cas 3535-37-3, 3,4-Dimethoxybenzoyl chloride

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Remarkably Efficient Iridium Catalysts for Directed C(sp2)-H and C(sp3)-H Borylation of Diverse Classes of Substrates
Here we describe the discovery of a new class of C-H borylation catalysts and their use for regioselective C-H borylation of aromatic, heteroaromatic, and aliphatic systems. The new catalysts have Ir-C(thienyl) or Ir-C(furyl) anionic ligands instead of the diamine-type neutral chelating ligands used in the standard C-H borylation conditions. It is reported that the employment of these newly discovered catalysts show excellent reactivity and ortho-selectivity for diverse classes of aromatic substrates with high isolated yields. Moreover, the catalysts proved to be efficient for a wide number of aliphatic substrates for selective C(sp3)-H bond borylations. Heterocyclic molecules are selectively borylated using the inherently elevated reactivity of the C-H bonds. A number of late-stage C-H functionalization have been described using the same catalysts. Furthermore, we show that one of the catalysts could be used even in open air for the C(sp2)-H and C(sp3)-H borylations enabling the method more general. Preliminary mechanistic studies suggest that the active catalytic intermediate is the Ir(bis)boryl complex, and the attached ligand acts as bidentate ligand. Collectively, this study underlines the discovery of new class of C-H borylation catalysts that should find wide application in the context of C-H functionalization chemistry.
Chattopadhyay, Buddhadeb,Hassan, Mirja Md Mahamudul,Hoque, Md Emdadul
supporting information
p. 5022 - 5037
(2021/05/04)

Synthesis and antitumor activity of novel pyridoxine-based structural analogs of saccharumoside-B
A series of 11 new pyridoxine-based structural analogs of saccharumoside-B were obtained using original synthetic approach. Antitumor activity of these compounds against nine human tumor cell lines (MCF-7, MDA-MB-231, A-498, SNB-19, M-14, NCI-H322M, HCT-115, HCT-116, and PC-3) was studied, and cytotoxic activity to three normal (HEK-293, Chang Liver, and MSC) cell lines was evaluated. Among the synthesized compounds, 12d, 12e, 13b, 13d, 13e, and 14 exhibited the highest antitumor activity, comparable to that of camptothecin and doxorubicin, but with significantly increased selectivity toward tumor cells. [Figure not available: see fulltext.]
Pugachev, Mikhail V.,Agafonova, Maria N.,Bastrikova, Oksana A.,Gnezdilov, Oleg I.,Nikishova, Tatyana V.,Balakin, Konstantin V.,Shtyrlin, Yurii G.
p. 1139 - 1150
(2021/03/31)

Synthesis of N -(Hetero)arylconvolvine Derivatives through a Palladium-Catalyzed Buchwald-Hartwig Cross-Coupling
The present study describes the isolation of convolvine from the roots of the Tunisian plant Convolvulus dorycnium L. and its synthesis through a four-step sequence starting from tropine. Then, an efficient synthesis of N -(het)aryltropanes derivatives by
Alami, Mouad,Ghermani, Noureddine,Hassine, Manel,Jannet, Hichem Ben,Messaoudi, Samir
p. 450 - 458
(2020/01/23)

Palladium-Catalyzed Chlorocarbonylation of Aryl (Pseudo)Halides Through In Situ Generation of Carbon Monoxide
An efficient palladium-catalyzed chlorocarbonylation of aryl (pseudo)halides that gives access to a wide range of carboxylic acid derivatives has been developed. The use of butyryl chloride as a combined CO and Cl source eludes the need for toxic, gaseous carbon monoxide, thus facilitating the synthesis of high-value products from readily available aryl (pseudo)halides. The combination of palladium(0), Xantphos, and an amine base is essential to promote this broadly applicable catalytic reaction. Overall, this reaction provides access to a great variety of carbonyl-containing products through in situ transformation of the generated aroyl chloride. Combined experimental and computational studies support a reaction mechanism involving in situ generation of CO.
Bismuto, Alessandro,Boehm, Philip,Morandi, Bill,Roediger, Sven
supporting information
p. 17887 - 17896
(2020/08/19)

Preparation method of 3,4-dimethoxybenzoyl chloride
The invention discloses a preparation method of 3,4-dimethoxybenzoyl chloride and belongs to the technical field of medicine techniques. The technical problem to be solved by the invention is to relate to a more advanced preparation method of 3,4-dimethox
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(2018/12/03)

A chlorinated nitidine synthesis method
The invention discloses a synthetic method of nitidine chloride. The synthetic method comprises the following steps: 1) dissolving 3,4-dimethoxybenzoic acid in a first organic solvent, adding thionyl chloride to react, evaporating out the solvent from reactants to obtain an intermediate 1; 2) dissolving the intermediate 1 by use of the first organic solvent, adding 3,4-methylenedioxy naphthylamine, and performing nucleophilic substitution reaction to obtain an intermediate 2; 3) dissolving the intermediate 2 in the first organic solvent, adding boron trifluoride diethyl etherate and di(trifluoroacetoxyl) iodobenzene to react, removing the solvent from the reactants, performing column chromatography on obtained residues on silica gel to obtain an intermediate 3; 4) dissolving the intermediate 3 in a second organic solvent, and performing lithium aluminum hydride reduction, dehydration and dimethyl sulfate methylation under an atmosphere protection condition, and then treating with sodium chloride to obtain the target product nitidine chloride. The synthetic method disclosed by the invention is relatively simple in synthesis route and relatively high in yield of the target product and the yield is higher than 27%.
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Paragraph 0025; 0026; 0037

(2017/07/01)

Benzoylsalicylic acid derivatives as defense activators in tobacco and Arabidopsis
Systemic acquired resistance (SAR) is a long lasting inducible whole plant immunity often induced by either pathogens or chemical elicitors. Salicylic acid (SA) is a known SAR signal against a broad spectrum of pathogens in plants. In a recent study, we have reported that benzoylsalicylic acid (BzSA) is a SAR inducer in tobacco and Arabidopsis plants. Here, we have synthesized BzSA derivatives using SA and benzoyl chlorides of various moieties as substrates. The chemical structures of BzSA derivatives were elucidated using Infrared spectroscopy (IR), Nuclear magnetic spectroscopy (NMR) and High-resolution mass spectrometer (HRMS) analysis. The bioefficacy of BzSA derivatives in inducing defense response against tobacco mosaic virus (TMV) was investigated in tobacco and SA abolished transgenic NahG Arabidopsis plants. Interestingly, pre-treatment of local leaves of tobacco with BzSA derivatives enhanced the expression of SAR genes such as NPR1 [Non-expressor of pathogenesis-related (PR) genes 1], PR and other defense marker genes (HSR203, SIPK, WIPK) in systemic leaves. Pre-treatment of BzSA derivatives reduced the spread of TMV infection to uninfected areas by restricting lesion number and diameter both in local and systemic leaves of tobacco in a dose-dependent manner. Furthermore, pre-treatment of BzSA derivatives in local leaves of SA deficient Arabidopsis NahG plants induced SAR through AtPR1 and AtPR5 gene expression and reduced leaf necrosis and curling symptoms in systemic leaves as compared to BzSA. These results suggest that BzSA derivatives are potent SAR inducers against TMV in tobacco and Arabidopsis.
Kamatham, Samuel,Pallu, Reddanna,Pasupulati, Anil Kumar,Singh, Surya Satyanarayana,Gudipalli, Padmaja
p. 160 - 169
(2017/08/29)

A General Cp*CoIII-Catalyzed Intramolecular C?H Activation Approach for the Efficient Total Syntheses of Aromathecin, Protoberberine, and Tylophora Alkaloids
Herein, we report a Cp*CoIII-catalyzed C?H activation approach as the key step to create highly valuable isoquinolones and pyridones as building blocks that can readily be applied in the total syntheses of a variety of aromathecin, protoberberine, and tylophora alkaloids. This particular C?H activation/annulation reaction was achieved with several terminal as well as internal alkyne coupling partners delivering a broad scope with excellent functional group tolerance. The synthetic applicability of this protocol reported herein was demonstrated in the total syntheses of two Topo-I-Inhibitors and two 8-oxyprotoberberine cores that can be further elaborated into the tetrahydroprotoberberine and the protoberberine alkaloid core. Moreover these building blocks were also transformed to six different tylophora alkaloids in expedient fashion.
Lerchen, Andreas,Knecht, Tobias,Koy, Maximilian,Daniliuc, Constantin G.,Glorius, Frank
supporting information
p. 12149 - 12152
(2017/09/13)

Diphenylurea derivatives for combating methicillin- and vancomycin-resistant Staphylococcus aureus
A new class of diphenylurea was identified as a novel antibacterial scaffold with an antibacterial spectrum that includes highly resistant staphylococcal isolates, namely methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA & VRSA). Starting with a lead compound 3 that carries an aminoguanidine functionality from one side and a n-butyl moiety on the other ring, several analogues were prepared. Considering the pharmacokinetic parameters as a key factor in structural optimization, the structure-activity-relationships (SARs) at the lipophilic side chain were rigorously examined leading to the discovery of the cycloheptyloxyl analogue 21n as a potential drug-candidate. This compound has several notable advantages over vancomycin and linezolid including rapid killing kinetics against MRSA and the ability to target and reduce the burden of MRSA harboring inside immune cells (macrophages). Furthermore, the potent anti-MRSA activity of 21n was confirmed in?vivo using a Caenorhabditis elegans animal model. The present study provides a foundation for further development of diphenylurea compounds as potential therapeutic agents to address the burgeoning challenge of bacterial resistance to antibiotics.
Eissa, Ibrahim H.,Mohammad, Haroon,Qassem, Omar A.,Younis, Waleed,Abdelghany, Tamer M.,Elshafeey, Ahmed,Abd Rabo Moustafa, Mahmoud M.,Seleem, Mohamed N.,Mayhoub, Abdelrahman S.
p. 73 - 85
(2017/03/02)

METHOD FOR PREPARATION OF CARBOXYLIC ACID CHLORIDES FROM METHYL KETONES WITH TWO REAGENTS
The invention discloses a method for the preparation of carboxylic acid chlorides starting from methyl ketones with a sulfur chloride and a chlorinating reagent.
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(2017/01/26)

METHOD FOR PREPARATION OF CARBOXYLIC ACID CHLORIDES FROM METHYL KETONES
The invention discloses a method for the preparation of carboxylic acid chlorides starting from methyl ketones with a sulfur chloride.
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(2017/01/02)

Rhodium(iii)-catalyzed C-H/C-C activation sequence: Vinylcyclopropanes as versatile synthons in direct C-H allylation reactions
Succession of C-H activation and C-C activation was achieved by using a single rhodium(iii) catalyst. Vinylcyclopropanes were used as versatile coupling partners. Mechanistic studies suggest that the olefin insertion step is rate-determining and a facile β-carbon elimination is involved, which represents a novel ring opening mode of vinylcyclopropanes. This journal is
Wu, Jia-Qiang,Qiu, Zhi-Ping,Zhang, Shang-Shi,Liu, Jing-Gong,Lao, Ye-Xing,Gu, Lian-Quan,Huang, Zhi-Shu,Li, Juan,Wang, Honggen
supporting information
p. 77 - 80
(2015/01/09)

Design and synthesis of N-methylpyrimidone derivatives as HIV-1 integrase inhibitors
A series of novel β-diketo derivatives which combined the virtues of dihydroxypyrimidine carboxamide derived from the evolution of DKA and polyhydroxylated aromatics moieties, were designed and synthesized as potential HIV-1 integrase (IN) inhibitors and
Wang, Yujie,Rong, Jie,Zhang, Bin,Hu, Liming,Wang, Xiaoli,Zeng, Chengchu
p. 735 - 741
(2015/02/19)

Design, synthesis and evaluation of rhodanine derivatives as aldose reductase inhibitors
Aldose reductase (ALR) enzyme plays a significant role in conversion of excess amount of glucose into sorbitol in diabetic condition, inhibitors of which decrease the secondary complication of diabetes mellitus. To understand the structural interaction of inhibitors with ALR enzyme and develop more effective ALR inhibitors, a series of substituted 5-phenylbenzoate containing N-substituted rhodanine derivatives were synthesized and evaluated for their in vitro ALR inhibitory activity. Docking studies of these compounds were carried out, which revealed that the 5-phenylbenzoate moiety deeply influenced the key π-π stacking while 4-oxo-2-thioxothiazolidines contributed in hydrogen bond interactions. The phenyl ring of benzylidene system occupied in specific pocket constituted from Phe115, Phe122, Leu300 and Cys303 while the rhodanine ring forms a tight net of hydrogen bond with Val47 at anionic binding site of the enzyme. The structural insights obtained from the docking study gave better understanding of rhodanine and macromolecular interaction and will help us in further designing and improving of ALR inhibitory activity of rhodanine analogs. Series of substituted 5-phenylbenzoate rhodanine analogs were synthesized and evaluated for their ALR inhibitory activity. The docking study of synthesized compounds was carried out, which revealed that the 5-phenylbenzoate moiety deeply influenced the key π-π stacking while 4-oxo-2-thioxothiazolidines contributed in hydrogen bond interactions.
Agrawal, Yogesh P.,Agrawal, Mona Y.,Gupta, Arun K.
p. 172 - 180
(2015/01/30)

Scaffold identification of a new class of potent and selective BCRP inhibitors
We recently reported the synthesis and quantitative structure-activity relationships of a new breast cancer resistance protein (BCRP) inhibitor class. In the study presented herein, we investigated the possibility to better define the scaffold of this compound class by removing or modifying the aromatic ring A with various substituents selected on the basis of their electronic and lipophilic properties. The results show that this aromatic ring is important, but not essential, for activity. Many of the selected substituents led to compounds with low activity, but in some cases activity was retained. Among these, a phenolic hydroxy group proved to impart as much potency to the molecule as a hydroxyethyl side chain, initially considered necessary for activity. This derivative is one of the most active compounds in this class, maintaining an inhibitory activity similar to that of the reference compound; it is also selective for BCRP.
Marighetti, Federico,Steggemann, Kerstin,Karbaum, Maria,Wiese, Michael
p. 742 - 751
(2015/04/14)

Structure-activity studies in the development of a hydrazone based inhibitor of adipose-triglyceride lipase (ATGL)
Adipose triglyceride lipase (ATGL) catalyzes the degradation of cellular triacylglycerol stores and strongly determines the concentration of circulating fatty acids (FAs). High serum FA levels are causally linked to the development of insulin resistance a
Mayer, Nicole,Schweiger, Martina,Melcher, Michaela-Christina,Fledelius, Christian,Zechner, Rudolf,Zimmermann, Robert,Breinbauer, Rolf
p. 2904 - 2916
(2015/03/30)

One-Step Conversion of Methyl Ketones to Acyl Chlorides
Treatment of aromatic and heteroaromatic methyl ketones with sulfur monochloride and catalytic amounts of pyridine in refluxing chlorobenzene leads to the formation of acyl chlorides. Both electron-rich and electron-poor aryl methyl ketones can be used as starting materials. The resulting C1-byproduct depends on the precise reaction conditions chosen.
Zaragoza, Florencio
p. 10370 - 10374
(2015/11/03)

Design, synthesis, molecular docking studies and in vitro screening of ethyl 4-(3-benzoylthioureido) benzoates as urease inhibitors
Thioureas are exceptionally versatile building blocks towards the synthesis of wide variety of heterocyclic systems, which also possess extensive range of pharmacological activities. The substituted benzoic acids were converted into corresponding acid chlorides, these acid chlorides were then treated with potassium thiocyanate in acetone and then the reaction mixture was refluxed for 1-2 h afford ethyl 4-(3-benzoylthioureido)benzoates thioureas in good yields. All the newly synthesized compounds were evaluated for their urease inhibitory activities and were found to be potent inhibitors of urease enzyme. Compounds 1f and 1g were identified as the most potent urease inhibitors (IC50 0.21 and 0.13 μM, respectively), and was 100-fold more potent than the standard inhibitors. Further molecular docking studies were carried out using the crystal structure of urease to find out the binding mode of the inhibitors with the enzyme.
Saeed, Aamer,Khan, Muhammad Siraj,Rafique, Hummera,Shahid, Mohammad,Iqbal, Jamshed
p. 1 - 7
(2013/12/04)

Triazole-assisted ruthenium-catalyzed C-H arylation of aromatic amides
Site-selective ruthenium(II)-catalyzed direct arylation of amides was achieved through C-H cleavages with modular auxiliaries, derived from easily accessible 1,2,3-triazoles. The triazolyldimethylmethyl (TAM) bidentate directing group was prepared in a highly modular fashion through copper(I)-catalyzed 1,3-dipolar cycloaddition and allowed for ruthenium-catalyzed C-H arylations on arenes and heteroarenes, as well as alkenes, by using easy-to-handle aryl bromides as the arylating reagents. The triazole-assisted C-H activation strategy was found to be widely applicable, to occur under mild reaction conditions, and the catalytic system was tolerant of important electrophilic functionalities. Notably, the flexible triazole-based auxiliary proved to be a more potent directing group for the optimized ruthenium(II)-catalyzed direct arylations, compared with pyridyl-substituted amides or substrates derived from 8-aminoquinoline. Assisting activation: Ruthenium(II)-catalyzed C-H arylations of (hetero)arenes and alkenes have been achieved with aryl halides through removable bidentate auxiliaries derived from modular 1,2,3-triazoles (see scheme; TAM=triazolyldimethylmethyl).
Al Mamari, Hamad H.,Diers, Emelyne,Ackermann, Lutz
supporting information
p. 9739 - 9743
(2014/08/18)

Discovery and early clinical development of 2-{6-[2-(3,5-dichloro-4- pyridyl)acetyl]-2,3-dimethoxyphenoxy}- N -propylacetamide (LEO 29102), a soft-drug inhibitor of phosphodiesterase 4 for topical treatment of atopic dermatitis
Development of orally available phosphodiesterase 4 (PDE4) inhibitors as anti-inflammatory drugs has been going on for decades. However, only roflumilast has received FDA approval. One key challenge has been the low therapeutic window observed in the clin
Felding, Jakob,S?rensen, Morten D.,Poulsen, Tina D.,Larsen, Jens,Andersson, Christina,Refer, Pia,Engell, Karen,Ladefoged, Lotte G.,Thormann, Thorsten,Vinggaard, Anne Marie,Hegardt, Pontus,S?hoel, Anders,Nielsen, Simon Feldb?k
p. 5893 - 5903
(2014/08/18)

Synthesis and structure-activity relationship of non-peptidic antagonists of neuropilin-1 receptor
Neuropilins (NRPs) are VEGF-A165 co-receptors over-expressed in tumor cells, and considered as targets in angiogenic-related pathologies. We previously identified compound 1, the first non-peptidic antagonist of the VEGF-A165/NRP binding, which exhibits in vivo anti-angiogenic and anti-tumor activities. We report here the synthesis and biological evaluations of new antagonists structurally-related to compound 1. Among these molecules, 4a, 4c and 4d show cytotoxic effects on HUVEC and MDA-MB-31 cells, and antagonize VEGF-A165/NRP-1 binding. This study confirmed our key structure-activity relationships hypothesis and paved the way to compound 1 'hit to lead' optimization.
Liu, Wang-Qing,Megale, Valentino,Borriello, Lucia,Leforban, Bertrand,Montes, Matthieu,Goldwaser, Elodie,Gresh, Nohad,Piquemal, Jean-Philip,Hadj-Slimane, Reda,Hermine, Olivier,Garbay, Christiane,Raynaud, Francoise,Lepelletier, Yves,Demange, Luc
p. 4254 - 4259
(2014/09/29)

Ni(II)-catalyzed oxidative coupling between C(sp2)-H in benzamides and C(sp3)-H in toluene derivatives
Oxidative coupling between C(sp2)-H bonds and C(sp3)-H bonds is achieved by the Ni(II)-catalyzed reaction of benzamides containing an 8-aminoquinoline moiety as the directing group with toluene derivatives in the presence of heptafluoroisopropyl iodide as the oxidant. The method has a broad scope and shows high functional group compatibility. Toluene derivatives can be used as the coupling partner in an unreactive solvent.
Aihara, Yoshinori,Tobisu, Mamoru,Fukumoto, Yoshiya,Chatani, Naoto
supporting information
p. 15509 - 15512
(2014/12/11)

Mild rhodium(III)-catalyzed C-H allylation with 4-vinyl-1,3-dioxolan-2-ones: Direct and stereoselective synthesis of (E)-allylic alcohols
A rhodium(III)-catalyzed C-H direct allylation reaction with 4-vinyl-1,3-dioxolan-2-ones has been developed. The reaction provides a facile and stereoselective access to substituted-(E)-allylic alcohols under mild and redox-neutral reaction conditions. Olefinic C-H activation is applicable, giving multifunctionalized skipped dienes in good yields. Minimal double-bond migration was observed.
Zhang, Shang-Shi,Wu, Jia-Qiang,Lao, Ye-Xing,Liu, Xu-Ge,Liu, Yao,Lv, Wen-Xin,Tan, Dong-Hang,Zeng, Yao-Fu,Wang, Honggen
supporting information
p. 6412 - 6415
(2015/01/09)

Dynamic mirror-symmetry breaking in bicontinuous cubic phases
Chiral segregation of enantiomers or chiral conformers of achiral molecules during self-assembly in well-ordered crystalline superstructures has fascinated chemists since Pasteur. Here we report spontaneous mirror-symmetry breaking in cubic phases formed
Dressel, Christian,Liu, Feng,Prehm, Marko,Zeng, Xiangbing,Ungar, Goran,Tschierske, Carsten
supporting information
p. 13115 - 13120
(2015/01/16)

Design, synthesis and evaluation of novel heterodimers of donepezil and huperzine fragments as acetylcholinesterase inhibitors
Four series of novel heterodimers comprised of donepezil and huperzine A (HupA) fragments were designed, synthesized, and evaluated in search of potent acetylcholinesterase (AChE) inhibitors as potential therapeutic treatment for Alzheimer's disease. Hete
Hu, Yueqing,Zhang, Jun,Chandrashankra, Oormila,Ip, Fanny C.F.,Ip, Nancy Y.
supporting information
p. 676 - 683
(2013/02/25)

Synthesis and Quantitative Structure-Activity Relationships of Selective BCRP Inhibitors
The breast cancer resistance protein (BCRP/ABCG2) is a member of the ABC transporter superfamily. This protein has a number of physiological functions, including protection of the human body from xenobiotics. The overexpression of BCRP in certain tumor cell lines causes cross-resistance against various drugs used in chemotherapeutic treatment. In a previous work we showed that a new class of compounds derived from XR9576 (tariquidar) selectively inhibits BCRP. In this work we synthesized more members of this class, with modification on the second and third aromatic rings. The inhibitory activities against BCRP and P-gp were assayed using a Hoechst 33342 assay for BCRP and a calcein AM assay for P-gp. Finally, quantitative structure-activity relationships for both aromatic rings were established. The results obtained show the importance of the electron density on the third aromatic ring, influenced by substituents, pointing to interactions with aromatic residues of the protein binding site. In the second aromatic ring the activity of compounds is influenced by the steric volume of the substituents.
Marighetti, Federico,Steggemann, Kerstin,Hanl, Markus,Wiese, Michael
p. 125 - 135
(2013/02/26)

Discovery of a series of thiazole derivatives as novel inhibitors of metastatic cancer cell migration and invasion
Effective inhibitors of cancer cell migration and invasion can potentially lead to clinical applications as a therapy to block tumor metastasis, the primary cause of death in cancer patients. To this end, we have designed and synthesized a series of thiazole derivatives that showed potent efficacy against cell migration and invasion in metastatic cancer cells. The most effective compound, 5k, was found to have an IC50 value of 176 nM in the dose-dependent transwell migration assays in MDA-MB-231cells. At a dose of 10 μM, 5k also blocked about 80% of migration in HeLa and A549 cells and 60% of invasion of MDA-MB-231 cells. Importantly, the majority of the derivatives exhibited no apparent cytotoxicity in the clonogenic assays. The low to negligible inhibition of cell proliferation is a desirable property of these antimigration derivatives because they hold promise of low toxicity to healthy cells as potential therapeutic agents. Mechanistic studies analyzing the actin cytoskeleton by microscopy demonstrate that compound 5k substantially reduced cellular f-actin and prevented localization of fascin to actin-rich membrane protrusions. These results suggest that the antimigration activity may result from impaired actin structures in protrusions that are necessary to drive migration.
Zheng, Shilong,Zhong, Qiu,Jiang, Quan,Mottamal, Madhusoodanan,Zhang, Qiang,Zhu, Naijue,Burow, Matthew E.,Worthylake, Rebecca A.,Wang, Guangdi
supporting information
p. 191 - 196
(2013/03/28)

Synthesis, antimycobacterial, antiviral, antimicrobial activity and QSAR studies of N2-acyl isonicotinic acid hydrazide derivatives
A series of N2-acyl isonicotinic acid hydrazides (1-17) was synthesized and tested for its in vitro antimycobacterial activity against Mycobacterium tuberculosis and the results indicated that the compound, isonicotinic acid N′- tetradecanoyl-hydrazide (12) was more active than the reference compound isoniazid. The results of antimicrobial activity of the synthesized compounds against S. aureus, B. subtilis, E. coli, C. albicans and A. niger indicated that compounds with dichloro, hydroxyl, tri-iodo and N 2 -tetradecanoyl substituent were the most active ones. The antiviral activity studies depicted that none of the tested compounds were active against DNA or RNA viruses. The multi-target QSAR model was found to be effective in describing the antimicrobial activity of N2-acyl isonicotinic acid hydrazides.
Judge, Vikramjeet,Narasimhan, Balasubramanian,Ahuja, Munish,Sriram, Dharmarajan,Yogeeswari, Perumal,De Clercq, Erik,Pannecouque, Christophe,Balzarini, Jan
p. 53 - 76
(2013/04/24)

Nickel-catalyzed direct alkylation of C-H bonds in benzamides and acrylamides with functionalized alkyl halides via bidentate-chelation assistance
The alkylation of the ortho C-H bonds in benzamides and acrylamides containing an 8-aminoquinoline moiety as a bidentate directing group with unactivated alkyl halides using nickel complexes as catalysts is described. The reaction shows high functional group compatibility. In reactions of meta-substituted aromatic amides, the reaction proceeds in a highly selective manner at the less hindered C-H bond.
Aihara, Yoshinori,Chatani, Naoto
supporting information
p. 5308 - 5311
(2013/05/21)

An efficient method for the preparation of hydroxamic acids
Reactions of acyl chlorides with hydroxylamine hydrochloride and NaHCO 3 generate the corresponding hydroxamic acid products in ethyl acetate and water at room temperature for 5 min. This is a simple and efficient method to synthesize a wide range of hydroxamic acids from carboxylic acids in excellent yield and high purity after simple post-treatment without chromatographic purification. In this process, the highlights are the simple separation of products and cheaply available reagents.
Gao, Xi-Ai,Wang, Xian-Xue,Yan, Hao,Li, Jian,Yan, Ru-Long,Huang, Guo-Sheng
p. 381 - 385
(2013/05/22)

Synthesis, antioxidant, and antimicrobial evaluation of some 2-arylbenzimidazole derivatives
A series of 2-arylbenzimidazole derivatives (3a-3p and 4a-4i) were synthesized and evaluated as potential antioxidant and antimicrobial agents. Their antioxidant properties were evaluated by various in vitro assays including hydroxyl radical (HO) scavenging, superoxide radical anion (O2 -) scavenging, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, and ferric reducing antioxidant power. Results demonstrated that compounds with hydroxyl group at the 5-position of benzimidazole ring had a comparable or better antioxidant activity in comparison to standard antioxidant tert-butylhydroquinone (TBHQ). Markedly, compound 4h that showed the highest HO scavenging activity (EC50 = 46 μM) in vitro had a significant reduction of 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH)-induced intracellular oxidative stress and H2O2-induced cell death. In addition, these compounds showed moderate to good inhibitory activity against Staphylococcus aureus selectively at noncytotoxic concentrations.
Zhou, Binhua,Li, Baojian,Yi, Wei,Bu, Xianzhang,Ma, Lin
supporting information
p. 3759 - 3763
(2013/07/27)

Design, synthesis, biological and structural evaluation of functionalized resveratrol analogues as inhibitors of quinone reductase 2
Resveratrol (3,5,4′-trihydroxylstilbene) has been proposed to elicit a variety of positive health effects including protection against cancer and cardiovascular disease. The highest affinity target of resveratrol identified so far is the oxidoreductase enzyme quinone reductase 2 (QR2), which is believed to function in metabolic reduction and detoxification processes; however, evidence exists linking QR2 to the metabolic activation of quinones, which can lead to cell toxicity. Therefore, inhibition of QR2 by resveratrol may protect cells against reactive intermediates and eventually cancer. With the aim of identifying novel inhibitors of QR2, we designed, synthesized, and tested two generations of resveratrol analogue libraries for inhibition of QR2. In addition, X-ray crystal structures of six of the resveratrol analogues in the active site of QR2 were determined. Several novel inhibitors of QR2 were successfully identified as well as a compound that inhibits QR2 with a novel binding orientation.
St. John, Sarah E.,Jensen, Katherine C.,Kang, Soosung,Chen, Yafang,Calamini, Barbara,Mesecar, Andrew D.,Lipton, Mark A.
p. 6022 - 6037
(2013/09/23)

Synthesis of B-ring substituted flavones and evaluation of their antitumor and antioxidant activities
A series of flavones, substituted at the ring B, were synthesized using either Claisen-Schimdt Condensation or Baker-Venkataraman rearrangement. The synthesized compounds were tested for in vitro cytotoxic activity by sulforhodamine B assay against three cell lines of different origin, viz. HepG2, MCF-7, and MOLT-4. The compounds were also tested for a possible antioxidant activity by determination of inhibition of lipid peroxidation. Quercetin was taken as a standard for antioxidant activity. Compound 1c showed the highest cytotoxic activity against MCF-7 (GI50 0.1 μM) and MOLT-4 (GI50 0.1 μM) cell lines and was comparable to adriamycin, the standard used. Compounds 1b, 1g, and 1h also showed promising activity against MCF-7 and MOLT-4 cell lines. In the absence of a hydroxyl group, one or more methoxy groups present on the B-ring (compounds 1c-1e) were major determinants of inhibition of lipid peroxidation.
Joshi, Akshada J.,Gadhwal, Manoj K.,Joshi, Urmila J.,D'Mello, Priscilla,Sinha, Ragini,Govil, Girjesh
p. 4293 - 4299
(2013/09/02)

Direct conversion of N -alkoxyamides to carboxylic esters through tandem nbs-mediated oxidative homocoupling and thermal denitrogenation
Treatment of N-alkoxyamides with NBS in toluene was found to conveniently afford the corresponding carboxylic esters, including those bearing a bulky or long-chain substituent, in satisfactory to excellent yields. This approach not only represents a convenient and economic approach to a direct transformation of an alkoxyamide moiety into the carboxylic ester functional group, via oxidative homocoupling and the subsequent thermal denitrogenation, but also facilitates the synthesis of sterically hindered carboxylic esters.
Zhang, Ningning,Yang, Rui,Zhang-Negrerie, Daisy,Du, Yunfei,Zhao, Kang
p. 8705 - 8711
(2013/09/24)

Restraining the flexibility of the central linker in terameprocol results in constrained analogs with improved growth inhibitory activity
The semi-synthetic lignan terameprocol inhibits the transcription of several inflammatory and oncogenic genes and has been evaluated for its anti-cancer properties. Here we investigated the effect of restricting the flexibility of the carbon linker connecting the terminal rings of terameprocol on its growth inhibitory activity. Conformational restriction was explored by introducing unsaturation, inserting polar entities with limited flexibility and cyclization of the connecting linker. Twenty three compounds were synthesized and evaluated on a panel of malignant human cells. The most promising compounds were those with non-polar linkers, as seen in butadiene 1a and the cyclized benzylideneindane analog 7. Both compounds were more potent than terameprocol on pancreatic BxPC-3 cells with GI50 values of 3.4 and 8.1 μM, respectively. Selected isomers of 1a (E,E) and 7 (Z) adopted low energy bent conformations that mimicked the low energy conformer of terameprocol. It is tempting to propose that conformational similarity to terameprocol may have contributed to their good activity. The scaffolds of 1a and 7 should be further investigated for their anticancer potential.
Ho, Sherman Si Han,Go, Mei Lin
supporting information
p. 6127 - 6133
(2013/11/06)

Metal-free aryltrifluoromethylation of activated alkenes
Metal-free: The first metal-free aryltrifluoromethylation of activated alkenes has been developed. With this method, trifluoromethylated isoquinolinediones, spirobicycles, oxindoles, and α-aryl-β- trifluoromethylamides were obtained with high control of the regioselectivity. Copyright
Kong, Wangqing,Casimiro, Maria,Fuentes, Noelia,Merino, Estibaliz,Nevado, Cristina
supporting information
p. 13086 - 13090
(2014/01/06)

Synthesis and biological activities of new halophenols
A series of new halophenols were synthesized, and their structures were established on the basis of 1H, 13C NMR and mass spectral data. All of the prepared compounds were screened for their in vitro protein tyrosine kinase (PTK) and vascular smooth muscle cell (VSMC) proliferation inhibitory activity. Twelve halophenols showed significant PTK inhibitory activity, most of them exhibited stronger activities than that of genistein, a positive reference compound. Several halophenols also displayed moderate VSMC proliferation inhibitory activity, compound 8c showed higher activity than that of tetrandrine, a positive reference compound. The preliminary structure-activity relationships of these compounds were investigated and discussed. The results provided a foundation for the action mechanism study and further structure optimization of the halophenols.
Zheng, Fei Lang,Ban, Shu Rong,Feng, Xiu E.,Zhao, Cheng Xiao,Du, Guan Hua,Li, Qing Shan
p. 303 - 311
(2013/07/28)

Acylthiourea, acylurea, and acylguanidine derivatives with potent Hedgehog inhibiting activity
The Smoothened (Smo) receptor is the major transducer of the Hedgehog (Hh) signaling pathway. On the basis of the structure of the acylthiourea Smo antagonist (MRT-10), a number of different series of analogous compounds were prepared by ligand-based structural optimization. The acylthioureas, originally identified as actives, were converted into the corresponding acylureas or acylguanidines. In each series, similar structural trends delivered potent compounds with IC50 values in the nanomolar range with respect to the inhibition of the Hh signaling pathway in various cell-based assays and of BODIPY-cyclopamine binding to human Smo. The similarity of their biological activities, in spite of discrete structural differences, may reveal the existence of hydrogen-bonding interactions between the ligands and the receptor pocket. Biological potency of compounds 61, 72, and 86 (MRT-83) were comparable to those of the clinical candidate GDC-0449. These findings suggest that these original molecules will help delineate Smo and Hh functions and can be developed as potential anticancer agents.
Solinas, Antonio,Faure, Hélène,Roudaut, Hermine,Traiffort, Elisabeth,Schoenfelder, Angèle,Mann, André,Manetti, Fabrizio,Taddei, Maurizio,Ruat, Martial
body text
p. 1559 - 1571
(2012/04/17)

Enantioselective synthesis of anti-β-hydroxy-α-amido esters by asymmetric transfer hydrogenation in emulsions
Herein, we present two methods for an asymmetric transfer hydrogenation through the dynamic kinetic resolution of α-amido-β-ketoesters. These procedures yield the corresponding anti-β-hydroxy-α-amido esters in good yields and with good diastereo- and enantioselectivities. First, the scope of the reduction of α-amido-β-ketoesters by using triethylammonium formate azeotrope is examined. Then, an emulsion technology with sodium formate is explored, which allows for broader substrate scope, faster reaction times, and lower catalyst loading. Furthermore, these reactions are operationally simple and can be set up in air.
Seashore-Ludlow, Brinton,Villo, Piret,Somfai, Peter
supporting information; experimental part
p. 7219 - 7223
(2012/07/13)

Synthesis, modeling and functional activity of substituted styrene-amides as small-molecule CXCR7 agonists
The chemokine receptor CXCR7 is an atypical G protein-coupled receptor as it preferentially signals through the β-arrestin pathway rather than through G proteins. CXCR7 is thought to be of importance in cancer and the development of CXCR7-targeting ligands is of huge importance to further elucidate the pharmacology and the therapeutic potential of CXCR7. In the present study, we synthesized 24 derivatives based on a compound scaffold patented by Chemocentryx and obtained CXCR7 ligands with pKi values ranging from 5.3 to 8.1. SAR studies were supported by computational 3D Fingerprint studies, revealing several important affinity descriptors. Two key compounds (29 and 30, VUF11207 and VUF11403) were found to be high-potency ligands that induce recruitment of β-arrestin2 and subsequent internalization of CXCR7, making them important tool compounds in future CXCR7 research.
Wijtmans, Maikel,Maussang, David,Sirci, Francesco,Scholten, Danny J.,Canals, Meritxell,Muji?-Deli?, Azra,Chong, Milagros,Chatalic, Kristell L.S.,Custers, Hans,Janssen, Elwin,De Graaf, Chris,Smit, Martine J.,De Esch, Iwan J.P.,Leurs, Rob
supporting information; experimental part
p. 184 - 192
(2012/07/14)

Synthesis and Preliminary Biologic Evaluation of 5-Substituted-2-(4-substituted phenyl)-1,3-Benzoxazoles as A Novel Class of Influenza Virus A Inhibitors
The diversity-oriented chemistry synthesis together with the random screening approach has permitted the discovery and optimization of novel antiviral lead compounds. In this paper, a series of novel 5-substituted-2-(4-substituted phenyl)-1,3-benzoxazoles was synthesized and evaluated for their in vitro anti-influenza A virus and anti-influenza B virus activity. The activity was monitored by the MTS assay in the Madin-Darby canine kidney cells. Compound 7h showed excellent inhibitory activity and selective index against A/H3N2 (EC50=37.03μm, SI>5), which were all higher than that of the reference drug oseltamivir (EC50>59.00μm, SI>1). However, no compound displays inhibitory activity against influenza B virus.
Li, Zhenyu,Zhan, Peng,Naesens, Lieve,Vanderlinden, Evelien,Liu, Ailin,Du, Guanhua,De Clercq, Erik,Liu, Xinyong
experimental part
p. 1018 - 1024
(2012/07/30)

Synthesis and evaluation of boronic acids as inhibitors of Penicillin Binding Proteins of classes A, B and C
In response to the widespread use of β-lactam antibiotics bacteria have evolved drug resistance mechanisms that include the production of resistant Penicillin Binding Proteins (PBPs). Boronic acids are potent β-lactamase inhibitors and have been shown to display some specificity for soluble transpeptidases and PBPs, but their potential as inhibitors of the latter enzymes is yet to be widely explored. Recently, a (2,6-dimethoxybenzamido) methylboronic acid was identified as being a potent inhibitor of Actinomadura sp. R39 transpeptidase (IC50: 1.3 μM). In this work, we synthesized and studied the potential of a number of acylaminomethylboronic acids as inhibitors of PBPs from different classes. Several derivatives inhibited PBPs of classes A, B and C from penicillin sensitive strains. The (2-nitrobenzamido)methylboronic acid was identified as a good inhibitor of a class A PBP (PBP1b from Streptococcus pneumoniae, IC50 = 26 μM), a class B PBP (PBP2xR6 from Streptococcus pneumoniae, IC50 = 138 μM) and a class C PBP (R39 from Actinomadura sp., IC50 = 0.6 μM). This work opens new avenues towards the development of molecules that inhibit PBPs, and eventually display bactericidal effects, on distinct bacterial species.
Zervosen, Astrid,Bouillez, Andre,Herman, Alexandre,Amoroso, Ana,Joris, Bernard,Sauvage, Eric,Charlier, Paulette,Luxen, Andre
experimental part
p. 3915 - 3924
(2012/08/28)

COMPOUNDS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
Compounds and their pharmaceutically acceptable salts for treatment of synucleinopathies, such as Parkinson's disease and tauopathies.
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(2012/09/21)

Design, synthesis, and pharmacological evaluation of N-acylhydrazones and novel conformationally constrained compounds as selective and potent orally active phosphodiesterase-4 inhibitors
Among a small series of tested N-acylhydrazones (NAHs), the compound 8a was selected as a selective submicromolar phosphodiesterase-4 (PDE4) inhibitor associated with anti-TNF-α properties measured both in vitro and in vivo. The recognition pattern of compound 8a was elucidated through molecular modeling studies based on the knowledge of the 3D-structure of zardaverine, a PDE4 inhibitor resembling the structure of 8a, cocrystallized with the PDE4. Based on further conformational analysis dealing with N-methyl-NAHs, a quinazoline derivative (19) was designed as a conformationally constrained NAH analogue and showed similar in vitro pharmacological profile, compared with 8a. In addition 19 was found active when tested orally in LPS-evoked airway hyperreactivity and fully confirmed the working hypothesis supporting this work.
Kümmerle, Arthur E.,Schmitt, Martine,Cardozo, Suzana V. S.,Lugnier, Claire,Villa, Pascal,Lopes, Alexandra B.,Romeiro, Nelilma C.,Justiniano, Hélène,Martins, Marco A.,Fraga, Carlos A. M.,Bourguignon, Jean-Jacques,Barreiro, Eliezer J.
p. 7525 - 7545
(2012/11/06)

PET imaging of nobiletin based on a practical total synthesis
A practical synthesis of nobiletin, a polymethoxylated citrus flavone, was accomplished by utilizing our novel flavone synthesis. Synthetic nobiletin was labelled by selective demethylation and rapid incorporation of 11C atom. Positron emission tomography images successfully visualized the brain distribution, which may provide therapeutic benefits in the treatment of Alzheimer's disease. The Royal Society of Chemistry.
Asakawa, Tomohiro,Hiza, Aiki,Nakayama, Miho,Inai, Makoto,Oyama, Dai,Koide, Hiroyuki,Shimizu, Kosuke,Wakimoto, Toshiyuki,Harada, Norihiro,Tsukada, Hideo,Oku, Naoto,Kan, Toshiyuki
supporting information; experimental part
p. 2868 - 2870
(2011/04/22)

Synthesis of polyhydroxylated aromatics having amidation of piperazine nitrogen as HIV-1 integrase inhibitor
(E)-N-[3-(4-Cinnamoylpiperazin-1-yl)propyl]-3,4-dihydroxybenzamide and (E)-N-[3-(4-cinnamoylpiperazin-1-yl)propyl]-3,4,5-trihydroxybenzamide were designed and synthesized as potential HIV-1 integrase inhibitors and evaluated their inhibition to the strand
Yang, Leifu,Xu, Xuemei,Huang, Yali,Zhang, Bin,Zeng, Chengchu,He, Hongqiu,Wang, Cunxin,Hu, Liming
supporting information; experimental part
p. 5469 - 5471
(2010/12/24)

Enantioselective synthesis of anti -β-hydroxy-α-amido esters via transfer hydrogenation
The asymmetric transfer hydrogenation of α-amido-β-keto esters to provide the corresponding anti-β-hydroxy-α-amido esters in good to excellent yields, diastereoselectivity, and enantioselectivity is reported. The procedure is operationally simple, and delicate handling of the catalyst is not necessary.
Seashore-Ludlow, Brinton,Villo, Piret,Haecker, Christine,Somfai, Peter
supporting information; experimental part
p. 5274 - 5277
(2011/01/12)

Synthesis of antimitotic polyalkoxyphenyl derivatives of combretastatin using plant allylpolyalkoxybenzenes (1)
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Semenov, Victor V.,Kiselyov, Alex S.,Titov, Ilia Y.,Sagamanova, Irina K.,Ikizalp, Natalie N.,Chernysheva, Natalia B.,Tsyganov, Dmitry V.,Konyushkin, Leonid D.,Firgang, Sergei I.,Semenov, Roman V.,Karmanova, Irina B.,Raihstat, Mikhail M.,Semenova, Marina N.
experimental part
p. 1796 - 1802
(2011/03/18)

Regioselectivity in direct arylation of benzanilide possessing oxygen substituent in the benzoyl part using palladium without phosphine ligand
The direct arylation of benzanilide (1) possessing ether oxygen(s) in benzoyl part was examined under phosphine ligand-free conditions, which afforded ortho-product (2) and para-product (3) in very similar ratio to presence of P(o-Tol)3 conditi
Harayama, Takashi,Nagura, Chie,Miyagoe, Taeko,Kawata, Yuko,Abe, Hitoshi,Takeuchi, Yasuo
experimental part
p. 2609 - 2616
(2011/04/15)

NOVEL PROCESS FOR SYNTHESIS OF ITOPRIDE AND ITS NOVEL INTERMEDIATE N-(4-HYDROXYBENZYL)- 3,4-DIMETHOXYBENZAMIDE
The present invention relates to a novel and improved process for the preparation of N-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide—known as Itopride, via a novel intermediate N-(4?hydroxybenzyl)-3,4-dimethoxybenzamide.
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(2009/07/18)