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

A comprehensive review on the biological interest of quinoline and its derivatives.

Metalloenzymes are central to a wide range of essential biological activities, including nucleic acid modification, protein degradation, and many others The role of metalloenzymes in these processes also makes them central for the progression of many diseases and, as such, makes metalloenzymes attractive targets for therapeutic intervention Increasing awareness of the role metalloenzymes play in disease and their importance as a class of targets has amplified interest in the development of new strategies to develop inhibitors and ultimately useful drugs In this Review, we provide a broad overview of several drug discovery efforts focused on metalloenzymes and attempt to map out the current landscape of high-value metalloenzyme targets

Targeting Metalloenzymes for Therapeutic Intervention

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.

The eight enzymes responsible for the biosynthesis of the three branched-chain amino acids (l-isoleucine, l-leucine, and l-valine) were identified decades ago using classical genetic approaches based on amino acid auxotrophy. This review will highlight the recent progress in the determination of the three-dimensional structures of these enzymes, their chemical mechanisms, and insights into their suitability as targets for the development of antibacterial agents. Given the enormous rise in bacterial drug resistance to every major class of antibacterial compound, there is a clear and present need for the identification of new antibacterial compounds with nonoverlapping targets to currently used antibacterials that target cell wall, protein, mRNA, and DNA synthesis.

Bacterial Branched-Chain Amino Acid Biosynthesis: Structures, Mechanisms, and Drugability

BACKGROUND

1,2,4-Triazolo[4,3-a]pyridine derivatives represent a new series of compounds that possess good herbicidal activity against Echinochloa crusgalli (L.) Beauv., Setaria faberii, Digitaria sanguinalis (L.) Scop., Brassica juncea Coss., Amaranthus retroflexus L. and Eclipta prostrata L.



RESULTS

A total of 23 novel 1,2,4-triazolo[4,3-a]pyridine derivatives were synthesised and identified by 1H NMR, IR, single-crystal X-ray diffraction, mass-spectroscopic and elemental analysis, and their herbicidal activities were tested against E. crusgalli (L.) Beauv., S. faberii, D. sanguinalis (L.) Scop., B. juncea Coss., A. retroflexus L. and E. prostrata L. at 150 g a.i. ha−1. It was found that the title compound 8-chloro-3-(4-propylphenyl)-[1,2,4]-triazolo[4,3-a]pyridine possesses high herbicidal activity and a broad spectrum against the 22 test weeds, with an inhibition effect of about 50% at a dosage of 37.5 g a.i. ha−1, and is safe for corn, cotton and rice at a dosage of 150 g a.i. ha−1. Furthermore, comparative molecular field analysis contour models were established to study the structure–activity relationship of the title compounds.



CONCLUSION

It is possible that, with further structure modification, 1,2,4-triazolo[4,3-a]pyridine derivatives, which possess good herbicidal activities, may become novel lead compounds for the development of herbicides against dicotyledonous weeds. © 2014 Society of Chemical Industry

Synthesis, crystal structure, herbicidal activities and 3D-QSAR study of some novel 1,2,4-triazolo[4,3-a]pyridine derivatives

Synthesis and Antifungal Activity of 1,3,4-Thiadiazole Derivatives Containing Pyridine Group

A new triazole compound, C46H46N10O2S2, has been synthesized, and the crystal structure was determined by a single crystal X-ray diffraction study. The fungicidal activity of the title compound was determined, and the results showed that it displays moderate fungicidal activity. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. GRAPHICAL ABSTRACT

Synthesis, Dimeric Crystal Structure, and Fungicidal Activity of 1-(4-Methylphenyl)-2-(5-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)ethanone

BACKGROUND
Aedes aegypti is a major mosquito vector for the transmission of serious diseases, especially dengue and yellow fever. More than 1 billion people in developing countries are at risk. The widespread and continual use of pesticides can lead to resistant mosquitoes. In order to maintain mosquito control gains, it is critical to develop and evaluate novel bioactive molecules that differ in mode of action from currently used products.

RESULTS
A series of novel pyrimidine derivatives were designed and synthesized. Their structures were elucidated by proton nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. The biological activities of these compounds were tested against Ae. aegypti. Many of them exhibited insecticidal activity against adult and larval mosquitoes. Compound 4d displayed relatively good activity to reach 70% mortality at 2 µg mL−1. Furthermore, density functional theory calculations were established to study the structure–activity relationship of these novel compounds.

CONCLUSION
A practical synthetic route for pyrimidine derivatives is presented. This study suggests that these pyrimidine derivatives exhibit some activity against the yellow fever mosquito and, with further structure modification, could be novel lead compounds for the development of insecticides against mosquitoes. © 2016 Society of Chemical Industry

Synthesis and insecticidal activity of novel pyrimidine derivatives containing urea pharmacophore against Aedes aegypti.

A series of novel 1,2,4-triazolo[4,3-a]pyridines were synthesized, and their structures were characterized by (1) H NMR, MS, elemental analysis, and single-crystal X-ray diffraction analysis. The antifungal activities were evaluated. The antifungal activity results indicated that the compound 2b, 2g, 2p, and 2i exhibited good activities. The activity of compound 2b, 2g, 2p, and 2i can compare with the commercial pesticide. The 3D-QSAR model was developed using CoMFA method. Both the steric and electronic field distributions of CoMFA are in good agreement in this work and will be very helpful in designing a new set of analogues.

Jian-Quan Weng

Papers

Synthesis, crystal structure, herbicidal activities and 3D-QSAR study of some novel 1,2,4-triazolo[4,3-a]pyridine derivatives

Synthesis and Antifungal Activity of 1,3,4-Thiadiazole Derivatives Containing Pyridine Group

Synthesis, Dimeric Crystal Structure, and Fungicidal Activity of 1-(4-Methylphenyl)-2-(5-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)ethanone

Synthesis and insecticidal activity of novel pyrimidine derivatives containing urea pharmacophore against Aedes aegypti.

Microwave Assistant One Pot Synthesis, Crystal Structure, Antifungal Activities and 3D‐QSAR of Novel 1,2,4‐Triazolo[4,3‐a]pyridines