- Discovery of Novel Pyrazole-Quinazoline-2,4-dione Hybrids as 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors
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4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) has been identified as one of the most significant targets in herbicide discovery for resistant weed control. In a continuing effort to discover potent novel HPPD inhibitors, we adopted a ring-expansion strategy to design a series of novel pyrazole-quinazoline-2,4-dione hybrids based on the previously discovered pyrazole-isoindoline-1,3-dione scaffold. One compound, 3-(2-chlorophenyl)-6-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4-carbonyl)-1,5-dimethylquinazoline-2,4(1H,3H)-dione (9bj), displayed excellent potency against AtHPPD, with an IC50 value of 84 nM, which is approximately 16-fold more potent than pyrasulfotole (IC50 = 1359 nM) and 2.7-fold more potent than mesotrione (IC50 = 226 nM). Furthermore, the co-crystal structure of the AtHPPD-9bj complex (PDB ID 6LGT) was determined at a resolution of 1.75 ?. Similar to the existing HPPD inhibitors, compound 9bj formed a bidentate chelating interaction with the metal ion and a π-πstacking interaction with Phe381 and Phe424. In contrast, o-chlorophenyl at the N3 position of quinazoline-2,4-dione with a double conformation was surrounded by hydrophobic residues (Met335, Leu368, Leu427, Phe424, Phe392, and Phe381). Remarkably, the greenhouse assay indicated that most compounds displayed excellent herbicidal activity (complete inhibition) against at least one of the tested weeds at the application rate of 150 g of active ingredient (ai)/ha. Most promisingly, compounds 9aj and 9bi not only exhibited prominent weed control effects with a broad spectrum but also showed very good crop safety to cotton, peanuts, and corn at the dose of 150 g of ai/ha.
- Chen, Qiong,Hao, Ge-Fei,He, Bo,Lin, Hong-Yan,Wu, Feng-Xu,Wu, Lei,Yang, Guang-Fu,Yang, Wen-Chao,Yu, Liang-Kun
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p. 5059 - 5067
(2020/05/20)
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- SELF-IMMOLATIVE SYSTEMS
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The present invention is concerned with self-immolative recognition and/or responsive systems for electrophilic compounds, especially alkylating agents, which systems may comprise disclosure or detection of the alkylating agent. The present invention is especially concerned with non-protic triggered self-immolative systems, molecules, and methods, and in particular for detection of non- protic electrophilic agents, and especially alkylating agents, for example alkyl or benzylic halides, which may be found in pesticides or fumigants, or chemical warfare agents.
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Page/Page column 11; 32
(2020/05/28)
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- Quinazolin-2,4-dione derivative and preparation method and application thereof
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The invention provides a quinazolin-2,4-dione derivative and a preparation method and application thereof, and specifically, the invention provides a quinazolin-2,4-dione derivative shown as formula (I) and a composition comprising same. The invention further provides the method for preparing the derivative and the application of the derivative in selectively controlling unexpected plants among useful crops, wherein Q, W, Z, Y, R, R and R have the meanings as described by the invention. The formula (I) is as shown in the description below.
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Paragraph 0284; 0290; 0291
(2019/04/04)
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- Triketone-based compound preparation method
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The invention relates to the field of preparation of pesticides, and discloses a triketone-based compound preparation method, wherein the triketone-based compound has a structure represented by a formula (1). The method comprises that 1) a compound represented by a formula (2), 1,3-cyclohexanedione and CO are subjected to a reaction in the presence of a first catalyst under an alkali condition toobtain a product represented by a formula (3); and 2) the product represented by the formula (3) contacts a second catalyst and an alkali substance under a rearrangement reaction condition to obtain the triketone-based compound represented by the formula (1). According to the present invention, with the method, the triketone-based compound can be obtained in the low-cost and high-yield manner; andthe purity of the triketone-based compound obtained through the method is high. The formulas (1), (2) and (3) are defined in the specification.
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Paragraph 0094; 0097
(2018/07/06)
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- TRIKETONE COMPOUND AND PREPARATION METHOD AND USE THEREOF
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Disclosed in the present invention is a triketone compound which has a structure shown in Formula (I). Also disclosed in the present invention is a method for preparing the triketone compound having a structure as shown by Formula (I), which comprise that under the rearrangement reaction conditions, the compound having a structure as shown by Formula (II) is contacted with a catalyst in the presence of a base and a solvent. Further disclosed in the present invention is the use of a triketone compound having a structure as shown by Formula (I) in preventing and controlling weeds. Said triketone compound having a structure as shown by formula (I) in the present invention has the effect of preventing and controlling weeds, in particular having an excellent effect on preventing and controlling broadleaved weeds and/or gramineae weeds.
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- Rationally designed cooperatively enhanced receptors to magnify host-guest binding in water
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When disengaged interactions within a receptor are turned on by its guest, these intrahost interactions will contribute to the overall binding energy. Although such receptors are common in biology, their synthetic mimics are rare and difficult to design. By engineering conflictory requirements between intrareceptor electrostatic and hydrophobic interactions, we enabled complementary guests to eliminate the "electrostatic frustration" within the host and turn on the intrahost interactions. The result was a binding constant of Ka >105 M-1 from ammonium-carboxylate salt bridges that typically function poorly in water. These cooperatively enhanced receptors displayed excellent selectivity in binding, despite a large degree of conformational flexibility in the structure.
- Gunasekara, Roshan W.,Zhao, Yan
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supporting information
p. 843 - 849
(2015/01/30)
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- Synthesis and herbicidal evaluation of triketone-containing quinazoline-2,4-diones
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Exploring novel 4-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) inhibitors is one of the most promising research directions in herbicide discovery. To discover new triketone herbicides with broad-spectrum weed control as well as excellent crop selectivity, a series of (total 52) novel triketone-containing quinazoline-2,4-dione derivatives were synthesized and further bioevaluated. The greenhouse testing indicated that many of the newly synthesized compounds showed better or excellent herbicidal activity against broadleaf and monocotyledonous weeds at the dosages of 37.5-150 g of active ingredient (ai)/ha. The structure and activity relationship in this study indicated that the triketone-containing quinazoline-2,4-dione motif has possessed great impact on herbicide activity and may be used for further optimization. Among the new compounds, III-b and VI-a-VI-d displayed a broader spectrum of weed control than mesotrione. In addition, the compound III-b also demonstrated comparatively superior crop selectivity to mesotrione, thus possessing great potential for weed control in the field.
- Wang, Da-Wei,Lin, Hong-Yan,Cao, Run-Jie,Yang, Sheng-Gang,Chen, Qiong,Hao, Ge-Fei,Yang, Wen-Chao,Yang, Guang-Fu
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p. 11786 - 11796
(2015/02/19)
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- Second-generation sulfonamide inhibitors of d-glutamic acid-adding enzyme: Activity optimisation with conformationally rigid analogues of d-glutamic acid
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d-Glutamic acid-adding enzyme (MurD) catalyses the essential addition of d-glutamic acid to the cytoplasmic peptidoglycan precursor UDP-N-acetylmuramoyl- l-alanine, and as such it represents an important antibacterial drug-discovery target enzyme. Based on a series of naphthalene-N-sulfonyl-d-Glu derivatives synthesised recently, we synthesised two series of new, optimised sulfonamide inhibitors of MurD that incorporate rigidified mimetics of d-Glu. The compounds that contained either constrained d-Glu or related rigid d-Glu mimetics showed significantly better inhibitory activities than the parent compounds, thereby confirming the advantage of molecular rigidisation in the design of MurD inhibitors. The binding modes of the best inhibitors were examined with high-resolution NMR spectroscopy and X-ray crystallography. We have solved a new crystal structure of the complex of MurD with an inhibitor bearing a 4-aminocyclohexane-1,3-dicarboxyl moiety. These data provide an additional step towards the development of sulfonamide inhibitors with potential antibacterial activities.
- Sosi?, Izidor,Barreteau, Hélne,Sim?i?, Mihael,?ink, Roman,Cesar, Jo?ko,Zega, Anamarija,Grdadolnik, Simona Goli?,Contreras-Martel, Carlos,Dessen, Andréa,Amoroso, Ana,Joris, Bernard,Blanot, Didier,Gobec, Stanislav
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scheme or table
p. 2880 - 2894
(2011/07/08)
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- 2 -AMINOQUINAZOLINE DERIVATIVES AND THEIR THERAPEUTIC USES
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A compound of formula (I) wherein X is NH2or OH and W is -C(O)-O- or -O-C(O)-; use thereof as a medicament, in particular for the treatment of inflammation, autoimmune disorder, immunogenic rejection reactions and cancer and for non-surgical abortion.
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Page/Page column 26
(2009/01/24)
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- CYCLIC COMPOUNDS CONTAINING ZINC BINDING GROUPS AS MATRIX METALLOPROTEINASE INHIBITORS
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This invention provides compounds defined by Formula I Z-L-R1-Q-D-(V1)m-R2 I or a pharmaceutically acceptable salt thereof, wherein Z, L, R1, Q, D, V1, m, and R2 are as defined in the specification. The invention also provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, as defined in the specification, together with a pharmaceutically acceptable carrier, diluent, or excipient. The invention also provides methods of inhibiting an MMP-13 enzyme in an animal, comprising administering to the animal a compound of Formula I, or a pharmaceutically acceptable salt thereof. The invention also provides methods of treating a disease mediated by an MMP-13 enzyme in a patient, comprising administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, either alone or in a pharmaceutical composition. The invention also provides methods of treating diseases such as heart disease, multiple sclerosis, osteo- and rheumatoid arthritis, arthritis other than osteo- or rheumatoid arthritis, cardiac insufficiency, inflammatory bowel disease, heart failure, age-related macular degeneration, chronic obstructive pulmonary disease, asthma, periodontal diseases, psoriasis, atherosclerosis, and osteoporosis in a patient, comprising administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, either alone or in a pharmaceutical composition. The invention also provides combinations, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, together with another pharmaceutically active component as described in the specification.
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Page/Page column 157
(2010/02/06)
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- Matrix metalloproteinase inhibitors
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Compounds are provided that bind allosterically to the catalytic domain of MMP-13 and comprise a hydrophobic group, first and second hydrogen bond acceptors and at least one, and preferably both, of a third hydrogen bond acceptor and a second hydrophobic group. Cartesian coordinates for centroids of the above features are defined in the specification. When the ligand binds to MMP-13, the first, second and third (when present) hydrogen bond acceptors bond respectively with Thr245, Thr 247 and Met 253, the first hydrophobic group locates within the S1' channel of MMP-13 and the second hydrophobic group (when present) is relatively open to solvent. The compounds specifically inhibit the matrix metalloproteinase-13 enzyme and thus are useful for treating diseases resulting from tissue breakdown, such as heart disease, multiple sclerosis, arthritis, atherosclerosis, and osteoporosis.
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- Quinazolines as MMP-13 inhibitors
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A compound selected from those of formula (I): in which: R1 represents a group selected from hydrogen, amino, alkyl, alkenyl, aminoalkyl, aryl, arylalkyl, heterocycle, and cycloalkylalkyl, optionally substituted, W represents oxygen, sulfhur, or ═N—R′, in which R′ is as defined in the description, X1, X2 and X3 represent nitrogen or —C—R6 in which R6 is as defined in the description, Y represents oxygen, sulfhur, —NH, or —N(C1-C6)alkyl, Z represents oxygen, sulfhur, —NR7 in which R7 is as defined in the description, and 59 optionally carbon atom, n is an integer from 1 to 8 inclusive, Z1 represents —CR8R9 wherein R8 and R9 are as defined in the description, A represents aromatic or non-aromatic, heterocyclic or non-heterocyclic ring system, m is an integer from 0 to 7 inclusive, the group(s) R2 is (are) is as defined in the description, R3 represents hydrogen, alkyl, alkenyl, alkynyl, ot a group of formula: in which Z2, B, R5, P and q are as defined in the description, optionally, the racemic forms thereof, isomers thereof, N-oxydes thereof, and the pharmaceutically acceptable salts thereof, and medicinal products containing the same are useful as specific inhibitors of type-13 matrix metalloprotease.
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- Diels-Alder Reaction of 2-Amino-Substituted Furans as a Method for Preparing Substituted Anilines
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5-Amino-2-furancarboxylic acid methyl ester undergoes a facile Diels-Alder cycloaddition with a variety of dienophiles to afford ring-opened cycloadducts that are readily dehydrated using BF3-OEt2 to give polysubstituted anilines. In each case, the cycloaddition proceeds with high regioselectivity, with the electron-withdrawing group being located ortho to the amino group. The most favorable FMO interaction is between the HOMO of the furanamine and the LUMO of the dienophile. The atomic coefficient at the ester carbon of the furan is larger than that at the amino center, and this nicely accommodates the observed regioselectivity. The [4 + 2]-cycloaddition of N-(5-nitrofuranyl)morpholine with methyl vinyl ketone affords a mixture of three phenols. One of the phenols is derived from a Diels - Alder reaction followed by nitro group ejection and subsequent aromatization. The remaining two phenols are the result of cleavage of the initially formed oxabicyclic intermediate with concomitant migration of the nitro group. The mild reaction conditions with which furan-2-carbamic acid tert-butyl ester undergoes Diels - Alder cycloaddition with N-phenylmaleimide allow for the ready isolation of the initial oxybridged cycloadduct.
- Padwa, Albert,Dimitroff, Martin,Waterson, Alex G.,Wu, Tianhua
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p. 4088 - 4096
(2007/10/03)
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- Synthesis of polysubstituted anilines using the Diels-Alder reaction of methyl 5-aminofuroate
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Methyl 5-aminofuroate undergoes a facile [4+2]-cycloaddition with a variety of dienophiles to afford ring opened cycloadducts which are readily dehydrated using BF3·OEt2 to give polysubstituted anilines.
- Cochran, John E.,Wu, Tianhua,Padwa, Albert
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p. 2903 - 2906
(2007/10/03)
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- Fused pyridazinoquinazolone derivatives as neurotrophic agents
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Fused pyridazinoquinazoline compounds, salts thereof, methods of production, intermediates in their production, pharmaceutical compositions containing said compounds and methods for treating neurodegenerative disorders using said compositions are disclosed.
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