- DNA-Encoded Libraries: Hydrazide as a Pluripotent Precursor for On-DNA Synthesis of Various Azole Derivatives
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DNA-encoded combinatorial chemical library (DEL) technology, an approach that combines the power of genetics and chemistry, has emerged as an invaluable tool in drug discovery. Skeletal diversity plays a fundamental importance in DEL applications, and relies heavily on novel DNA-compatible chemical reactions. We report herein a phylogenic chemical transformation strategy using DNA-conjugated benzoyl hydrazine as a common versatile precursor in azole chemical expansion of DELs. DNA-compatible reactions deriving from the common benzoyl hydrazine precursor showed excellent functional group tolerance with exceptional efficiency in the synthesis of various azoles, including oxadiazoles, thiadiazoles, and triazoles, under mild reaction conditions. The phylogenic chemical transformation strategy provides DELs a facile way to expand into various unique chemical spaces with privileged scaffolds and pharmacophores.
- Ma, Fei,Li, Jie,Zhang, Shuning,Gu, Yuang,Tan, Tingting,Chen, Wanting,Wang, Shuyue,Ma, Peixiang,Xu, Hongtao,Yang, Guang,Lerner, Richard A.
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supporting information
p. 8214 - 8220
(2021/05/03)
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- 4-Amino-1,2,4-triazole-3-thione-derived Schiff bases as metallo-β-lactamase inhibitors
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Resistance to β-lactam antibiotics in Gram-negatives producing metallo-β-lactamases (MBLs) represents a major medical threat and there is an extremely urgent need to develop clinically useful inhibitors. We previously reported the original binding mode of 5-substituted-4-amino/H-1,2,4-triazole-3-thione compounds in the catalytic site of an MBL. Moreover, we showed that, although moderately potent, they represented a promising basis for the development of broad-spectrum MBL inhibitors. Here, we synthesized and characterized a large number of 4-amino-1,2,4-triazole-3-thione-derived Schiff bases. Compared to the previous series, the presence of an aryl moiety at position 4 afforded an average 10-fold increase in potency. Among 90 synthetic compounds, more than half inhibited at least one of the six tested MBLs (L1, VIM-4, VIM-2, NDM-1, IMP-1, CphA) with Ki values in the μM to sub-μM range. Several were broad-spectrum inhibitors, also inhibiting the most clinically relevant VIM-2 and NDM-1. Active compounds generally contained halogenated, bicyclic aryl or phenolic moieties at position 5, and one substituent among o-benzoic, 2,4-dihydroxyphenyl, p-benzyloxyphenyl or 3-(m-benzoyl)-phenyl at position 4. The crystallographic structure of VIM-2 in complex with an inhibitor showed the expected binding between the triazole-thione moiety and the dinuclear centre and also revealed a network of interactions involving Phe61, Tyr67, Trp87 and the conserved Asn233. Microbiological analysis suggested that the potentiation activity of the compounds was limited by poor outer membrane penetration or efflux. This was supported by the ability of one compound to restore the susceptibility of an NDM-1-producing E. coli clinical strain toward several β-lactams in the presence only of a sub-inhibitory concentration of colistin, a permeabilizing agent. Finally, some compounds were tested against the structurally similar di-zinc human glyoxalase II and found weaker inhibitors of the latter enzyme, thus showing a promising selectivity towards MBLs.
- Baud, Damien,Bebrone, Carine,Becker, Katja,Benvenuti, Manuela,Cerboni, Giulia,Chelini, Giulia,Cutolo, Giuliano,De Luca, Filomena,Docquier, Jean-Denis,Feller, Georges,Fischer, Marina,Galleni, Moreno,Gavara, Laurent,Gresh, Nohad,Kwapien, Karolina,Legru, Alice,Mangani, Stefano,Mercuri, Paola,Pozzi, Cecilia,Sannio, Filomena,Sevaille, Laurent,Tanfoni, Silvia,Verdirosa, Federica,Berthomieu, Dorothée,Bestgen, Beno?t,Frère, Jean-Marie,Hernandez, Jean-Fran?ois
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supporting information
(2020/09/16)
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- Colchicine derivatives, and preparation method and medical application thereof
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The invention specifically relates to colchicine derivatives (I) as described in the specification and a preparation method thereof, and pharmaceutical compositions containing the colchicine derivatives, belonging to the field of medicinal chemistry. The results of pharmacodynamic experiments prove that the colchicine derivatives of the invention have treatment effect on lumbar disc herniation andliver fibrosis.
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Paragraph 0092; 0093; 0118; 0120; 0121
(2018/09/14)
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- Directed β C-H Amination of Alcohols via Radical Relay Chaperones
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A radical-mediated strategy for β C-H amination of alcohols has been developed. This approach employs a radical relay chaperone, which serves as a traceless director that facilitates selective C-H functionalization via 1,5-hydrogen atom transfer (HAT) and enables net incorporation of ammonia at the β carbon of alcohols. The chaperones presented herein enable direct access to imidate radicals, allowing their first use for H atom abstraction. A streamlined protocol enables rapid conversion of alcohols to their β-amino analogs (via in situ conversion of alcohols to imidates, directed C-H amination, and hydrolysis to NH2). Mechanistic experiments indicate HAT is rate-limiting, whereas intramolecular amination is product- and stereo-determining.
- Wappes, Ethan A.,Nakafuku, Kohki M.,Nagib, David A.
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supporting information
p. 10204 - 10207
(2017/08/10)
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- Guanidine Synthesis: Use of Amidines as Guanylating Agents
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The use of amidines for the tandem or one-pot synthesis of guanidines is reported. Guanidines are obtained by oxidative rearrangement of readily available and stable amidines into carbodiimides, followed by in situ reaction with amines. The protocol can be executed under mild reaction conditions (30°C), in a green solvent (dimethyl carbonate). The amine scope is broad, including sterically hindered, oxidation-sensitive and chiral amines. Examples for the synthesis of both acyclic and cyclic guanidines are provided. 2-Propoxyphenyl iodide (2-PrOPhI) by-product, generated from the oxidant [N-(p-toluenesulfonyl)imino](2-propoxyphenyl)iodinane (2-PrOPhINTs), can be isolated in high yields making regeneration of the hypervalent iodine reagent possible. The utility and greenness of the synthetic method versus the state-of-the-art is demonstrated by a new route towards the antihypertensive drug Pinacidil. The process mass intensity (PMI) of the new route is only 24% of the classical one.
- Baeten, Mattijs,Maes, Bert U. W.
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supporting information
p. 826 - 833
(2016/03/12)
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- Synthesis of Some Novel 2-Substitutedbenzyl-(4)7-phenyl-1H-benzo[d]imidazoles in Mild Conditions as Potent Anti-Tyrosinase and Antioxidant Agents
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Novel 2-substitutedbenzyl-4(7)-phenyl-1H-benzo[d]imidazole compounds were synthesized and characterized. Although 2a and 2b were reported previously in the literature, 11 compounds were synthesized (nine of them were newly synthesized) and the tyrosinase inhibitory effects and antioxidant activities of these compounds were studied for the first time. All of the synthesized compounds displayed certain inhibitory effects on tyrosinase, with IC50 values ranging from 37.86 ± 0.24 to 75.81 ± 2.49 μM. Among the compounds, 2j exhibited similar tyrosinase inhibitory effect (IC50 = 37.86 ± 0.24 μM) to the positive control, kojic acid (IC50 = 21.93 ± 0.11 μM). Kinetic studies revealed it to act as non-competitive tyrosinase inhibitor with a Ki value of 50.2 μM. The antioxidant activities of the compounds were investigated by using in vitro antioxidant assays, including 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP). All of these results indicated that the compounds might have potential application as tyrosinase inhibitors.
- Do?an, ?nci S.,?zel, Arzu,Birinci, Zeynep,Barut, Burak,Sellitepe, Hasan E.,Kahveci, Bahittin
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p. 881 - 888
(2016/11/09)
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- 'Green' synthesis of 2-substituted 6-hydroxy-[3H]-pyrimidin-4-ones and 4,6-dichloropyrimidines: Improved strategies and mechanistic study
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An improved route to 2-substituted 6-hydroxy-[3H]-pyrimidin-4-ones 4 and to 2-substituted 4,6-dichloropyrimidines 5 is reported. Without using highly toxic reactants, compounds 4 can be prepared conveniently in a one pot synthesis on a one mol scale with average yields up to 80%. 4,6-Dichloropyrimidines 5, which are usually prepared in small quantities, are synthesized with average yields of 80%, using up to 80g of starting material. The mechanism of the chlorination of 4 is investigated computationally for the first time. The results suggest that the chlorination with phosphoryl chloride occurs in an alternating phosphorylation-chlorination manner (pathway 1) which is preferred over a sequence which starts with two phosphorylations. The investigated 4,6-dichloropyrimidines described herein form strong complexes with dichlorophosphoric acid but weak complexes with hydrochloric acid (generated during workup). These latter complexes explain the necessity of using aqueous sodium carbonate during the working up. In order to prevent possible formation of pyrimidinium salts between intermediates or the final dichloropyrimidines and unreacted hydroxypyrimidone, the latter could be deactivated with a strong acid such as dichlorophosphoric acid, thus allowing chlorination but prohibiting salt formation. Because of its general applicability to all nitrogen heterocycle chlorinations with phosphoryl chloride, the proposed route to dichloropyrimidines without solvent or side products, using less toxic reactants, is of general synthetic interest.
- Opitz, Andreas,Sulger, Werner,Daltrozzo, Ewald,Koch, Rainer
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p. 814 - 824
(2015/05/20)
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- Synthesis of protected α-alkyl lanthionine derivatives
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Protected α-alkyl lanthionine derivatives were synthesized in five steps starting from a known phenyloxazoline precursor. This approach involved the synthesis of a family of substituted cyclic sulfamidates and their regioselective opening by nucleophilic attack with a protected cysteine. This efficient multistep strategy affords various α-alkylated lanthionine derivatives in high yields.
- Deno?l, Thibaut,Zervosen, Astrid,Lemaire, Christian,Plenevaux, Alain,Luxen, André
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p. 4526 - 4533
(2014/06/10)
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- Facile synthesis of 3,5-diaryl-1,2,4-triazoles via copper-catalyzed domino nucleophilic substitution/oxidative cyclization using amidines or imidates as substrates
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Two methods for the synthesis of 3,5-diaryl-1,2,4-triazoles, both domino reactions, are reported. The first procedure, the Cu(OTf)2-catalyzed reaction between two amidines using NaHCO3 as a base, 1,10-phenanthroline as an additive and K3[Fe(CN)6]/ atmospheric oxygen as the oxidant, delivers 3,5-diaryl-1,2,4-triazoles with yields up to 68%. The second procedure for the synthesis of 3,5-diaryl-1,2,4- triazoles with yields up to 64% rests on the Cu(OTf)2-catalyzed reaction between two imidates and ammonium carbonate. This method features the formation of three bonds in a single synthetic step.
- Sudheendran, Kavitha,Schmidt, Dietmar,Frey, Wolfgang,Conrad, Jürgen,Beifuss, Uwe
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p. 1635 - 1645
(2014/02/14)
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- One-flask synthesis of 1,3,5-trisubstituted 1,2,4-triazoles from nitriles and hydrazonoyl chlorides via 1,3-dipolar cycloaddition
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A one-flask strategy for the synthesis of 1,3,5-trisubstituted 1,2,4-triazoles 4a-s and 8a and b from nitriles 5a-i with N-arylhydrazonoyl hydrochlorides 3a-h and 7a and b under basic conditions was developed. The reaction provided the desired 1,2,4-triazoles in moderate to excellent yields (56-98%), and was applicable to aliphatic and aromatic nitriles as well as N-phenylhydrazonoyl hydrochlorides bearing ester and acetyl functionalities. A 1,3-dipolar cycloaddition between imidate and nitrilimine generated from the respective nitrile and N-arylhydrazonoyl chloride in one flask was proposed for the new transformation.
- Wang, Li-Ya,Tsai, Henry J.,Lin, Hui-Yi,Kaneko, Kimiyoshi,Cheng, Fen-Ying,Shih, Hsin-Siao,Wong, Fung Fuh,Huang, Jiann-Jyh
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p. 14215 - 14220
(2014/04/17)
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- Hydrothermal synthesis, crystal structures and properties of zinc(2) Di-Nuclear complex and copper(1) coordination polymer based on building block 2-Phenyl-4,6-Di(pyridin-2-yl)pyrimidine
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A tetradentate ligand of 2-phenyl-4,6-di(pyridin-2-yl)pyrimidine (L) has been synthesized and its complexes with ZnI2 and CuI have been obtained by hydrothermal method. single crystal X-ray diffraction analysis indicates that ligand L coordinates with Zn(2) ions to form a simple four-coordinate di-nuclear complex, while the complexation of L with Cu(1) constructs a one-dimensional chain polymer. The existence of I-ion hampers the L to assemble grid-type complexes with Zn(2) and Cu(1). Fluorescence spectra show that the L emits blue fluorescence while its Cu(1) polymer decrease the fluorescence intensity and Zn(2) complex quenches the fluorescence.
- Zhao, Pusu,Jing, Wang,Jing, Long,Jian, Fangfang,Li, Yufeng
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p. 3743 - 3748
(2014/01/17)
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- Pd(ii)-catalyzed direct C5-arylation of azole-4-carboxylates through double C-H bond cleavage
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The first palladium-catalyzed direct C5-arylation of azole-4-carboxylates with simple unactivated arenes through double C-H bond cleavage is realized. This protocol provided a straightforward access to diverse 5-arylsubstituted azole-4-carboxylic derivatives with good functional group tolerance. The Royal Society of Chemistry 2012.
- Li, Ziyuan,Ma, Ling,Xu, Jinyi,Kong, Lingyi,Wu, Xiaoming,Yao, Hequan
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supporting information; scheme or table
p. 3763 - 3765
(2012/06/15)
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- Camphor-annelated imidazolines with various N1 and C2 pendants as tunable ligands for nitroaldol reactions
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Starting from (1R,2S,3R)-camphordiamine and (hetero)aromatic imidates and orthoformate, nine new camphor-annelated NH-imidazolines were synthesized. Subsequent N-modification was carried out via methylation, acylation, benzoylation, and sulfonylation. Two regioisomers were usually isolated with the ratios reflecting the structure of the starting NH-imidazoline and the electrophile used. All of the successfully prepared N1- and C2-substituted camphor-annelated imidazolines were applied to the asymmetric version of a Cu(II)-catalyzed Henry reaction. The electronic effects of both N1- and C2-pendants on the chemical and asymmetric outcomes of the nitroaldol reaction have been studied and discussed. 2012 Elsevier Ltd.
- Tydlitat, Jiri,Bures, Filip,Kulhanek, Jiri,Mloston, Grzegorz,Ruzicka, Ales
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scheme or table
p. 1010 - 1018
(2012/09/25)
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- New imidazoline/α2-adrenoceptors affecting compounds-4(5)-(2-aminoethyl)imidazoline (dihydrohistamine) derivatives. Synthesis and receptor affinity studies
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Compilation of agmatine structure and imidazoline moiety leads to a new group of imidazoline/α2-adrenoceptor ligands, 4(5)-(2-aminoethyl)imidazoline derivatives. In this study the exploration of previously unknown 4(5)-(2-aminoethyl)imidazolines including the analogues of reported imidazoline and α2-aderenoceptors ligands: clonidine, rilmenidine, idazoxan, efaroxan, antazoline, tracizoline is described. The synthesis of a variety of novel 4(5)-(2-aminoethyl)imidazolines and their I 1, I2, α2-adrenoceptors affinities are reported.
- Treder, Adam P.,Andruszkiewicz, Ryszard,Zgoda, W?odzimierz,Walkowiak, Aleksandra,Ford, Celeste,Hudson, Alan L.
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experimental part
p. 156 - 167
(2011/03/18)
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- 2-Phenyl-1-[4-(2-piperidine-1-yl-ethoxy)benzyl]-1H-benzimidazoles as ligands for the estrogen receptor: Synthesis and pharmacological evaluation
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2-Phenyl-1H-benzimidazoles 7a-e were synthesized and tested for gene activation on ERα-positive MCF-7 breast cancer cells, stably transfected with the reporter plasmid EREwtcluc (MCF-7-2a cells). None of the compounds showed agonistic properties, but they antagonized dependent on hydroxyl groups at the benzimidazole core (5- or 6-OH) and at the aromatic ring in the 2-position (4-OH) in high concentrations the gene activation induced by estradiol (E2, 1 nM). All compounds exhibited significant antiproliferative properties on MCF-7 cells but they were inactive against hormone independent, ER negative MDA-MB-231 cells.
- Dettmann, Sandra,Szymanowitz, Katrin,Wellner, Anja,Schiedel, Anke,Mueller, Christa E.,Gust, Ronald
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experimental part
p. 4905 - 4916
(2010/09/10)
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- Reverse-benzamidine antimalarial agents: Design, synthesis, and biological evaluation
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In the frame of the development of bis-cationic choline analogs, the RSA of bis-N-alkylamidines were studied and a new series of reverse-benzamidine derivatives was designed. Contrary to the lipophilicity, the basicity of alkylamidine compounds directly influences their antimalarial potencies.
- Berger, Olivier,Wein, Sharon,Duckert, Jean-Frederic,Maynadier, Marjorie,Fangour, Siham El,Escale, Roger,Durand, Thierry,Vial, Henri,Vo-Hoang, Yen
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scheme or table
p. 5815 - 5817
(2010/11/17)
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- 1,2-disubstituted hexahydro-1 H -benzo[d]imidazoles: Synthesis, characterization, and stability
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Starting from commercially available (hetero)aromatic nitriles and (1R,2R)-cyclohexane-1,2-diamine, nine NH-imidazolines (hexahydro-1H-benzo[d] imidazoles) were synthesized in good yields. The molecular structures of three imidazolines were confirmed by X-ray analysis. N-Benzylation afforded some of the desired N-benzylimidazolines, but was incompatible with imidazolines that possessed strong electron-accepting heteroaromatic groups at C2. In the latter cases, the products decomposed during column chromatography to form N,N-disubstituted cyclohexane-1,2-diamines. Georg Thieme Verlag Stuttgart · New York.
- Tydlitat, Jiri,Bures, Filip,Kulhanek, Jiri,Ruzicka, Ales
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scheme or table
p. 3934 - 3940
(2010/12/29)
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- Synthesis and antiproliferative activity of imidazole and imidazoline analogs for melanoma
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We have previously reported substituted 2-aryl-thiazolidine-4-carboxylic acid amides as potent and selective antiproliferative agents for melanoma. To understand the importance of the thiazolidine ring and to reduce potential complications associated with the two chiral centers, we designed and synthesized sets of new analogs by modifying this ring. These new analogs were tested in two melanoma cell lines and fibroblast cells (negative controls). Compared with the older analogs containing the thiazolidine ring, these new analogs have lower potency in general, but some of these analogs still have very good selectivity. These structure-activity studies indicated that the thiazolidine ring is very critical for the activity for these series of compounds.
- Chen, Jianjun,Wang, Zhao,Lu, Yan,Dalton, James T.,Miller, Duane D.,Li, Wei
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body text
p. 3183 - 3187
(2009/04/11)
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- Synthesis, structures of some unsymmetrical 3,6-disubstituted-1,2,4,5- tetrazines
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(Chemical Equation Presented) A series of new unsymmetrical 3-phenyl-6-benzyl-1,2,4,5-tetrazine derivatives 10a-i were synthesized and characterized by IR, NMR, MS, and element analysis. The structures of 4a, 10c, 10d and 10h were analyzed by X-ray crystallography, which had intermolecular C-H...N, C-H...Cl, C-H...Π and Π...Π H interactions.
- Hu, Wei-Xiao,Xu, Feng
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scheme or table
p. 1745 - 1750
(2009/05/31)
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- MODULATORS OF C3A RECEPTOR AND METHODS OF USE THEREOF
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Provided are compounds that are modulators of C3a receptor activity, compositions containing the compounds and methods of use of the compounds and compositions. In certain embodiments, the compounds are pyridones. In certain embodiments, provided are methods for treatment or amelioration of diseases associated with modulation of C3a receptor activity.
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Page/Page column 164
(2008/12/07)
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- Novel N1-(benzyl)cinnamamidine derived NR2B subtype-selective NMDA receptor antagonists.
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Novel (E)-N(1)-(benzyl)cinnamamidines were prepared and evaluated as NR2B subtype NMDA receptor ligands. Excellent affinity was achieved by appropriate substitution of either phenyl ring. The 2-methoxybenzyl compound 1h had approximately 1,000-fold lower IC(50) in NR2B than NR2A-containing cells. Replacement of the styryl unit by 2-naphthyl was well tolerated.
- Curtis, Neil R,Diggle, Helen J,Kulagowski, Janusz J,London, Clare,Grimwood, Sarah,Hutson, Peter H,Murray, Fraser,Richards, Pawel,Macaulay, Alison,Wafford, Keith A
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p. 693 - 696
(2007/10/03)
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- Orally efficacious NR2B-selective NMDA receptor antagonists
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A novel series of benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 31 is orally active in a carrageenan-induced rat hyperalgesia model of pain and shows no motor coordination side effects.
- Claiborne, Christopher F.,McCauley, John A.,Libby, Brian E.,Curtis, Neil R.,Diggle, Helen J.,Kulagowski, Janusz J.,Michelson, Stuart R.,Anderson, Kenneth D.,Claremon, David A.,Freidinger, Roger M.,Bednar, Rodney A.,Mosser, Scott D.,Gaul, Stanley L.,Connolly, Thomas M.,Condra, Cindra L.,Bednar, Bohumil,Stump, Gary L.,Lynch, Joseph J.,Macaulay, Alison,Wafford, Keith A.,Koblan, Kenneth S.,Liverton, Nigel J.
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p. 697 - 700
(2007/10/03)
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- An enantioselective ketene-imine cycloaddition method for synthesis of substituted ring-fused 2-pyridinones
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Previously, a method for the stereoselective synthesis of β-lactams, starting from 2H-δ2-thiazolines and Meldrum's acid derivatives, has been reported from our laboratory. We now report a new method for the synthesis of optically active, highly substituted ring-fused 2-pyridinones. This was discovered when 2-alkyl-δ2-thiazolines and Meldrum's acid derivatives were treated with HCl(g) in benzene at 5 → 78 °C. Further refinement of the synthetic protocol revealed that use of 1,2-dichloroethane as solvent at 0 → 64 °C led to the desired 2-pyridinones in good yields and with excellent enantioselectivity. Use of these conditions allowed preparation of 2-pyridinones from several different δ2-thiazolines and Meldrum's acid derivatives and may be a general route to 2-pyridinones.
- Emtenaes,Alderin,Almqvist
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p. 6756 - 6761
(2007/10/03)
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- Novel chiral organoselenenyl halides stabilized by Se ··· N nonbonded interactions: Synthesis and structural characterization
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The first examples of structurally characterized chiral organoselenenyl halides stabilized by Se ··· N intramolecular interactions are described. The existence of strong nonbonded Se ··· N interactions in the solid state as well as in solution was unambiguously determined by single-crystal X-ray analysis and 77Se NMR spectroscopy.
- Mugesh,Singh, Harkesh B.,Butcher, Ray J.
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p. 237 - 242
(2007/10/03)
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- HETEROCYCLIC AMIDE COMPOUNDS AND PHARMACEUTICAL USE OF THE SAME
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Heterocyclic amide compounds of the formula (I) STR1 wherein each symbol is as defined in the specification, pharmacologically acceptable salts thereof, pharmaceutical compositions thereof and pharmaceutical use thereof. The heterocyclic amide compounds and pharmacologically acceptable salts thereof of the present invention have superior inhibitory activity against chymase groups in mammals inclusive of human, and can be administered orally or parenterally. Therefore, they are useful as chymase inhibitors and can be effective for the prophylaxis and treatment of various diseases caused by chymase, such as those caused by angiotensin II.
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- Benzamide analogs useful as PARP (ADP-ribosyltransferase, ADPRT) DNA repair enzyme inhibitors
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A range of 3-oxybenzamide compounds and related quinazolinone compounds are disclosed which can act as potent inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase or PARP enzyme (EC 2.4.2.30), and which thereby can provide useful therapeutic compounds for use in conjunction with DNA-damaging cytotoxic drugs or radiotherapy to potentiate the effects of the latter. The compounds disclosed include 3-benzyloxybenzamides, 3-oxybenzamides in which a chain of 5 or more methylene groups terminate in a halogen atom or in a purin-9-yl moiety, certain benzoxazole-4-carboxamide compounds and certain quinazolinone compounds. In formula X and Y together may form a bride -X-Y- that represents the grouping (a), (b) or (c )wherein R5 is H, alkyl, aryl or aralkyl.
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- Natural Products as Pesticides: Two Examples of Stereoselective Synthesis
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The strategy and synthetic efforts leading to efficient stereoselective syntheses of thiangazole, a tris-thiazolinyl-oxazole metabolite isolated from Polyangium spp., and hydantocidin, a spironucleoside metabolite isolated from Streptomyces hygroscopicus, are discussed.
- Frueh, Thomas,Chemla, Philippe,Ehrler, Juerg,Farooq, Saleem
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- Asymmetric addition to chiral aromatic and unsaturated oxazolines using a novel chiral auxillary
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By utilizing S-serine, both enantiomers of the reduced methoxyamino alcohol (12) were efficiently prepared. The corresponding oxazolines, prepared from these auxiliaries, showed favorable properties toward additions to naphthalenes 22 and cyclohexene, 27.
- Meyers,Schmidt,McKennon
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p. 250 - 262
(2007/10/02)
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- N1-substituted benzamidines: Synthesis, antiproteinase activity and inhibition of tumor cell growth
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We have synthesized N1-substituted benzamidines and polybenzamidines with the aim to produce antitumor drugs retaining differential biological properties with respect to unsubstituted compounds. Antiproliferative activity on in vitro cultured human leukemic cells was exhibited by N1-substituted polybenzamidines, while N1-substituted benzamidines were found to retain very low antitumor effects. Furthermore, our results suggest that N1-substituted benzamidines and some of polybenzamidines exhibit low activity on trypsin and kallikrein. Taken together these data indicate that some N1-substituted polybenzamidines could be of interest for experimental antitumor therapy, since are likey to retain low side effects due to alteration of proteinase activity.
- Ferroni,Simoni,Binato,Nastruzzi,Manfredini,Orlandini,Feriotto,Gambari
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p. 1311 - 1321
(2007/10/02)
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- Formation of 1,2,4-Triazoles by Cation Radical Induced Oxidative Addition of Arylhydrazones of Benzaldehyde and Butyraldehyde to Nitriles
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1,3,5-Trisubstituted 1,2,4-triazoles have been made in excellent yields by oxidative cycloaddition of arylhydrazones of benzaldehyde and butyraldehyde to aceto-, propio-, and acrylonitrile.Oxidation was achieved with the cation radicals thianthrenyl perchlorate (Th(radical)+ClO4-) and tris(2,4-dibromophenyl)aminium hexachloroantimonate (Ar3N(radical)+SbCl6-).The triazoles thus had a phenyl, p-nitrophenyl, or 2,4-dinitrophenyl group in the 1-position, either a phenyl or propyl group in the 3-position, and a methyl, ethyl, or vinyl group in the 5-position.The formation of 5-vinyltriazoles was confirmed by their hydrogenation to 5-ethyltriazoles, which were obtained also by cycloadditions to propionitrile.New triazoles (eight) were also synthesized by a known alternative route, but in lower yields.The fact that 5-vinyltriazoles were formed instead of 5-cyano-2-pyrazolines shows that cation radical induced cycloadditions do not go through the nitrilimines.Cycloadditions with N-phenylbenzohydrazonoyl chloride and acrylonitrile in the presence of aluminum chloride and of triethylamine were carried out for comparison with the corresponding cation radical reaction.
- Shine, Henry J.,Hoque, A. K. M. Mansurul
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p. 4349 - 4353
(2007/10/02)
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- Process for the preparation of organo N-hydroxyimidates
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Organo N-hydroxyimidates are prepared by reacting an organonitrile with an organic alcohol and with a hydrogen halide, in the presence of an organic solvent (which may include an excess of the organonitrile reactant), under anhydrous conditions, to form the corresponding organoimidate hydrohalide, and then reacting said organoimidate hydrohalide with a hydroxylamine salt and ammonia gas in the presence of an organic solvent (which can be the excess organonitrile from the first step), under anhydrous conditions, to produce the corresponding organo N-hydroxyimidate.
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- REACTION OF ARENESULFENYL CHLORIDES WITH N-CHLOROCARBONIMIDIC AND N-CHLOROBENZENECARBOXIMIDIC ESTERS. N-(ETHOXYCARBONYL)- AND N-BENZOYLARENESULFINIMIDOYL CHLORIDES
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In the reaction of arenesulfonyl chlorides with diethyl N-chlorocarbonimidate or N-chlorobenzenecarboximidic esters at 20 deg C 1:1 adducts are formed, and they probably have the structure of tetracoordinated compounds of sulfur.The latter are also formed during the chlorination of N-(arylthio)carbonimidic or N-(arylthio)benzenecarboximidic esters.The obtained compounds are dechlorinated by the action of bases with the formation of N-(arylthio)carbonimidic or N-(arylthio)benzenecarboximidic esters.During acidolysis they split into arenesulfenyl chlorides and the salts of the corresponding carbonimidic and benzenecarboximidic esters.During thermolysis they eliminate alkyl chlorides and are converted into N-(ethoxycarbonyl)- or N-benzoylarenesulfinimidoyl chlorides.
- Levchenko, E. S.,Dubinina, T. N.,Budnik, L. V.,Romanenko, E. A.
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p. 1166 - 1171
(2007/10/02)
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- Synthesis and Structure of Alkyl N-Acylimidates
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Alkyl N-acylimidates 1 are prepared more easily and in higher yields than before by reaction of alkyl imidate hydrochlorides 5 with acyl halides 7 in the presence of 2.2 mol of base (14 examples).The X-ray analysis of a crystalline derivative (1dbd) shows, that the C=N- and C=O parts are twisted significantly (torsional angle 77.6 deg).The stereochemical, dynamic and electronic properties of the compounds 1 are interpreted by means of ab initio 3-21 G calculations on conformers of the parent system HO-CH=N-CH=O (8).Low rotational (ca. 6 kcal/mol) and inversional (max. 8 kcal/mol) barriers indicate the many favourable electronic interactions between the C=N- and the C=O groups in such N-functionalised imine derivatives.The compound 1 are significantly higher in energy than bisacylamines and are therefore suggested to be superior, more reactive synthetic C-N-C building blocks.The spectroscopic properties (IR, 13C- and 1H NMR, MS) are given and discussed.
- Kupfer, Rainer,Nagel, Michael,Wuerthwein, Ernst-Ulrich,Allmann, Rudolf
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p. 3089 - 3104
(2007/10/02)
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