- Discovery of Novel Piperidinylthiazole Derivatives As Broad-Spectrum Fungicidal Candidates
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Oxathiapiprolin is one of the best active fungicides discovered for oomycetes control. To develop a fungicide candidate with a broad spectrum of activity, 22 new piperidinylthiazole derivatives were designed and synthesized. Compound 5l showed the best activity against Pseudoperonospora cubensis (Berk. et Curt.) Rostov and Phytophthora infestans in vivo with 100% and 80% of inhibition, respectively, at 1 mg/L, and 72.87% of field efficacy against P. cubensis at 1 g ai/667 m2 validated these results. Compound 5i exhibited a broad spectrum of excellent activity against Sclerotinia sclerotiorum with EC50 = 0.30 mg/L (>10 times more active than oxathiapiprolin and azoxystrobin in vitro), good activity against Botrytis cinerea, Cercospora arachidicola, and Gibberella zeae with EC50 of 14.54, 5.57, and 14.03 mg/L in vitro and against P. cubensis and P. infestans with 60% and 30% inhibition rates, respectively, at 1 mg/L in vivo. Mode of action studies by RNA sequencing analysis discovered oxysterol-binding protein (OSBP), chitin synthase (CHS1), and (1,3)-β-glucan synthase (FKS2) as the potent target of 5i against S. sclerotiorum. Quenching studies validated that OSBP was the same target of both 5i and oxathiapiprolin; it was quenched by both of them. Our studies discovered isothiazole-containing piperidinylthiazole as an OSBP target-based novel lead for fungicide development.
- Wu, Qifan,Zhao, Bin,Fan, Zhijin,Guo, Xiaofeng,Yang, Dongyan,Zhang, Nailou,Yu, Bin,Zhou, Shuang,Zhao, Jiabao,Chen, Fan
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- Design, Synthesis, and Fungicidal Activities of Novel Piperidyl Thiazole Derivatives Containing Oxime Ether or Oxime Ester Moieties
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To explore the influence of the positions of the two nitrogen atoms on the thiazole ring and the isoxazoline ring on the activity, a series of novel piperidyl thiazole derivatives containing oxime ether and oxime ester moieties with two nitrogen atoms on the same or opposite sides have been designed, synthesized, and first evaluated for their fungicidal activities against Phytophthora capsici in vitro. The bioassay results showed that the target compounds possessed moderate to good fungicidal activities against P. capsici, among which oxime ether compound 11b shows the highest fungicidal activity in vitro (EC50 = 0.0104 μg/mL) which is higher than dimethomorph (EC50 = 0.1148 μg/mL) and diacetylenyl amide (EC50 = 0.040 μg/mL). Compared with oxime ether compounds (the two nitrogen atoms are on the opposite sides), the activities of oxime ester compounds were significantly reduced. It is different from the commercial fungicide fluoxapiprolin, and the activities of the compounds with the two nitrogen atoms on the same side were significantly reduced compared to the compounds with the two nitrogen atoms on the opposite sides. Moreover, compounds 11b, 11d, 11e, and 11g showed moderate to good antifungal activities in vivo against Phytophthora capsici, Pseudoperonospora cubensis, and Phytophthora infestans. Scanning electron microscopy of compound 11b on the hyphae morphology showed that compound 11b might cause mycelial abnormalities of P. capsici.
- Bian, Qiang,Zhao, Rui-Qi,Peng, Xing-Jie,Gao, Li-Jie,Zhou, Guo-Na,Yu, Shu-Jing,Zhao, Wei-Guang
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- Design and biological evaluation of tetrahydropyridine derivatives as novel human GPR119 agonists
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A series of novel tetrahydropyridine derivatives were prepared and evaluated using cell-based measurements. Systematic optimization of general structure G-1 led to the identification of compound 35 (EC50 = 4.9 nM) and 37 (EC50 = 8.8 nM) with high GPR119 agonism activity and moderate clog P. Through single and long-term pharmacodynamic experiments, we found that compound 35 showed a hypoglycemic effect and may have an effect on improving basal metabolic rate in DIO mice. Both in vitro and in vivo tests indicated that compound 35 was a potential potent GPR119 agonist in allusion to T2DM treatment.
- Zuo, Zeping,Chen, Miaomiao,Shao, Xiaoni,Qian, Xinying,Liu, Xiaocong,Zhou, Xia,Xiang, Jiawei,Deng, Pengchi,Li, Yan,Jie, Hui,Liu, Chunqi,Cen, Xiaobo,Xie, Yongmei,Zhao, Yinglan
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- Piperidyl tetrahydrobenzothiazole oxime ether derivative and application thereof
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The invention relates to a piperidyl tetrahydrobenzothiazole oxime ether derivative as shown in a general formula (I) and application of the piperidyl tetrahydrobenzothiazole oxime ether derivative asa bactericide. The compound represents a novel bactericide structure type, has excellent sterilization activity and can be used for preventing and treating diseases such as downy mildew, late blightand downy mildew generated by oomycetes pathogenic bacteria, particularly cucumber downy mildew, grape downy mildew, cabbage downy mildew, tomato late blight, potato late blight, pepper late blight, litchi downy blight and soybean phytophthora root rot. The compound is also suitable for sclerotinia sclerotiorum, ring rot, gray mold, banded sclerotial blight and the like. The compound disclosed bythe invention can be directly used, can also be used together with an agriculturally acceptable carrier, and can also be compounded with other bactericides for use.
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- Synthetic method and application of piperidyl thiazole formamide compound
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The invention relates to a 2-(4-piperidyl)-thiazole-4-formamide compound and a synthetic method and medicinal evaluation thereof. The synthetic method comprises the following steps: carrying out a substitution reaction between N-Boc-4-piperidine-carboxylic acid and ammonium chloride to prepare an intermediate 2; carrying out a thiolation reaction between the compound 2 and a Lawesson reagent to obtain an intermediate 3; carrying out a reaction between the compound 3 and ethyl bromopyruvate to obtain an intermediate 4; carrying out esterolysis on the compound 4 to obtain a compound 5; carryingout a reaction between the compound 5 and ammonia to obtain an intermediate 6; deprotecting the Boc protected compound 6 to obtain a compound 7; performing acid condensation on the compound 7 to obtain an intermediate 8; deprotecting the Boc protected intermediate 8 to obtain a compound 9; and carrying out a reaction between the compound 9 and different isocyanates to obtain a final product. An MTT method is adopted for tests, and it shows that part of the 2-(4-piperidyl)-thiazole-4-formamide compounds have certain anti-tumor activity, wherein the antitumor activity of a compound 10f-10m is superior to that of a compound 10a-10d.
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- Piperidine thiazole derivative containing bisamide structure as well as preparation method and application thereof
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The invention discloses a piperidine thiazole derivative containing a bisamide structure, and also discloses a preparation method of the piperidine thiazole derivative and application of the piperidine thiazole derivative as a sterilization agent and an insecticide. The invention provides the novel piperidine thiazole derivative containing the bisamide structure; the preparation method is simpleand convenient; the piperidine thiazole derivative can be used for preventing and treating cucumber gray mold, rice sheath blight diseases and potato late blight diseases, has good sterilization activity, can be used for preventing and treating insect pest of armyworm, black bean aphid, tetranychus telarius linne and the like, and lays the foundation for the invention and development of piperidinethiazole pesticides.
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Paragraph 0016
(2019/02/03)
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- Alpha-amino acid derivative containing piperidine thiazole heterocycle and preparation method and application of alpha-amino acid derivative
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The invention discloses an alpha-amino acid derivative containing piperidine thiazole heterocycle. The alpha-amino acid derivative has a structural formula of formula I shown in the description, wherein in formula I, Ar is a phenyl group or a substituted phenyl group, a substituted group of the substituted phenyl group is one of a trifluoromethyl group, fluorine, chlorine or bromine, and R is oneof H and isopropyl. The invention further discloses a preparation method of the alpha-amino acid derivative and application of the alpha-amino acid derivative serving as an insecticide to prevention and control of armyworms. The novel alpha-amino acid derivative containing the piperidine thiazole heterocycle is simple in preparation method, can be used for prevention and control of armyworm insectpests, particularly has a good insecticidal activity against the armyworms, and provides bases for research and development of amino acid pesticides.
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Paragraph 0018
(2019/02/27)
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- Application of piperidine-containing thiazole compound and preparation method thereof
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The invention discloses application of a piperidine-containing thiazole compound as a bactericide in controlling cucumber downy mildew and rice sheath blight, and a preparation method of the piperidine-containing thiazole compound. The invention provides a novel application of the piperidine-containing thiazole compound. The compound is a new compound with bactericidal activity and provides a foundation for the research and development of piperidine thiazole pesticides. The preparation method of the invention provides a raw material foundation for the preparation of a bactericide.
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Paragraph 0006; 0014
(2018/04/02)
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- COMPOUNDS AND USES THEREOF
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The present invention features compounds useful in the treatment of neurological disorders. The compounds of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing neurological disorders.
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Page/Page column 134
(2018/05/17)
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- Synthesis and biological evaluation of thiazole derivatives as GPR119 agonists
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A series of 4-(phenoxymethyl)thiazole derivatives was synthesized and evaluated for their GPR119 agonistic effect. Several 4-(phenoxymethyl)thiazoles with pyrrolidine-2,5-dione moieties showed potent GPR119 agonistic activities. Among them, compound 27 and 32d showed good in vitro activity with an EC50 value of 49 nM and 18 nM, respectively with improved human and rat liver microsomal stability compare with MBX-2982. Compound 27 & 32d did not exhibit significant CYP inhibition, hERG binding, and cytotoxicity. Moreover, these compounds lowered the glucose excursion in mice in an oral glucose-tolerance test.
- Kim, Hyojin,Cho, Suk Joon,Yoo, Minjin,Kang, Seung Kyu,Kim, Kwang Rok,Lee, Hwan Hee,Song, Jin Sook,Rhee, Sang Dal,Jung, Won Hoon,Ahn, Jin Hee,Jung, Jae-Kyung,Jung, Kwan-Young
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p. 5213 - 5220
(2017/11/21)
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- GLYCOSIDASE INHIBITORS
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Compounds of formula (I) wherein A, R, W, Q, n and m have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
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- Sterilization compound and preparation method and application thereof
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The invention relates to the field of agricultural plant protection, and particularly relates to a sterilization compound and a preparation method and an application thereof. The compound has the structure represented by a formula defined in the specification, wherein R is selected from one of components defined in the specification; the compound has excellent bacteriostatic activity on potato phytophthora infestans, phytophthora capsici, phytophthora nicotianae, peronophthora litchii, pseudoperonospora cubensis and other plant pathogenic oomycetes, and has broad application prospects in prevention and control of oomycete diseases.
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- SUBSTITUTED NICOTINIMIDE INHIBITORS OF BTK AND THEIR PREPARATION AND USE IN THE TREATMENT OF CANCER, INFLAMMATION AND AUTOIMMUNE DISEASE
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Compounds of Formula I, as shown below and defined herein: and pharmaceutically acceptable salts, syntheses, intermediates, formulations, and methods of treating diseases including cancer, inflammation, and autoimmune disease mediated at least in part by Bruton's Tyrosine Kinase (BTK).
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Page/Page column 89; 114
(2015/04/15)
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- Diarylthiazole: An antimycobacterial scaffold potentially targeting PrrB-PrrA two-component system
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Diarylthiazole (DAT), a hit from diversity screening, was found to have potent antimycobacterial activity against Mycobacterium tuberculosis (Mtb). In a systematic medicinal chemistry exploration, we demonstrated chemical opportunities to optimize the potency and physicochemical properties. The effort led to more than 10 compounds with submicromolar MICs and desirable physicochemical properties. The potent antimycobacterial activity, in conjunction with low molecular weight, made the series an attractive lead (antibacterial ligand efficiency (ALE) >0.4). The series exhibited excellent bactericidal activity and was active against drug-sensitive and resistant Mtb. Mutational analysis showed that mutations in prrB impart resistance to DAT compounds but not to reference drugs tested. The sensor kinase PrrB belongs to the PrrBA two component system and is potentially the target for DAT. PrrBA is a conserved, essential regulatory mechanism in Mtb and has been shown to have a role in virulence and metabolic adaptation to stress. Hence, DATs provide an opportunity to understand a completely new target system for antimycobacterial drug discovery.
- Bellale, Eknath,Naik, Maruti,Vb, Varun,Ambady, Anisha,Narayan, Ashwini,Ravishankar, Sudha,Ramachandran, Vasanthi,Kaur, Parvinder,McLaughlin, Robert,Whiteaker, James,Morayya, Sapna,Guptha, Supreeth,Sharma, Sreevalli,Raichurkar, Anandkumar,Awasthy, Disha,Achar, Vijayshree,Vachaspati, Prakash,Bandodkar, Balachandra,Panda, Manoranjan,Chatterji, Monalisa
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p. 6572 - 6582
(2014/10/15)
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- THIAZOLYLPHENYL-BENZENESULFONAMIDO DERIVATIVES AS KINASE INHIBITORS
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Thiazolylphenyl-benzenesulfonamido derivatives of formula (I) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.
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- THIAZOLYLPHENYL-BENZENESULFONAMIDO DERIVATIVES AS KINASE INHIBITORS
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Thiazolylphenyl-benzenesulfonamido derivatives of formula (I) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.
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- PREPARATION OF 5-ETHYL-2-{4-[4-(4-TETRAZOL-1-YL-PHENOXYMETHYL)-THIAZOL-2-YL]-PIPERIDIN-1-YL}-PYRIMIDINE
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Processes and intermediates for the synthesis of 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine are provided.
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- COMPOSITIONS OF 5-ETHYL-2--PYRIMIDINE
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This invention relates to the field of pharmaceutical chemistry and, more specifically, to pharmaceutical formulations as well as to intermediates used to prepare such formulations and to methods for manufacturing such formulations.
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- THIAZOLE DERIVATIVES AS CXCR3 RECEPTOR MODULATORS
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The invention encompasses compounds of Formula I (I) or pharmaceutically acceptable salts thereof, which are antagonist of the CXCR3 chemokine receptor useful for the treatment or prevention of pathogenic inflammatory processes, autoimmune diseases or graft rejection processes. Methods of use and pharmaceutical compositions are also encompassed.
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Page/Page column 28
(2008/06/13)
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- NEW SUBSTITUTED 1,3-THIAZOLE DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF HAVING IMMUNOSUPPRESSION AND INFLAMMATION INHIBITORY ACITIVITY, INTERMEDIATE COMPOUNDS OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, A PROCESS FOR THE PREPARATION THEREOF, AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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Disclosed relates to new substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppresion and inflammation inhibitory activity, intermediate compounds or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and a pharmaceutical composition comprising the same. The compound of the present invention having excellent TNF-α inhibitory activity and inflammation inhibitory activity can be effectively used in the prevention and treatment of TNF-α related diseases.
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Page/Page column 120-121
(2010/11/25)
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- Design and synthesis of tri-ring P3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K
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We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.
- Palmer, James T.,Bryant, Clifford,Wang, Dan-Xiong,Davis, Dana E.,Setti, Eduardo L.,Rydzewski, Robert M.,Venkatraman, Shankar,Tian, Zong-Qiang,Burrill, Leland C.,Mendonca, Rohan V.,Springman, Eric,McCarter, John,Chung, Tobee,Cheung, Harry,Janc, James W.,McGrath, Mary,Somoza, John R.,Enriquez, Philip,Yu, Z. Walter,Strickley, Robert M.,Liu, Liang,Venuti, Michael C.,Percival, M. David,Falgueyret, Jean-Pierre,Prasit, Peppi,Oballa, Renata,Riendeau, Denis,Young, Robert N.,Wesolowski, Gregg,Rodan, Sevgi B.,Johnson, Colena,Kimmel, Donald B.,Rodan, Gideon
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p. 7520 - 7534
(2007/10/03)
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- Substituted 1,3-thiazole compounds, their production and use
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(1) A 1,3-thiazole compound of which the 5-position is substituted with a 4-pyridyl group having a substituent including no aromatic group or (2) a 1,3-thiazole compound of which the 5-position is substituted with a pyridyl group having at the position adjacent to a nitrogen atom of the pyridyl group a substituent including no aromatic group has an excellent p38 MAP kinase inhibitory activity.
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- PIPERIDINYL-THIAZOLE CARBOXYLIC ACID DERIVATIVES AS ANGIOGENESIS INHIBITORS
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This invention relates to compounds of formula (I) and (II) that are useful in treating vascular endothelial growth factor (VEGF)-mediated disorders, particularly endometriosis and acute macular degenerative disorder. The invention also relates to a topical system for the treatment of acute macular degenerative disorder comprising a VEGF inhibitor.
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- Pyrrolidine modulators of chemokine receptor activity
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The present invention is directed to pyrrolidine compounds of the formula I: (wherein R1, R2, R3, R4, R5, R6, R14and n are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-5 and/or CCR-3.
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