- Further hit optimization of 6-(trifluoromethyl)pyrimidin-2-amine based TLR8 modulators: Synthesis, biological evaluation and structure–activity relationships
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Toll-like receptor 8 (TLR8) is an endosomal TLR that has an important role in the innate human immune system, which is involved in numerous pathological conditions. Excessive activation of TLR8 can lead to inflammatory and autoimmune diseases, which highlights the need for development of TLR8 modulators. However, only a few small-molecule modulators that selectively target TLR8 have been developed. Here, we report the synthesis and systematic investigation of the structure–activity relationships of a series of novel TLR8 negative modulators based on previously reported 6-(trifluoromethyl)pyrimidin-2-amine derivatives. Four compounds showed low-micromolar concentration-dependent inhibition of TLR8-mediated signaling in HEK293 cells. These data confirm that the 6-trifluoromethyl group and two other substituents on positions 2 and 4 are important structural elements of pyrimidine-based TLR8 modulators. Substitution of the main scaffold at position 2 with a methylsulfonyl group or para hydroxy/hydroxymethyl substituted benzylamine is essential for potent negative modulation of TLR8. Our best-in-class TLR8-selective modulator 53 with IC50 value of 6.2 μM represents a promising small-molecule chemical probe for further optimization to a lead compound with potent immunomodulatory properties.
- Dol?ak, Ana,?ribar, Dora,Scheffler, Alexander,Grabowski, Maria,?vajger, Urban,Gobec, Stanislav,Holze, Janine,Weindl, Günther,Wolber, Gerhard,Sova, Matej
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- Discovery and structure-resistance relationship study of new thieno[2,3-b] pyridine HCV NS4B inhibitors
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The non-structural protein 4B (NS4B) of hepatitis C virus (HCV) has emerged as a promising target for chronic hepatitis C treatment. The thieno[2,3-b]pyridine HCV inhibitor 2 has demonstrated properties as a NS4B inhibitor. Subsequent hybridization of 2 with our recently published imidazo[2,1-b]thiazole NS4B inhibitor 3 resulted in the discovery of several more potent compounds with sub-micromolar EC50 against HCV genotype 1b replicon. More importantly, the resistant profile study of the new synthesized HCV inhibitors illustrated that the bicyclic scaffold would mediate the resistance of H3R and Q26R mutations, while the piperazinone motif would mediate the resistance of H94R, F98C and V105M mutations, and the C3- amino group would disrupt the interaction between piperazinone motif and NS4B. This structure-resistance relationship detail could help us to develop new NS4B inhibitors with higher resistant barrier in the future.
- Xiao, Kun-Jie,Zuo, Wei-Qiong,Xu, Ying,Tao, Xin,Yu, Luo-Ting,Wang, Ning-Yu
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p. 321 - 325
(2019/08/22)
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- Design and synthesis of novel benzenesulfonamide containing 1,2,3-triazoles as potent human carbonic anhydrase isoforms I, II, IV and IX inhibitors
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In a quest to discover new biologically active compounds, a series of twenty novel heterocyclic derivatives substituted at position 5 with -H (7a-7j) or -CF3 (8a-8j), bearing benzenesulfonamide at N-1 position and various aroyl groups at position 4 of the 1,2,3-triazole ring was synthesized and screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibition potential against four human (h) isoforms hCA I, II, IV and IX. All the compounds (7a-7j and 8a-8j) were synthesized via [3+2] cycloaddition reaction from 4-azidobenzenesulfonamide. Interestingly, compounds 7a-7j were prepared in one pot manner via enaminone intermediate using novel methodology. All the newly synthesized compounds (7a-7j & 8a-8j) were found to be excellent inhibitors of edema related isoform hCA I with their inhibition constant (Ki) ranging from 30.1 to 86.8 nM as compared to standard drug acetazolamide (AAZ) with Ki = 250 nM. Further it was found that most of tested compounds were weaker inhibitors of isoform, hCA II although compounds 7b, 7d-7e, 8a, 8d-8f, 8i (mostly with electron withdrawing substituents) have shown better inhibition potential (Ki i = 52.4 nM) than AAZ (Ki = 74 nM) while against tumor associated hCA IX, all the compounds have shown moderate inhibition potential. Present study have added one more step in exploring the 1,2,3-triazlole moiety in the medicinal field.
- Kumar, Rajiv,Vats, Lalit,Bua, Silvia,Supuran, Claudiu T.,Sharma, Pawan K.
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p. 545 - 551
(2018/06/18)
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- Synthesis, nematicidal activity and docking study of novel chromone derivatives containing substituted pyrazole
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A series of chromone derivatives containing substituted pyrazole were designed and synthesized. Preliminary bioassays showed that most of the synthesized compounds exhibited good nematicidal activity in vivo against Meloidogyne incognita at 10 mg/L. Among the tested compounds, A10 and A11 exhibited 100% inhibition rates. In addition, the molecular docking results indicated that both compound A10 and A11 interacts with amino acid residue Tyr121, Trp279, Tyr70, Trp84 and Phe330 of AChE via hydrogen bond and π–π stacking. This investigation suggested that the chromone containing substituted pyrazole scaffold could be further optimized to explore novel, high-bioactivity nematicidal leads.
- Li, Wei,Li, Jiuhui,Shen, Hongfeng,Cheng, Jiagao,Li, Zhong,Xu, Xiaoyong
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supporting information
p. 911 - 914
(2017/11/01)
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- A Sequential Route to Cyclopentenes from 1,6-Enynes and Diazo Ketones through Gold and Rhodium Catalysis
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This work reports the construction of cyclopentene cores from 1,6-enynes and aryl diazo ketones through two new reaction sequences involving initial gold-catalyzed cyclization of 1,6-enynes with diazo species, followed by rhodium-catalyzed skeletal rearrangement of the resulting 3-cyclopropyl-2-en-1-ones. In most instances the rhodium-catalyzed reactions afforded cyclopentene derivatives whereas several n-alkyl- or ortho-substituted phenyl ketones delivered seven-membered oxacycles. A plausible mechanism provides rationales for these two distinct products. (Figure presented.).
- Kale, Balaji S.,Lee, Hsin-Fu,Liu, Rai-Shung
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supporting information
p. 402 - 409
(2017/02/10)
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- Design, synthesis and biological activity of novel substituted pyrazole amide derivatives targeting EcR/USP receptor
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In order to discover highly active ecdysone analogs, a series of new substituted pyrazole amide derivatives were obtained using structure-guided optimization method and further screened for their insecticidal activities, in the basis of the core structures of the two active compounds N-(3-methoxyphenyl)-3-(tert-butyl)-1-phenyl-1H-pyrazole-5-carboxamide (6e) and N-(4-(tert-butyl)phenyl)-3-(tert-butyl)-1-phenyl-1H-pyrazole-5-carboxamide (6i), previously presented by us. The chemical structures of the title compounds were identified by spectral analyses. The preliminary bioassay results indicated that one among the synthesized pyrazole derivatives, compound 34, endowed with good activity against Mythimna Separata at 10 mg/L, which was equal to that displayed by the positive control tebufenozide. In addition, examples of molecular docking and molecular dynamics studies demonstrated that 34 may be the potential inhibitor to EcR and its docking conformation was similar to that of tebufenozide. In addition, increasing the hydrophobic effect and considering the suitable bulk effect on pyrazole ring are beneficial to the inhibiting activity to EcR and activity in vivo.
- Deng, Xi-Le,Xie, Jin,Li, Yong-Qiang,Yuan, De-Kai,Hu, Xue-Ping,Zhang, Li,Wang, Qing-Min,Chi, Ming,Yang, Xin-Ling
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supporting information
p. 566 - 570
(2016/04/26)
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- 1,5-Diketones Synthesis via Three-Component Cascade Reaction
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A mild and efficient cascade synthesis of 1,5-diketones from readily available N,N-dicyclohexylmethylamine, 1,3-dicarbonyl compounds, and trifluoromethyl β-diketones has been developed. This cascade reaction occurs via an oxidation/Mannich reaction/Cope elimination/Michael addition/retro-Claisen reaction sequence, and provides multiple C-C bond formations in one pot. In addition, exquisite chemoselectivity is achieved in the reaction between 1,3-dicarbonyl compounds and trifluoromethyl β-diketones.
- Xing, Li-Juan,Lu, Tao,Fu, Wei-Li,Lou, Mei-Mei,Chen, Bo,Wang, Zhi-Shen,Jin, Yang,Li, Dan,Wang, Bin
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supporting information
p. 3076 - 3080
(2015/11/03)
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- Discovery and structure-activity relationships study of novel thieno[2,3-b]pyridine analogues as hepatitis C virus inhibitors
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Current treatment for hepatitis C is barely satisfactory, there is an urgent need to develop novel agents for combating hepatitis C virus infection. This study discovered a new class of thieno[2,3-b]pyridine derivatives as HCV inhibitors. First, a hit compound characterized by a thienopyridine core was identified in a cell-based screening of our privileged small molecule library. And then, structure activity relationship study of the hit compound led to the discovery of several potent compounds without obvious cytotoxicity in vitro (12c, EC50 = 3.3 μM, SI >30.3, 12b, EC50 = 3.5 μM, SI >28.6, 10l, EC50 = 3.9 μM, SI >25.6, 12o, EC 50 = 4.5 μM, SI >22.2, respectively). Although the mechanism of them had not been clearly elucidated, our preliminary optimization of this class of compounds had provided us a start point to develop new anti-HCV agents.
- Wang, Ning-Yu,Zuo, Wei-Qiong,Xu, Ying,Gao, Chao,Zeng, Xiu-Xiu,Zhang, Li-Dan,You, Xin-Yu,Peng, Cui-Ting,Shen, Yang,Yang, Sheng-Yong,Wei, Yu-Quan,Yu, Luo-Ting
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supporting information
p. 1581 - 1588
(2014/03/21)
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- Comparative study of the regioselectivity and reaction media for the synthesis of 1-tert-butyl-3(5)-trifluoromethyl-1H-pyrazoles
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A study is presented for the synthesis of a series of 1-tert-butyl-3(5)- (trifluoromethyl)-1H-pyrazoles from the reaction of 4-alkoxy-1,1,1-trifluoro-3- alken-2-ones [CF3C(O)CH=C(R1)(OR), where R = Et and R 1 = H or R = Me and R1 = Me, Ph, 4-Me-C6H 4, 4-MeO-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-I-C 6H4, fur-2-yl, thien-2-yl, or naphth-2-yl] with tert-butylhydrazine hydrochloride. When [BMIM][BF4] (1-butyl-3-methylimidazolium tetrafluoroborate) and pyridine were used as the reaction media, we obtained a mixture of 1-tert-butyl-3(5)- trifluoromethylpyrazoles. The formation of 5-trifluoromethyl-1-tert-butyl-1H- pyrazoles with high regioselectivity occurred when the reaction was carried out with NaOH in EtOH. The formation of 1-tert-butyl-3-trifluoromethyl-1H-pyrazoles occurred, after hydrolysis of the 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones in H2O and H2SO4, followed by cyclization in [BMIM][BF4] and pyridine.
- Martins, Marcos A. P.,Marzari, Mara R. B.,Frizzo, Clarissa P.,Zanatta, Marcileia,Buriol, Lilian,Andrade, Valquiria P.,Zanatta, Nilo,Bonacorso, Helio G.
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p. 7112 - 7119
(2013/02/21)
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- PYRAZOLE DERIVATIVES AS MODULATORS OF CALCIUM RELEASE -ACTIVATED CALCIUM CHANNEL
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Disclosed are novel calcium release-activated calcium (CRAC) channel inhibitors, methods for preparing them, pharmaceutical compositions containing them, and methods of treatment using them. The present disclosure also relates to methods for treating non-small cell lung cancer (NSCLC) with CRAC inhibitors, and to methods for identifying therapeutics for treating and of diagnosing cancer.
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Page/Page column 58
(2011/04/26)
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- COMPOUNDS, COMPOSITIONS AND METHODS FOR CONTROL OF HEPATITIS C VIRAL INFECTIONS
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Various tetrahydropyrazolo[1,5-a]pyrimidine compounds, compositions, methods of making, and methods for the prevention and treatment of HCV infections and associated diseases are disclosed. The invention further relates to biomarkers for identification of HCV strains which are resistant to the tetrahydropyrazolo[1,5- a]pyrimidine compounds.
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Page/Page column 55-56
(2010/09/17)
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- LXR AND FXR MODULATORS
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Compounds of the invention are disclosed, such as compounds of formulae LX - LXIV, and pharmaceutically acceptable salts, isomers, or prodrugs thereof, which are useful as modulators of the activity of liver X receptors (LXR) and Farnesoid X receptors (FXR), where R00, R200, R400, R500, J11, J21, G1, G21, and Q are defined herein. Pharmaceutical compositions containing the compounds and methods of using the compounds are also disclosed.
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Page/Page column 134
(2011/03/17)
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- Interactions of aroyl- and heteroaroyltrifluoroacetones with thiobenzoylhydrazine
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The interaction of aroyl(heteroaroyl)trifluoroacetones with thiobenzoylhydrazine may occur at both carbonyl groups. Reaction at the trifluoroacetyl group is facilitated by terminal substituents in the 1,3-dicarbonyl part, which leads can effectively conjugate with the adjacent carbonyl group. The products of condensation at the trifluoroacetyl group are 2-[2-aryl(heteroaroyl)-2-oxoethyl]-5-phenyl-2-trifluoromethyl-2,3-dihydro-1,3, 4-thiadiazoles, while condensation at the aroyl(heteroaroyl)group gave 3-aryl(heteroaryl)-5-hydroxy-1-thiobenzoyl-5-trifluoromethyl-4, 5-dihydro-1H-pyrazoles, which are not prone to tautomeric transformations in solution. 2008 Springer Science+Business Media, Inc.
- Pakalnis,Zerova,Yakimovitch,Alekseyev
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p. 606 - 614
(2013/07/25)
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- Reaction of aroyl- and hetaroyltrifluoroacetones with acylhydrazines: Regioselectivity and tautomerism of the condensation products
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Acylhydrazines react with 1,3-diketones of the general formula CF 3COCH2COR (where R is an aryl or hetaryl group) at both carbonyl groups. The reaction at the trifluoroacetyl group is favored by donor substituents in the aromatic ring of the 1,3-diketone or by the 2-furyl and, especially, 2-thienyl group as a hetaryl substituent, as well as by elevated temperature. The condensation products at the carbonyl group contiguous to the aryl or hetaryl ring have the structure of 5-hydroxy-4,5-dihydropyrazoles and do not undergo tautomeric transformations in solution. The condensation products at the trifluoroacetyl group have either 5-hydroxy-4,5-dihydropyrazole or hydrazone structure and give rise to ring-chain tautomeric equilibrium in solution. Electron-withdrawing substituents in the aromatic ring of the 1,3-dicarbonyl fragment and CDCl3 as solvent favor formation of the cyclic tautomer. The state of the tautomeric equilibrium is weakly sensitive to structural variations in the hydrazine component.
- Pakal'nis,Zerova,Yakimovich
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p. 1732 - 1741
(2008/04/05)
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- Novel potent and selective calcium-release-activated calcium (CRAC) channel inhibitors. Part 2: Synthesis and inhibitory activity of aryl-3-trifluoromethylpyrazoles
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To identify potent and selective calcium-release-activated calcium (CRAC) channel inhibitors, we examined the structure-activity relationships of the pyrazole and thiophene moieties in compound 4. Compound 25b was found to exhibit highly potent and selective inhibitory activity for CRAC channels and further modifications of the pyrazole and benzoyl moieties of compound 25b produced compound 29. These compounds were potent inhibitors of IL-2 production in vitro and also acted as inhibitors in pharmacological models of diseases resulting from T-lymphocyte activation, after oral administration.
- Yonetoku, Yasuhiro,Kubota, Hirokazu,Okamoto, Yoshinori,Ishikawa, Jun,Takeuchi, Makoto,Ohta, Mitsuaki,Tsukamoto, Shin-ichi
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p. 5370 - 5383
(2007/10/03)
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- Keto-enol and enol-enol tautomerism in trifluoromethyl-β-diketones
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The keto-enol (K?E) and enol-enol (E?E) equilibria of a variety of trifluoromethyl-β-diketones were investigated using 1H, 13C, 19F NMR spectroscopy, infrared spectroscopy and ultraviolet-visible spectrophotometry in nonpolar solvents. In general, NMR, IR and UV spectral evidence indicates that trifluoromethyl-β-diketones exist as mixtures of two chelated cis-enol forms in nonpolar media. Infrared spectroscopy and ultraviolet spectrophotometry show the E?E equilibrium lies in the direction of the enol form which maximizes conjugation in most cases. Exceptions are noted and discussed.
- Sloop, Joseph C.,Bumgardner, Carl L.,Washington, Gary,Loehle, W. David,Sankar, Sabapathy S.,Lewis, Adam B.
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p. 780 - 786
(2008/03/27)
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- Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. Part 4: Heterocycles at C3
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New indeno[1,2-c]pyrazol-4-one cyclin dependent kinase inhibitors have been disclosed. The most promising compounds are nanomolar enzyme inhibitors with excellent activity against tumor cells. The most advanced compound retains cell culture activity even in the presence of human serum proteins. The most advanced compound did not kill the normal fibroblast line AG1523.
- Yue, Eddy W.,DiMeo, Susan V.,Higley, C. Anne,Markwalder, Jay A.,Burton, Catherine R.,Benfield, Pamela A.,Grafstrom, Robert H.,Cox, Sarah,Muckelbauer, Jodi K.,Smallwood, Angela M.,Chen, Haiying,Chang, Chong-Hwan,Trainor, George L.,Seitz, Steven P.
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p. 343 - 346
(2007/10/03)
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- Synthesis of 1,1,1-trihalo-4-methoxy-4-[2-heteroaryl]-3-buten-2-ones, the corresponding butan-1,3-dione and azole derivatives
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The synthesis of 1,1,1-trihalo-4-methoxy-4-[2-thienyl]-3-buten-2-ones, 1,1,1-trihalo-4-methoxy-4-[2-furyl]-3-buten-2-ones and the respective trihalomethyl 1,3-butanone derivatives by trihaloacylation of dimethoxy acetals derived from 2-acetylthiophene and 2-acetylfuran are reported. This is a convenient method to obtain fluorinated and chlorinated 1,3-dielectrophiles from 2-acetylthiophene and 2-acetylfuran. The fluorinated 1,3-dielectrophiles were used to synthesize five new 2-thienyl- and 2-furylazoles. The structure of all products were assigned by 1HH- and 13C NMR and mass spectrometry.
- Flores, Alex F.C,Brondani, Sergio,Zanatta, Nilo,Rosa, Adriano,Martins, Marcos A.P
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p. 8701 - 8705
(2007/10/03)
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- Synthesis of fluorinated heterocycles
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Selected 1,3-diketones having a trifluoromethyl group and/or a fluorine in the 2-position were condensed with aromatic hydrazines, hydroxylamine, urea, thiourea, guanidine, and substituted anilines producing pyrazoles, isoxazoles, pyrimidines, and quinolines, respectively, in yields ranging from 27 to 87%.
- Sloop, Joseph C.,Bumgardner, Carl L.,Loehle, W. David
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p. 135 - 147
(2007/10/03)
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- A convenient and regioselective synthesis of 4-trifluoromethylpyridines
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Trifluoromethyl-substituted β-diketones regioselectively react with primary enamines such as β-aminocrotononitrile and ethyl β-aminocrotonate, providing moderate to good yields of 4-trifluoromethylpyridines.
- Katsuyama,Ogawa,Yamaguchi,Funabiki,Matsui,Muramatsu,Shibata
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p. 1321 - 1324
(2007/10/03)
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