- Optimisation of 2-(N-phenyl carboxamide) triazolopyrimidine antimalarials with moderate to slow acting erythrocytic stage activity
-
Malaria is a devastating parasitic disease caused by parasites from the genus Plasmodium. Therapeutic resistance has been reported against all clinically available antimalarials, threatening our ability to control the disease and therefore there is an ongoing need for the development of novel antimalarials. Towards this goal, we identified the 2-(N-phenyl carboxamide) triazolopyrimidine class from a high throughput screen of the Janssen Jumpstarter library against the asexual stages of the P. falciparum parasite. Here we describe the structure activity relationship of the identified class and the optimisation of asexual stage activity while maintaining selectivity against the human HepG2 cell line. The most potent analogues from this study were shown to exhibit equipotent activity against P. falciparum multidrug resistant strains and P. knowlesi asexual parasites. Asexual stage phenotyping studies determined the triazolopyrimidine class arrests parasites at the trophozoite stage, but it is likely these parasites are still metabolically active until the second asexual cycle, and thus have a moderate to slow onset of action. Non-NADPH dependent degradation of the central carboxamide and low aqueous solubility was observed in in vitro ADME profiling. A significant challenge remains to correct these liabilities for further advancement of the 2-(N-phenyl carboxamide) triazolopyrimidine scaffold as a potential moderate to slow acting partner in a curative or prophylactic antimalarial treatment.
- Bailey, Brodie L.,Nguyen, William,Ngo, Anna,Goodman, Christopher D.,Gancheva, Maria R.,Favuzza, Paola,Sanz, Laura M.,Gamo, Francisco-Javier,Lowes, Kym N.,McFadden, Geoffrey I.,Wilson, Danny W.,Laleu, Beno?t,Brand, Stephen,Jackson, Paul F.,Cowman, Alan F.,Sleebs, Brad E.
-
-
- CYCLAMINEPHENYLAMINOQUINOLINES AS FUNGICIDES
-
The present disclosure relates to fungicidal active compounds, more specifically to cyclaminephenylaminoquinolines of formula (I), intermediates for their preparation and use thereof as fungicidal active compound, particularly in the form of fungicide com
- -
-
-
- Access to Polycyclic Indole-3,4-Fused Nine-Membered Ring via Cascade 1,6-Hydride Transfer/Cyclization
-
A cascade aldimine condensation/1,6-hydride transfer/Mannich-type cyclization of indole-derived phenylenediamine with aldehydes was developed for one-step construction of a polycyclic indole-3,4-fused skeleton. Aldehyde serves as a key to start the whole process, including 1,6-hydride transfer enabled δ-C(sp3)-H activation of the secondary amine. The challenges of construction of medium-sized rings are addressed via hydride transfer chemistry.
- Yang, Shuo,An, Xiao-De,Qiu, Bin,Liu, Rui-Bin,Xiao, Jian
-
p. 9100 - 9105
(2021/11/24)
-
- Electrochemical Synthesis of Benzo[ d]imidazole via Intramolecular C(sp3)-H Amination
-
An electrochemical dehydrogenative amination for the synthesis of benzimidazoles was developed. This electrosynthesis method could address the limitations of the C(sp3)-H intramolecular amination synthesis reaction and provide novel access to obtain 1,2-disubstituted benzimidazoles without transition metals and oxidants. Under undivided electrolytic conditions, various benzimidazole derivatives could be synthesized, exhibiting functional group tolerance.
- Li, An,Li, Caohui,Li, Lijun,Liu, Yu,Tang, Kewen,Yang, Tao,Yang, Zan,Zhou, Congshan
-
-
- Photoswitching of ortho-Aminated Arylazopyrazoles with Red Light
-
Bidirectional photoswitching of arylazopyrazoles with visible light is enabled by substitution with pyrrolidine and piperidine in the ortho-position of the phenyl ring. The absorption maxima were red-shifted and the molar absorption coefficients in the vi
- Simke, Julian,B?sking, Tom,Ravoo, Bart Jan
-
supporting information
p. 7635 - 7639
(2021/10/05)
-
- Preparation method of benzimidazole [1, 3] aza-thio compound
-
The invention discloses a preparation method of a benzimidazole [1, 3] aza-thio compound, and belongs to the field of organic synthesis research. The preparation method provided by the invention comprises the following steps that: with 2-fluoronitrobenzen
- -
-
-
- Tert-amino effect-promoted rearrangement of aryl isothiocyanate: A versatile approach to benzimidazothiazepines and benzimidazothioethers
-
A general and practical approach to benzimidazothiazepine and benzimidazothioether derivatives via an intramolecular nucleophilic addition/ring expansion rearrangement of aryl isothiocyanates promoted by the tert-amino effect has been developed. This reaction is catalyzed by low-cost camphorsulfonic acid and tolerates a broad substrate scope with complete atom economy. Structurally intriguing benzimidazothiazepine and benzimidazothioether products could be easily obtained by a simple operation in good to excellent yield (up to 98%).
- Geng, Xinyu,Liu, Siyuan,Qu, Jingping,Wang, Baomin,Wang, Wenyao
-
p. 12635 - 12643
(2020/11/09)
-
- 1,2-Disubstituted Benzimidazoles by the Iron Catalyzed Cross-Dehydrogenative Coupling of Isomeric o-Phenylenediamine Substrates
-
Benzimidazoles are common in nature, medicines, and materials. Numerous strategies for preparing 2-arylbenzimidazoles exist. In this work, 1,2-disubstituted benzimidazoles were prepared from various mono- and disubstituted ortho-phenylenediamines (OPD) by iron-catalyzed oxidative coupling. Specifically, O2 and FeCl3·6H2O catalyzed the cross-dehydrogenative coupling and aromatization of diarylmethyl and dialkyl benzimidazole precursors. N,N′-Disubstituted-OPD substrates were significantly more reactive than their N,N-disubstituted isomers, which appears to be relative to their propensity for complexation and charge transfer with Fe3+. The reaction also converted N-monosubstituted OPD substrates to 2-substituted benzimidazoles; however, electron-poor substrates produce 1,2-disubstituted benzimidazoles by intermolecular imino-transfer. Kinetic, reagent, and spectroscopic (UV-vis and EPR) studies suggest a mechanism involving metal-substrate complexation, charge transfer, and aerobic turnover, involving high-valent Fe(IV) intermediates. Overall, comparative strategies for the relatively sustainable and efficient synthesis of 1,2-disubstituted benzimidazoles are demonstrated.
- Foss, Frank W.,Palacios, Philip M.,Pierce, Brad S.,Thapa, Pawan,Tran, Tam
-
p. 1991 - 2009
(2020/03/13)
-
- A Structure–Activity Study of Nickel NNN Pincer Complexes for Alkyl-Alkyl Kumada and Suzuki–Miyaura Coupling Reactions
-
A new series of Ni NNN pincer complexes were synthesized and characterized. The main difference among these complexes is the substituents on the side arm amino group(s). No major structural difference was found except for the C–N–C angle of the various substituents and the ‘pseudo bite angle’ of the complexes. Four new complexes were efficient for the alkyl-alkyl Kumada reaction of primary alkyl halides, and among them, one complex was also efficient with secondary alkyl halides. The influence of the substituents on the catalytic performance of the Ni complexes in alkyl-alkyl Kumada and Suzuki–Miyaura cross-coupling reactions was systematically investigated. No correlation was found between the catalytic activity and the key structural parameters (C–N–C angle and ‘pseudo bite angle’), redox properties or Lewis acidity of the complexes.
- Di Franco, Thomas,Stojanovic, Marko,Keller, Sébastien Carlos,Scopelliti, Rosario,Hu, Xile
-
p. 830 - 847
(2016/11/11)
-
- Synthesis, antifungal activity and QSAR of some novel carboxylic acid amides
-
A series of novel aromatic carboxylic acid amides were synthesized and tested for their activities against six phytopathogenic fungi by an in vitro mycelia growth inhibition assay. Most of them displayed moderate to good activity. Among them N-(2-(1H-indazol-1-yl)phenyl)-2-(trifluoromethyl)benzamide (3c) exhibited the highest antifungal activity against Pythium aphanidermatum (EC50 = 16.75 μg/mL) and Rhizoctonia solani (EC50 = 19.19 μg/mL), compared to the reference compound boscalid with EC50 values of 10.68 and 14.47 μg/mL, respectively. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were employed to develop a three-dimensional quantitative structure-activity relationship model for the activity of the compounds. In the molecular docking, a fluorine atom and the carbonyl oxygen atom of 3c formed hydrogen bonds toward the hydroxyl hydrogens of TYR58 and TRP173.
- Du, Shijie,Lu, Huizhe,Yang, Dongyan,Li, Hong,Gu, Xilin,Wan, Chuan,Jia, Changqing,Wang, Mian,Li, Xiuyun,Qin, Zhaohai
-
p. 4071 - 4087
(2015/05/13)
-
- Synthesis, antifungal activity and structure-activity relationships of novel 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid amides
-
A series of novel 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid amides were synthesized and their activities were tested against seven phytopathogenic fungi by an in vitro mycelia growth inhibition assay. Most of them displayed moderate to excellent activities. Among them N-(2-(5-bromo-1H-indazol-1-yl)phenyl)-3-(difluoro-methyl)-1-methyl-1H-pyrazole-4-carboxamide (9m) exhibited higher antifungal activity against the seven phytopathogenic fungi than boscalid. Topomer CoMFA was employed to develop a three-dimensional quantitative structure-activity relationship model for the compounds. In molecular docking, the carbonyl oxygen atom of 9m could form hydrogen bonds towards the hydroxyl of TYR58 and TRP173 on SDH.
- Du, Shijie,Tian, Zaimin,Yang, Dongyan,Li, Xiuyun,Li, Hong,Jia, Changqing,Che, Chuanliang,Wang, Mian,Qin, Zhaohai
-
p. 8395 - 8408
(2015/05/20)
-
- PYRIDAZINONE COMPOUNDS AND USES THEREOF
-
Disclosed herein are pyridazinone compounds, pharmaceutical compositions that include one or more pyridazinone compounds, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an orthomyxovirus infection, with a pyridazinone compounds. Examples of an orthomyxovirus viral infection includes an influenza infection.
- -
-
-
- Synthesis of benzimidazoles via iridium-catalyzed acceptorless dehydrogenative coupling
-
Iridium-catalyzed acceptorless dehydrogenative coupling of tertiary amines and arylamines has been developed. A number of benzimidazoles were prepared in good yields. An iridium-mediated C-H activation mechanism is suggested. This finding represents a novel strategy for the synthesis of benzimidazoles.
- Sun, Xiang,Lv, Xiao-Hui,Ye, Lin-Miao,Hu, Yu,Chen, Yan-Yan,Zhang, Xue-Jing,Yan, Ming
-
p. 7381 - 7383
(2015/07/15)
-
- Synthesis of benzimidazoles via iridium-catalyzed acceptorless dehydrogenative coupling
-
Iridium-catalyzed acceptorless dehydrogenative coupling of tertiary amines and arylamines has been developed. A number of benzimidazoles were prepared in good yields. An iridium-mediated C-H activation mechanism is suggested. This finding represents a novel strategy for the synthesis of benzimidazoles.
- Sun, Xiang,Lv, Xiao-Hui,Ye, Lin-Miao,Hu, Yu,Chen, Yan-Yan,Zhang, Xue-Jing,Yan, Ming
-
p. 7381 - 7383
(2015/11/27)
-
- A convenient synthesis of benzannelated diazacycloalkanes by reductive cleavage of 1,2-polymethylenebenzimidazoles
-
A facile procedure for the synthesis of benzannelated diazacycloalkanes 3 is elaborated on the basis of reductive cleavage of 1,2- polymethylenebenzimidazoles 2 with DIBAL-H. The reduction of the corresponding salts prepared by treatment of 1,2-polymethylenebenzimidazoles 2 with methyl iodide proceeded differently affording exclusively o-phenylenediamines 10. The limitations and scope of the method were established, and a tentative mechanism proposed.
- Shvidenko, Tatyana,Nazarenko, Kostiantyn,Shvidenko, Konstantin,Kostyuk, Aleksandr
-
supporting information
p. 279 - 281
(2014/01/06)
-
- Ligand-free solid supported palladium(0) nano/microparticles promoted C-O, C-S, and C-N cross coupling reaction
-
Ligand-free solid-supported nano and microparticles of Pd(0) (SS-Pd) were used as a heterogeneous catalyst in carbon-heteroatom bond formation reactions. Nitro substituted aryl halides reacted with oxygen, sulfur, and nitrogen nucleophiles to afford the corresponding products in good yields. A one-pot sequential cross coupling and nitro-reduction was also performed using the same SS-Pd catalyst to access amine substituted carbon-heteroatomic molecules. In addition, SS-Pd could be recycled up to seven runs without a significant loss of catalytic activity.
- Bandna,Guha, Nitul Ranjan,Shil, Arun K.,Sharma, Dharminder,Das, Pralay
-
p. 5318 - 5322
(2012/10/30)
-
- Optimisation of the Anti-Trypanosoma brucei Activity of the Opioid Agonist U50488
-
Screening of the Sigma-Aldrich Library of Pharmacologically Active Compounds (LOPAC) against cultured Trypanosoma brucei, the causative agent of African sleeping sickness, resulted in the identification of a number of compounds with selective antiproliferative activity over mammalian cells. These included (+)-(1R,2R)-U50488, a weak opioid agonist with an EC50 value of 59nM as determined in our T.brucei invitro assay reported previously. This paper describes the modification of key structural elements of U50488 to investigate structure-activity relationships (SAR) and to optimise the antiproliferative activity and pharmacokinetic properties of this compound.
- Smith, Victoria C.,Cleghorn, Laura A. T.,Woodland, Andrew,Spinks, Daniel,Hallyburton, Irene,Collie, Iain T.,YiMok,Norval, Suzanne,Brenk, Ruth,Fairlamb, Alan H.,Frearson, Julie A.,Read, Kevin D.,Gilbert, Ian H.,Wyatt, Paul G.
-
p. 1832 - 1840
(2012/06/18)
-
- Dipyrimidine amines: A novel class of chemokine receptor type 4 antagonists with high specificity
-
The C-X-C chemokine receptor type 4 (CXCR4)/stromal cell derived factor-1 (SDF-1 or CXCL12) interaction and the resulting cell signaling cascade play a key role in metastasis and inflammation. On the basis of the previously published CXCR4 antagonist 5 (WZ811), a series of novel nonpeptidic anti-CXCR4 small molecules have been designed and synthesized to improve potency. Following a structure-activity profile around 5, more advanced compounds in the N,N-(1, 4-phenylenebis(methylene)) dipyrimidin-2-amines series were discovered and shown to possess higher CXCR4 binding potential and specificity than 5. Compound 26 (508MCl) is the lead compound and exhibits subnanomolar potency in three in vitro assays including competitive binding, Matrigel invasion and Gαi cyclic adenosine monophosphate (cAMP) modulation signaling. Furthermore, compound 26 displays promising effects by interfering with CXCR4 function in three mouse models: paw inflammation, Matrigel plug angiogenesis, and uveal melanoma micrometastasis. These data demonstrate that dipyrimidine amines are unique CXCR4 antagonists with high potency and specificity.
- Zhu, Aizhi,Zhan, Weiqiang,Liang, Zhongxing,Yoon, Younghyoun,Yang, Hua,Grossniklaus, Hans E.,Xu, Jianguo,Rojas, Mauricio,Lockwood, Mark,Snyder, James P.,Liotta, Dennis C.,Shim, Hyunsuk
-
experimental part
p. 8556 - 8568
(2011/02/28)
-
- 0-amine-assisted cannizzaro reaction of glyoxal with new 2,6-diaminoanilines
-
The preparation of several new o-amine-substituted anilines was achieved according to a new bifunctional molecular design, and their reactions with glyoxal were conducted. Can- nizzaro reactions of glyoxal proceeded using specifically designed anilines, such as 2,6-dipyrrolidinyl-, 2,6-dipiperidinyl-, 2,6-dimorpholinyl-, and 2-pyrrolidinyl-aniline, which are new and can easily be synthesized by substitution of halogen-substituted nitrobenzene with amines and subsequent reduction with hydrogen, to form a-hydroxy acetamide and a-amino acetamide derivatives, as a result of the Cannizzaro reaction. In comparison with the reaction of glyoxal with p- pyrrolidinylaniline to form a common diimine product, the reaction with o-pyrrolidinylaniline leads only to a-hydroxy amides, strongly suggesting that the abnormal Cannizzaro reactions are attributed to the existence of basic nitrogen atoms at the o-positions, which suppress diimine formation and assist the generation of acetamides.
- Irie, Yuhki,Koga, Yuji,Matsumoto, Taisuke,Matsubara, Kouki
-
experimental part
p. 2243 - 2250
(2009/08/09)
-
- Potent 2′-aminoanilide inhibitors of cFMS as potential anti-inflammatory agents
-
A series of 2′-aminoanilides have been identified which exhibit potent and selective inhibitory activity against the cFMS tyrosine kinase. Initial SAR studies within this series are described which examine aroyl and amino group substitutions, as well as the introduction of hydrophilic substituents on the benzene core. Compound 47 inhibits the isolated enzyme (IC50 = 0.027 μM) and blocks CSF-1-induced proliferation of bone marrow-derived macrophages (IC50 = 0.11 μM) and as such, serves as a lead candidate for further optimization studies.
- Patch, Raymond J.,Brandt, Benjamin M.,Asgari, Davoud,Baindur, Nand,Chadha, Naresh K.,Georgiadis, Taxiarchis,Cheung, Wing S.,Petrounia, Ioanna P.,Donatelli, Robert R.,Chaikin, Margery A.,Player, Mark R.
-
p. 6070 - 6074
(2008/03/18)
-
- THIENOPYRIMIDINES FOR PHARMACEUTICAL COMPOSITIONS
-
The present invention relates to novel pharmaceutical compositions of general formula (I) comprising thienopyrimidine compounds. Moreover, the present invention relates to the use of the thienopyrimidine compounds of the invention for the production of pharmaceutical compositions for the prophylaxis and/or treatment of diseases which can be influenced by the inhibition of the kinase activity of Mnk1 and/or Mnk2 (Mnk2a or Mnk2b) and/or variants thereof.
- -
-
-
- Imidazoline derivatives as alpha-1A adrenoceptor ligands
-
Compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof are disclosed. Such compounds are useful in the treatment of Alpha-1A mediated diseases or conditions such as urinary incontinence.
- -
-
Page/Page column 27
(2010/02/11)
-
- gem-cyclodialkylation A facile synthetic route to N-substituted heterocycles
-
N-alkylated and N-arylated pyrroles, pyrrolidines, and piperidines are synthesized in high yield by the reaction between cyclic ethers and primary amines over a heterogeneous titania catalyst.
- Hargis, Duane C.,Shubkin, Ronald L.
-
p. 2991 - 2994
(2007/10/02)
-
