symptoms also include convulsions, and 3-NP is being looked at for inducing a model of epilepsy(8). Prior sub- acute 3-NP poisoning seems to provide resistance to ischemic damage to nervous tissue by a preconditioning effect(9) similar to that resulting from mild ischemia. The target of 3-NP is Complex II, which is both a member of the Krebs tricarboxylic acid cycle (oxidizing succinate to fumarate) and an entry-point for electrons into the respiratory chain at the level of ubiquinol. It consists of a large flavoprotein subunit (FP) containing covalently bound FAD, an iron-sulfur protein (IP) with three different iron-sulfur clusters, and two small membrane anchor subunits (chains C and D) ligating a single low-spin heme of type B. Human genetic defects in the IP subunits or chains C or D lead to

3-Nitropropionic Acid is a Suicide Inhibitor of Mitochondrial Respiration that, Upon Oxidation by Complex II, Forms a Covalent Adduct With a Catalytic Base Arginine in the Active Site of the Enzyme

Fluorinated pyrazoles play an important role in medicinal chemistry, drug discovery, agrochemistry, coordination chemistry, and organometallic chemistry. Since the early 1990s, their popularity has grown exponentially. Moreover, more than 50% of all contributions on the topic have been published in the last 5 years. In this review, analysis of novel synthetic approaches to fluorinated pyrazoles that appeared in recent years is performed. A particular emphasis is devoted to a detailed consideration of reaction mechanisms. In addition, the reasons that have led to the ever-increasing popularity of fluorinated pyrazoles in various areas of science are discussed. At the end of the review, several potentially interesting but yet mostly unknown classes of fluorinated pyrazoles are outlined.

Fluorinated Pyrazoles: From Synthesis to Applications.

Pyrazole, a five-membered heterocycle containing two nitrogen atoms, is extensively found as a core framework in a huge library of heterocyclic compounds that envelops promising agro-chemical, fluorescent and biological potencies. Attributed to its several potential applications, there is a rise in the significance of designing novel pyrazoles, disclosing innovative routes for synthesizing pyrazoles, examining different potencies of pyrazoles, and seeking for potential applications of pyrazoles. This review consists of two parts. The first part provides an overview on the recent developments in synthetic approaches to pyrazoles, which is related to the new or advanced catalysts and other ‘environment-friendly’ procedures, including heterogeneous catalytic systems, ligand-free systems, ultrasound and microwave-assisted reactions. The second part focuses on the recently reported novel biological affinities of pyrazoles. This systematic review covers the published studies from 1990 to date. It is expected that this review will be helpful in future research and for new thoughts in the quest for rational designs for developing more promising pyrazoles. The review consists of two parts: (i) an overview on the recent advances in synthetic approaches for the preparation of pyrazoles, including eco-friendly methodologies, heterogeneous catalytic systems, ligand-free systems, ultrasound and microwave-assisted reactions, and (ii) a summary of recently reported novel biological affinities of pyrazoles.

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Recent developments in synthetic chemistry and biological activities of pyrazole derivatives

Plant-parasitic nematodes have caused huge economic losses to agriculture worldwide and seriously threaten the sustainable development of modern agriculture. Chemical nematicides are still the most effective means to manage nematodes. However, the long-term use of organophosphorus and carbamate nematicides has led to a lack of field control efficacy and increased nematode resistance. To meet the huge market demand and slow the growth of resistance, new nematicides are needed to enter the market. The rational design and synthesis of new chemical scaffolds to screen for new nematicides is still a difficult task. We reviewed the latest research progress of nematicidal compounds in the past decade, discussed the structure-activity relationship and mechanism of action, and recommended some nematicidal active fragments. It is hoped that this review can update the recent progress on nematicide discoveries and provide new ideas for the design and mechanism of action studies of nematicides.

Chemical Nematicides: Recent Research Progress and Outlook.

Background In recent years, carboxamide fungicides, targeting succinate dehydrogenase (SDH), have shown highly efficient and broad spectrum fungicidal activity. Structure-activity relationship (SAR) results for these commercial fungicides show that the carboxamide group was a key active group. This is useful information for the discovery of new pyrazole carboxamide derivatives with fungicidal activity. Results Twenty-seven novel pyrazole carboxamides were designed and synthesized. Their fungicidal activities against Gibberella zeae, Phytophthora infestans, Phytophthora capsici, Rhizoctonia solani, Alternaria solani, Botrytis cinerea, Fusarium oxysporum, Cercospora arachidicola, Sclerotinia sclerotiorum and Physalospora piricola were tested; derivatives possessed excellent inhibitory at 50 mg L-1 in particular. Furthermore, some pyrazole carboxamides exhibited remarkably high activities against Sclerotinia sclerotiorum in vitro with EC50 values of 2.04 to 15.2 μg mL-1 . In addition, some compounds also exhibited high activities against Physalospora piricola, Cercospora arachidicola and Phytophthora capsici. Inhibition activities against SDH proved that the designed analogues were effective at the enzyme level. The SAR of these pyrazole carboxamides was studied by using the docking method. Conclusion It is possible that pyrazole carboxamides, which exhibit good activity against Sclerotinia sclerotiorum, can be further optimized as a lead compounds of carboxamide fungicides. © 2019 Society of Chemical Industry.

Novel 4‐pyrazole carboxamide derivatives containing flexible chain motif: design, synthesis and antifungal activity

Background 4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) has been a good target for herbicide discovery. In order to discover novel HPPD herbicides, a series of pyrazole aromatic ketone analogs were designed and synthesized. Results The 25 pyrazole aromatic ketone analogs synthesized were tested for herbicidal activity and compounds A1, A3, A4, A17, A20 and A25 displayed excellent herbicidal activity against Chenopodium serotinum, Stellaria media and Brassica juncea at 37.5 g ha-1 . In addition, compounds A1, A5, A9, A10, A16, A17, A20 and A25 exhibited good crop selectivity for wheat, maize and rice at 150 g ha-1 . Inhibition activities against AtHPPD proved the compounds were HPPD inhibitors. The structure-activity relationship of these pyrazole aromatic ketone analogs was studied using molecular docking. Conclusion These pyrazole aromatic ketone derivatives could be used as lead structures for development of HPPD herbicides against dicotyledonous weeds with further structure modification. © 2019 Society of Chemical Industry.

Synthesis and herbicidal activity of novel pyrazole aromatic ketone analogs as HPPD inhibitor.

Synthesis and Mosquiticidal Activity of Novel Hydrazone Containing Pyrimidine Derivatives against Aedes aegypti

\n\nIn recent years, pyrazole carboxamide derivatives possessed excellent\nfungicidal activity. In the process of designing new fungicides, the carboxamide group was modified\nin order to find novel structure pyrazole carboxamide derivatives.\n\n\n\nTen novel trifluoromethyl pyrazole acyl thiourea derivatives were designed and synthesized.\nIn vivo fungicidal activities of these compounds were tested against Fusarium oxysporum,\nCorynespora mazei and Botrytis cinerea, respectively\n\n\n\nParticularly compounds exhibited significant control effective at 100 mg/L. More importantly,\nsome compounds showed the good control effective at 10 mg/L. Furthermore, docking\nwas established to study the structure-activity relationship of the title compounds.\n\n\n\n It is possible that trifluoromethylpyrazole acyl thiurea derivatives, which possess good\ncontrol effective against Botrytis cinerea, may become novel lead compounds for the development\nof fungicides with further structure modification.\n

Liang Han

Papers

Novel 4‐pyrazole carboxamide derivatives containing flexible chain motif: design, synthesis and antifungal activity

Synthesis and herbicidal activity of novel pyrazole aromatic ketone analogs as HPPD inhibitor.

Synthesis and Mosquiticidal Activity of Novel Hydrazone Containing Pyrimidine Derivatives against Aedes aegypti

Novel Trifluoromethylpyrazole Acyl Thiourea Derivatives: Synthesis, Antifungal Activity and Docking Study

Novel trifluoromethylpyrazole acyl urea derivatives: Synthesis, crystal structure, fungicidal activity and docking study