- Phenylquinoline transient receptor potential vanilloid 1 antagonists for the treatment of pain: Discovery of 1-(2-phenylquinoline-4-carbonyl)-N-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxamide
-
Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a phenylquinoline platform that evolved from Cinchophen lead. This design composes three sections: a phenylquinoline headgroup attached to an aliphatic carboxamides, which is tethered at a phenyl tail group. Optimization of this design led to the identification of 37, comprising a pyrrolidine linker and a trifluoromethyl–phenyl tail. In the TRPV1 functional assay, using cells expressed hTRPV1, 37 antagonized capsaicin-induced Ca2+ influx, with an IC50 value of 10.2 nM. In the complete mice analgesic model, 37 exhibited better antinociceptive activity than the positive control BCTC in diverse pain models. All of these results suggested that 37 could be considered as a lead candidate for the further development of antinociceptive drugs.
- Liao, Chen,Liu, Yan,Liu, Chunxia,Zhou, Jiaqi,Li, Huilan,Wang, Nasi,Li, Jieming,Liu, Taiyu,Ghaleb, Hesham,Huang, Wenlong,Qian, Hai
-
p. 845 - 854
(2018/01/10)
-
- Discovery of novel diaryl urea derivatives bearing a triazole moiety as potential antitumor agents
-
Herein, we report a novel series of diaryl urea derivatives bearing a triazole moiety, from which potent antitumor agents have been identified. With a modified triazole, most compounds showed high level activity in both cellular and enzymatic assays, accompanied with a suitable ClogD7.4 value. The most active compound, 13i, effectively suppressed proliferation of HT-29, H460 and MDA-MB-231 cancer cells, with IC50 values of 0.90, 0.85 and 1.54 μM, respectively. Compound 13i also exhibited significant inhibition of tyrosine kinases including c-Kit, RET and FLT3. Furthermore, compound 13i could obviously induce apoptosis of HT-29 cells in a concentration-dependent manner. The study of structure-activity relationships also revealed that a hydrophilic tail at the 4-position of the triazole was crucial for high activity of the compound.
- Qin, Mingze,Yan, Shuang,Wang, Lei,Zhang, Haotian,Zhao, Yanfang,Wu, Shasha,Wu, Di,Gong, Ping
-
-
- N-fluorinated phenyl-N′-pyrimidyl urea derivatives: Synthesis, biological evaluation and 3D-qsar study
-
With the increase of herbicide-resistant weeds, novel, more selective and even more potent herbicides to control weeds are needed. In this paper, a series of N-fluorinated phenyl-N′-pyrimidyl urea derivatives were synthesized and screened for their herbicidal activities against Amaranthus retroflexus (AR) and Setaria viridis (SV). Compound 25 (N-(3-trifluoromethylphenyl)-N′-(2- amino-4-chloro-6-methylpyrimidyl) urea) exhibited marked herbicidal activity against SV (IC50 = 11.67 mg/L) and is more potent than bensulfuron (IC50 = 27.45 mg/L), a commercially available herbicide. A statistically significant CoMFA model with high prediction abilities (q 2 = 0.869, r2 = 0.989) was obtained.
- Yue, Xia-Li,Li, Hu,Liu, Shuang-Shuang,Zhang, Qing-Ye,Yao, Jing-Jing,Wang, Fei-Yan
-
p. 1069 - 1072
(2014/08/18)
-
- Design, synthesis, and quantitative structure-activity relationship study of herbicidal analogues of pyrazolo[5,1-d][1,2,3,5]tetrazin-4(3H)ones
-
A series of pyrazolo[5,1-d][1,2,3,5]tetrazin-4(3H)one derivatives were designed, synthesized, and evaluated for their herbicidal activities where some of these compounds provided 0.8) with physicochemical parameters in this set of molecules. The herbicidal activity against B. campestris was mainly affected by the molar refractivity (MR) for R1, Taft (Es0) for R2 or R6, Verloop (Lm) for R3 or R5, and electronic parameters (Hammett's constants) for R4. The optimal MR for herbicidal activity is 0.95. The herbicidal activity against Echinochloa crus-galli was mainly related with the substituents' hydrophobic parameter. The optimal π parameters for R 1 and R4 for herbicidal activity are 0.72 and 0.68, respectively. In general, these compounds showed greater herbicidal activity toward B. campestris than E. crus-galli.
- Zhu, You-Quan,Wu, Chao,Li, Hua-Bin,Zou, Xiao-Mao,Si, Xue-Kai,Hu, Fang-Zhong,Yang, Hua-Zheng
-
experimental part
p. 1364 - 1369
(2009/09/06)
-
- Organosilicon synthesis of isocyanates: I. Synthesis of isocyanates of the furan, thiophene, and mono-and polyfluorophenyl series
-
A convenient synthesis of known and unknown isocyanates of the furan, thiophene, and mono-and polyfluorophenyl series, involving silylation of starting amines with hexamethyldisilazane or chlorotrimethylsilane, followed by phosgenation of the resulting N-silyl-substituted amines. An unusual high-temperature rearrangement of 3-(methoxycarbonyl)-4,5-dimethylthiophene-2-yl isocyanate into its 5-ethyl isomer. ortho-Fluorine substituent in anilines decreases the yield of isocyanates, whereas 2,3,5,6-tetrafluorophenyl isocyanate exists for only a short time as a 5% toluene solution. Pleiades Publishing, Inc. 2006.
- Lebedev,Lebedeva,Sheludyakov,Ovcharuk,Kovaleva,Ustinova
-
p. 110 - 115
(2008/01/27)
-
- Novel carbamates as potent histamine H3 receptor antagonists with high in vitro and oral in vivo activity
-
The known histamine H3 receptor antagonists burimamide, thioperamide, clobenpropit, and a related homohistamine thioamide derivative were taken as templates in search for new leads. Novel histamine H3 receptor antagonists structurally described as carbamate derivatives of 3-(1H-imidazol-4- yl)propanol were prepared in high yields by treatment of the alcohol with corresponding isocyanates or carbamoyl chlorides and investigated for their H3 receptor antagonist activity. Different chain lengths and various substituents possessing different electronic and steric parameters were introduced and structure-activity relationships established. In different functional tests, the new antagonists showed high H3 receptor antagonist potencies in vitro (-log K(i) values of 6.4-8.4) at synaptosomes of rat cerebral cortex and low activities at histamine H1 and H2 receptor subtypes. They were also screened for their central in vivo activity in mice after peroral administration. The most promising compounds (2, 16, 19) showed ED50 values of about 1-2 mg/kg and thus are potential drugs for the therapy of H3 receptor dependent diseases. Some of the novel carbamate derivatives are H3 receptor selective compounds with high in vitro and in vivo activity.
- Stark, Holger,Purand, Katja,Ligneau, Xavier,Rouleau, Agnès,Arrang, Jean-Michel,Garbarg, Monique,Schwartz, Jean-Charles,Schunack, Walter
-
p. 1157 - 1163
(2007/10/03)
-
- REARRANGEMENT OF N-(TRIFLUOROMETHYL)ANTHRANILOYL FLUORIDE TO 2-(TRIFLUOROMETHYL)ANILINE - KINETIC AND MECHANISTIC OBSERVATIONS
-
Pseudo first order rate constants for the rearrangement of N-(trifluoromethyl)anthraniloyl fluoride (2) to N-carbamoyl fluoride (3) in anhydrous HF have been determined.Increasing HF levels accelerate this process, but increasing KF concentrations retard the reaction.An ionic species has been proposed as the intermediate in the suggested mechanism.Further reaction of 3 with HF proceeded to give 2-(trifluoromethyl)aniline hydrofluoride (4) via an unprecedented expulsion of carbonyl fluoride.
- Lin, Henry C.,Cotter, Byron R.,Bieron, Joseph F.,Krishnamurti, Ramesh
-
p. 107 - 116
(2007/10/02)
-
- Synthesis of sulfilimines
-
Processes are disclosed for preparation of N-aryl-S,S-dihydrocarbylsulfilimines by reaction of phenylisocyanate compounds with hydrocarbyl sulfoxides. The sulfilimines can be rearranged to ortho-thioalkylene anilines and the reactions can be employed in a route for converting nitrobenzene compounds to ortho-thioalkylene anilines, which are useful intermediates for preparation of herbicidal compounds.
- -
-
-
- Inactivation of Leukocyte Elastase by Aryl Azolides and Sulfonate Salts. Structure-Activity Relationship Studies
-
The inhibitory activity of a series of aryl azolides and sulfonate salts toward human leukocyte elastase is reported.Several of the compounds were found to be potent inhibitors of the enzyme.Active compounds were obtained only when the specificity group and the reactive moiety were separated by a two-carbon chain.The introduction of hydrophobic groups enhanced the inhibitory activity of these compounds, with the exception of the sulfonate salts.The nature of the leaving group had had a profound effect on inhibitory activity, with compounds 23 and 26 being the most active (kobsd/ = 11722 and 13500 M-1 s-1, respectively).
- Groutas, W. C.,Brubaker, M. J.,Zandler, M. E.,Mazo-Gray, V.,Rude, S. A.,et al.
-
p. 1302 - 1305
(2007/10/02)
-
