- Expedient discovery for novel antifungal leads: 1,3,4-Oxadiazole derivatives bearing a quinazolin-4(3H)-one fragment
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Developing novel fungicide candidates are intensively promoted by the rapid emergences of resistant fungi that outbreak on agricultural production. Aiming to discovery novel antifungal leads, a series of 1,3,4-oxadiazole derivatives bearing a quinazolin-4(3H)-one fragment were constructed for evaluating their inhibition effects against phytopathogenic fungi in vitro and in vivo. Systematically structural optimizations generated the bioactive molecule I32 that was identified as a promising inhibitor against Rhizoctonia solani with the in vivo preventative effect of 58.63% at 200 μg/mL. The observations that were captured by scanning electron microscopy and transmission electron microscopy demonstrated that the bioactive molecule I32 could induce the sprawling growth of hyphae, the local shrinkage and rupture on hyphal surfaces, the extreme swelling of vacuoles, the striking distortions on cell walls, and the reduction of mitochondria numbers. The above results provided an indispensable complement for the discovery of antifungal lead bearing a quinazolin-4(3H)-one and 1,3,4-oxadiazole fragment.
- Chai, Jianqi,Chen, Min,Jin, Fei,Kong, Xiangyi,Wang, Xiaobin,Xue, Wei,Yang, Chunlong
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- Synthesis and computer-aided SAR studies for derivatives of phenoxyalkyl-1,3,5-triazine as the new potent ligands for serotonin receptors 5-HT6
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This research has provided the most active 5-HT6R agents among 1,3,5-triazine derivatives investigated to date and has also identified the world's first selenium-containing 5-HT6R ligands. The studies are focused on design, synthesis, biological evaluation and docking-supported SAR analysis for novel 5-HT6R agents as derivatives of lead structure 4-(4-methylpiperazin-1-yl)-6-(phenoxymethyl)-1,3,5-triazin-2-amine (7). The lead modifications included an introduction of: (i) various small substituents at benzene ring, (ii) a branched ether linker or (iii) the ether oxygen replacement with other chalcogen (S, Se) or sulfonyl moiety. Hence, a series of new compounds (7–24) was synthesized and examined on their affinities for 5-HT6R and selectivity, in respect to the 5-HT1AR, 5-HT2AR, 5-HT7R and dopamine D2 receptor, in the radioligand binding assays. For representative most active compounds functional bioassays and toxicity profile in vitro and antidepressant-like activity in vivo were examined. The 2-isopropyl-5-methylphenyl derivative (10) was found as the most active triazine 5-HT6R antagonist (Ki = 11 nM). SAR analysis indicated, that an exchange of oxygen to selenium (7 vs. 22), and especially, to sulfur (7 vs. 19) was beneficial to increase both affinity and antagonistic action for 5-HT6R. Surprisingly, an introduction of SO2 caused a drastic decrease of the 5-HT6R affinity, which was explained at a molecular level based on docking studies. All in vivo tested compounds (10, 18 and 21) did not show any risk of toxicity in the safety studies in vitro.
- Ali, Wesam,Wi?cek, Ma?gorzata,?a?ewska, Dorota,Kurczab, Rafa?,Jastrz?bska-Wi?sek, Magdalena,Sata?a, Grzegorz,Kucwaj-Brysz, Katarzyna,Lubelska, Annamaria,G?uch-Lutwin, Monika,Mordyl, Barbara,Siwek, Agata,Nasim, Muhammad Jawad,Partyka, Anna,Sudo?, Sylwia,Latacz, Gniewomir,Weso?owska, Anna,Kie?-Kononowicz, Katarzyna,Handzlik, Jadwiga
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supporting information
p. 740 - 751
(2019/06/24)
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- Synthesis and larvicidal activity of 1,3,4-oxadiazole derivatives containing a 3-chloropyridin-2-yl-1H-pyrazole scaffold
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Abstract: A new series of 1,3,4-oxadiazole derivatives with a 3-chloropyridin-2-yl-1H-pyrazole moiety was designed, synthesized, and characterized. The results of bioassay against Helicoverpa armigera and Plutella xylostella indicated that some of the synthesized compounds showed remarkable larvicidal activity. In particular, the LC50 values of the most active compounds against P. xylostella were 46.5, 23.9, and 13.9?mg/dm3, and against Helicoverpa armigera were 88.3 and 69.5?mg/dm3, the latter being slightly better than commercial chlorpyrifos (LC50 103.77?mg/dm3). Preliminary SAR was also discussed. Graphical abstract: [Figure not available: see fulltext.].
- Wang, Yanyan,Lu, Xiumian,Shi, Jun,Xu, Jiahong,Wang, Fenghua,Yang, Xiao,Yu, Gang,Liu, Zhiqian,Li, Chuanhui,Dai, Ali,Zhao, Yonghui,Wu, Jian
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p. 611 - 623
(2018/01/17)
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- The synthesis and evaluation of phenoxyacylhydroxamic acids as potential agents for Helicobacter pylori infections
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Two series of ω-phenoxy contained acylhydroxamic acids as novel urease inhibitors were designed and synthesized. Biological activity evaluations revealed that ω-phenoxypropinoylhydroxamic acids were more active than phenoxyacetohydroxamic acids. Out of these compounds, 3-(3,4-dichlorophenoxy)propionylhydroxamic acid c24 showed significant potency against urease in both cell free extract (IC50 = 0.061 ± 0.003 μM) and intact cell (IC50 = 0.89 ± 0.05 μM), being over 450- and 120-fold more potent than the clinically prescribed urease inhibitor AHA, repectively. Non-linear fitting of experimental data (V-[S]) suggested a mixed-type inhibition mechanism and a dual site binding mode of these compounds.
- Ni, Wei-Wei,Liu, Qi,Ren, Shen-Zhen,Li, Wei-Yi,Yi, Li-Li,Jing, Heng,Sheng, Li-Xin,Wan, Qin,Zhong, Ping-Fu,Fang, Hai-Lian,Ouyang, Hui,Xiao, Zhu-Ping,Zhu, Hai-Liang
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supporting information
p. 4145 - 4152
(2018/07/13)
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- An improved and efficient process for the preparation of (+)-cloprostenol
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Abstract An improved and efficient synthesis of (+)-cloprostenol has been accomplished in nine steps and 26% overall yield from commercially available (-)-Corey lactone 4-phenylbenzoate alcohol 1. The present route avoids tedious purifications and require
- Chen, Yi,Yan, Hui,Chen, Hui-Xuan,Weng, Jiang,Lu, Gui
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supporting information
p. 392 - 396
(2015/06/02)
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- PYRAZOLO[3,4-D]PYRIMIDIN-4(5H)-ONE DERIVATIVES AS PDE9 INHIBITORS
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A compound of the general formula (I) wherein R1 is selected from the group consisting of phenyl unsubstituted or substituted with 1 to 3 substituents selected from F, Cl, Br, I, CN, -O-C1-C3-alkyl, fluorinated -O-C1-C3-alkyl, -(CH2)mOH and 5-membered heterocyclic group with 1 or 2 heteroatoms selected from N, O and S; and 6- or 10-membered heteroaryl with 1 to 3 heteroatoms selected from O, N and S; R2 and R3 independently of each other represent H atom or straight or branched C1-C3 alkyl; R4 is selected from the group consisting of 4- to 6- membered cycloalkyl, wherein one of carbon atoms can be replaced by O atom, and which is unsubstituted or substituted with one or two halogen atoms,and straight or branched C1-C4 alkyl; Q represents a bond or C1-C3-alkylene, which can be optionally substituted by one to three C1-C3-alkyls; X is selected from the group consisting of O, NR5, and S(O)p; R5 represents H atom or C1-C3alkyl; m is 1, 2 or 3; p is 0, 1 or 2; and salts thereof, for use as a medicament, in particular for treating cognitive function disorders and neurodegenerative diseases.
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Page/Page column 24
(2014/02/16)
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- Aggrecanase-2 inhibitors based on the acylthiosemicarbazide zinc-binding group
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Osteoarthritis is a disabling disease characterized by the articular cartilage breakdown. Aggrecanases are potential therapeutic targets for the treatment of this pathology. At the starting point of this project, an acylthiosemicarbazide was discovered to inhibit aggrecanase-2. The acylthiosemicarbazide Zn binding group is also a convenient linker for library synthesis. A focused library of 920 analogs was thus prepared and screened to establish structure-activity relationships. The modification of the acylthiosemicarbazide was also explored. This strategy combining library design and discrete compounds synthesis yielded inhibitor 35, that is highly selective for aggrecanases over a panel of metalloproteases and inhibits the degradation of native fully glycosylated aggrecan. A docking study generated binding conformations explaining the structure-activity relationships.
- Maingot, Lucie,Elbakali, Jamal,Dumont, Julie,Bosc, Damien,Cousaert, Nicolas,Urban, Agathe,Deglane, Gaelle,Villoutreix, Bruno,Nagase, Hideaki,Sperandio, Olivier,Leroux, Florence,Deprez, Benoit,Deprez-Poulain, Rebecca
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p. 244 - 261
(2013/10/01)
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- Synthesis and xanthine oxidase inhibitory activity of 7-methyl-2- (phenoxymethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one derivatives
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An elevated level of blood uric acid (hyperuricemia) is the underlying cause of gout. Xanthine oxidase is the key enzyme that catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid. Allopurinol, a widely used xanthine oxidase inhibitor is the most commonly used drug to treat gout. However, a small but significant portion of the population suffers from adverse effects of allopurinol that includes gastrointestinal upset, skin rashes and hypersensitivity reactions. Moreover, an elevated level of uric acid is considered as an independent risk factor for cardiovascular diseases. Therefore use of allopurinol-like drugs with minimum side effects is the ideal drug of choice against gout. In this study, we report the synthesis of a series of pyrimidin-5-one analogues as effective and a new class of xanthine oxidase inhibitors. All the synthesized pyrimidin-5-one analogues are characterized by spectroscopic techniques and elemental analysis. Four (6a, 6b, 6d and 6f) out of 20 synthesized molecules in this class showed good inhibition against three different sources of xanthine oxidase, which were more potent than allopurinol based on their respective IC50 values. Molecular modeling and docking studies revealed that the molecule 6a has very good interactions with the Molybdenum-Oxygen-Sulfur (MOS) complex a key component in xanthine oxidase. These results highlight the identification of a new class of xanthine oxidase inhibitors that have potential to be more efficacious, than allopurinol, to treat gout and possibly against cardiovascular diseases.
- Sathisha,Khanum, Shaukath A.,Chandra, J.N. Narendra Sharath,Ayisha,Balaji,Marathe, Gopal K.,Gopal, Shubha,Rangappa
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experimental part
p. 211 - 220
(2011/03/17)
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- THIADIAZOLE DERIVATIVES, INHIBITORS OF STEAROYL-COA DESATURASE
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The present invention relates to substituted thiadiazole compounds of the formula (I) and pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing them and their use in medicine. In particular, the invention relates to compounds for modulating SCD activity.
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Page/Page column 43
(2008/12/07)
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- Hydrazide compounds
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Hydrazide compounds with GPCR desensitization inhibitory activity are provided that may be used to influence, inhibit or reduce the action of a G-protein receptor kinase. Pharmaceutical compositions including therapeutically effective amounts of the hydra
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Page/Page column 19
(2010/11/27)
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- Use of 9-deoxy prostaglandin derivatives to treat glaucoma
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Disclosed are 9-deoxyprostaglandins which are useful in the treatment of glaucoma and ocular hypertension. Some of these 9-deoxyprostaglandins are novel. Also disclosed are ophthalmic, pharmaceutical compositions comprising such prostaglandins.
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- 16-Phenoxy and phenylthio prostaglandin derivatives
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The present invention relates to compounds of the formula: STR1 wherein A represents a grouping of the formula: STR2 B represents an oxygen or sulphur atom, R1 and R2, which may be the same or different, each represent a hydrogen or halogen atom, a trifluoromethyl group, or a straight- or branched-chain alkyl or alkoxy group containing from 1 to 4 carbon atoms, R represents a group of the formula --COOR3, in which R3 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 12 carbon atoms, or a group of the formula --CH2 OR4, in which R4 represents a hydrogen atom or an alkylcarbonyl group containing from 2 to 5 carbon atoms and the double bonds depicted in positions C2 -C3, C5 -C6 and C13 -C14 are trans, cis and trans respectively, the cyclodextrin clathrates thereof and, when R3 in the group --COOR3 represents a hydrogen atom, non-toxic salts thereof. These compounds exhibit characteristics of prostaglandin-like activity.
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- 16-Phenoxy and 16-substituted phenoxy-prostatrienoic acid derivatives
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Novel racemic and 8R-antimeric 16-phenoxy- and 16-(o, m or p)-substituted phenoxy derivatives of 9α, 11α,15-trihydroxy-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acids, which may be further substituted at C-15 by a methyl or ethyl group, the pharmaceutically acceptable, non-toxic lower alkyl esters and salts thereof and processes for the production of such compounds. dl 9α,11α,15α-trihydroxy-16-m-trifluoromethylphenoxy-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid and dl 9α,11α,15 -trihydroxy-15 -methyl-16-m-trifluoromethylphenoxy-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid are representative compounds of the class. These compounds possess prostaglandin-like activities and thus are useful in the treatment of mammals where prostaglandins are indicated. They are particularly useful as luteolytic agents in female mammals.
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