- Synthesis of Amino Acid-Derived 1,2,3-Triazoles: Development of a Nontrivial Fluorescent Sensor in Solution for the Enantioselective Sensing of a Carbohydrate and Bovine Serum Albumin Interaction
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A series of amino acid-derived 1,2,3-triazoles presenting the amino acid and the aromatic moieties connected by a triazole-4-carboxylate spacer is discussed in this work. These compounds were achieved in good yields by organocatalytic enamine-azide [3 + 2] cycloadditions. One of the molecules obtained, bearing a 7-chloroquinoline moiety, was photoactive in the UV-violet region and was successfully employed as a probe for substrate-specific enantiomeric sensing using d-(-)-arabinose and l-(+)-arabinose. The potential application as a fluorescent probe to detect protein in phosphate buffer solution was also explored using as model bovine serum albumin (BSA). The studied compounds presented both suppression and association behavior in the presence of BSA. In addition, theoretical calculations were performed at levels ωB97XD/cc-pVDZ and PBE1PBE/6-311+G(d,p) together with the polarizable continuum model to understand the interaction of the molecules with the enantiomers.
- Debia, Natalí P.,Saraiva, Maiara T.,Martins, Bruna S.,Beal, Roiney,Gon?alves, Paulo F. B.,Rodembusch, Fabiano S.,Alves, Diego,Lüdtke, Diogo S.
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- Design, synthesis, and characterization of novel aminoalcohol quinolines with strong in vitro antimalarial activity
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Malaria is the fifth most lethal parasitic infections in the world. Herein, five new series of aminoalcohol quinolines including fifty-two compounds were designed, synthesized and evaluated in vitro against Pf3D7 and PfW2 strains. Among them, fourteen displayed IC50 values below or near of 50.0 nM whatever the strain with selectivity index often superior to 100.17b was found as a promising antimalarial candidate with IC50 values of 14.9 nM and 11.0 nM against respectively Pf3D7 and PfW2 and a selectivity index higher than 770 whatever the cell line is. Further experiments were achieved to confirm the safety and to establish the preliminary ADMET profile of compound 17b before the in vivo study performed on a mouse model of P. berghei ANKA infection. The overall data of this study allowed to establish new structure-activity relationships and the development of novel agents with improved pharmacokinetic properties.
- Dassonville-Klimpt,Schneider,Damiani,Tisnerat,Cohen,Azas,Marchivie,Guillon,Mullié,Agnamey,Totet, Anne,Dormoi,Taudon,Pradines,Sonnet
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- Construction and activity evaluation of novel benzodioxane derivatives as dual-target antifungal inhibitors
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Ergosterol exert the important function in maintaining the fluidity and osmotic pressure of fungal cells, and its key biosynthesis enzymes (Squalene epoxidase, SE; 14 α-demethylase, CYP51) displayed the obvious synergistic effects. Therefore, we expected to discover the novel antifungal compounds with dual-target (SE/CYP51) inhibitory activity. In the progress, we screened the different kinds of potent fragments based on the dual-target (CYP51, SE) features, and the method of fragment-based drug discovery (FBDD) was used to guide the construction of three different series of benzodioxane compounds. Subsequently, their chemical structures were synthesized and evaluated. These compounds displayed the obvious biological activity against the pathogenic fungal strains. Notably, target compounds 10a-2 and 22a-2 possessed the excellent broad-spectrum anti-fungal activity (MIC50, 0.125–2.0 μg/mL) and the activity against drug-resistant strains (MIC50, 0.5–2.0 μg/mL). Preliminary mechanism studies have confirmed that these compounds effectively inhibited the dual-target (SE/CYP51) activity, they could cause fungal rupture and death by blocking the bio-synthetic pathway of ergosterol. Further experiments discovered that compounds 10a-2 and 22a-2 also maintained a certain of anti-fungal effect in vivo. In summary, this study not only provided the new dual-target drug design strategy and method, but also discover the potential antifungal compounds.
- An, Yunfei,Fan, Haiyan,Han, Jun,Liu, Wenxia,Sun, Bin,Xie, Honglei
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- Design, Synthesis, and Cytotoxic Activity of New Tubulysin Analogues
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Synthesis of tubulysin analogues, containing an N-methyl substituent on tubuvaline-amide together with the replacement of either the hydrophobic N-terminal N-methyl pipecolic acid (Mep) or at both N- and C- terminal peptides with available heteroaromatic
- Le, Hai Van,Tran, Loc Van,Tran, Anh Tuan,Tran, Thao Thi Phuong,Tran, Sung Van,Tran, Chien Van
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supporting information
p. 187 - 195
(2021/12/03)
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- Design and synthesis of novel phe-phe hydroxyethylene derivatives as potential coronavirus main protease inhibitors
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In response to the current pandemic caused by the novel SARS-CoV-2, we design new compounds based on Lopinavir structure as an FDA-approved antiviral agent which is currently under more evaluation in clinical trials for COVID-19 patients. This is the first example of the preparation of Lopinavir isosteres from the main core of Lopinavir conducted to various heterocyclic fragments. It is proposed that main protease inhibitors play an important role in the cycle life of coronavirus. Thus, the protease inhibition effect of synthesized compounds was studied by molecular docking method. All of these 10 molecules, showing a good docking score compared. Molecular dynamics (MD) simulations also confirmed the stability of the best-designed compound in Mpro active site. Communicated by Ramaswamy H. Sarma.
- Khorsandi, Zahra,Afshinpour, Maral,Molaei, Fatemeh,Askandar, Rafee Habib,Keshavarzipour, Fariba,Abbasi, Maryam,Sadeghi-Aliabadi, Hojjat
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- Urea based foldamers
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N,N′-linked oligoureas are a class of enantiopure, sequence-defined peptidomimetic oligomers without amino acids that form well-defined and predictable helical structures akin to the peptide α-helix. Oligourea-based foldamers combine a number of features—such as synthetic accessibility, sequence modularity, and folding fidelity—that bode well for their use in a range of applications from medicinal chemistry to catalysis. Moreover, it was recently recognized that this synthetic helical backbone can be combined with regular peptides to generate helically folded peptide-oligourea hybrids that display additional features in terms of helix mimicry and protein-surface recognition properties. Here we provide detailed protocols for the preparation of requested monomers and for the synthesis and purification of homo-oligoureas and peptide-oligourea hybrids.
- Yoo, Sung Hyun,Li, Bo,Dolain, Christel,Pasco, Morgane,Guichard, Gilles
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- Total synthesis of tubulysin U and N14-desacetoxytubulysin H
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A concise and efficient procedure for the total synthesis of tubulysin U and N14-desacetoxytubulysin H has been developed with high stereoselectivity on a gram scale. This synthesis features an elegant cascade one-pot process to install the challenging th
- Cao, Meiqun,Li, Yinghong,Long, Bohua,Tao, Cheng,Wu, Zhengzhi,Zeng, Xiaobin
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supporting information
p. 5349 - 5353
(2020/08/03)
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- Nickel-Catalyzed Asymmetric Hydrogenation of 2-Amidoacrylates
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Earth-abundant nickel, coordinated with a suitable chiral bisphosphine ligand, was found to be an efficient catalyst for the asymmetric hydrogenation of 2-amidoacrylates, affording the chiral α-amino acid esters in quantitative yields and excellent enantioselectivity (up to 96 % ee). The active catalyst component was studied by NMR and HRMS, which helped us to realize high catalytic efficiency on a gram scale with a low catalyst loading (S/C=2000). The hydrogenated products could be simply converted into chiral α-amino acids, β-amino alcohols, and their bioactive derivatives. Furthermore, the catalytic mechanism was investigated using deuterium-labeling experiments and computational calculations.
- Chen, Jianzhong,Gridnev, Ilya D.,Hu, Yawen,Li, Bowen,Zhang, Wanbin,Zhang, Zhenfeng
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supporting information
p. 5371 - 5375
(2020/02/15)
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- Vinyl sulfone-based inhibitors of trypanosomal cysteine protease rhodesain with improved antitrypanosomal activities
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The number of reported cases of Human African Trypanosmiasis (HAT), caused by kinetoplastid protozoan parasite Trypanosoma brucei, is declining in sub-Saharan Africa. Historically, such declines are generally followed by periods of higher incidence, and one of the lingering public health challenges of HAT is that its drug development pipeline is historically sparse. As a continuation of our work on new antitrypanosomal agents, we found that partially saturated quinoline-based vinyl sulfone compounds selectively inhibit the growth of T. brucei but displayed relatively weak inhibitory activity towards T. brucei's cysteine protease rhodesain. While two nitroaromatic analogues of the quinoline-based vinyl sulfone compounds displayed potent inhibition of T. brucei and rhodesain. The quinoline derivatives and the nitroaromatic-based compounds discovered in this work can serve as leads for ADME-based optimization and pre-clinical investigations.
- Ajayi, Oluwatomi,Collins, Jasmine,Crown, Olamide,Nyamwihura, Rogers,Ogungbe, Ifedayo Victor,Zhang, Huaisheng
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supporting information
(2020/05/18)
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- The Synthesis of Chiral Allyl Carbamates via Merger of Photoredox and Nickel Catalysis
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A mild, and versatile, organophotoredox/Ni-mediated protocol was developed for the direct preparation of diverse, enantioenriched allyl carbamates. The reported approach represents a significant departure from classical step-by-step synthesis of allyl carbamates. This dual photoredox/Ni based strategy offers unrivalled capacity for convergent unification of readily available alkyl halides and chiral carbamates derived from 1-bromo-alken-3-ols with high chemoselectivity and efficiency. The reported photoredox/Ni catalyzed cross-coupling reaction is not limited to carbamates, but also to other O-derivatives such as esters, ethers, acetals, carbonates or silyl ethers. To demonstrate the utility of the reported protocol, the resulting allyl carbamates were transformed into functionalized non-racemic allylamines through a sigmatropic rearrangement reaction in enantiospecific manner. This approach allowed for synthesis of enantiomeric allylamines by a simple control of the geometry of a double bond of allyl carbamates. (Figure presented.).
- Garbacz, Mateusz,Stecko, Sebastian
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supporting information
p. 3213 - 3222
(2020/07/06)
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- Vinyl Sulfone-Based Inhibitors of Nonstructural Protein 2 Block the Replication of Venezuelan Equine Encephalitis Virus
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Emerging infectious diseases like those caused by arboviruses such as Venezuelan equine encephalitis virus (VEEV) pose a serious threat to public health systems. Development of medical countermeasures against emerging infectious diseases are of utmost importance. In this work, an acrylate and vinyl sulfone-based chemical series was investigated as promising starting scaffolds against VEEV and as inhibitors of the cysteine protease domain of VEEV's nonstructural protein 2 (nsP2). Primary screen and dose response studies were performed to evaluate the potency and cytotoxicity of the compounds. The results provide structural insights into a new class of potent nonpeptidic covalent inhibitors of nsP2 cysteine protease represented by compound 11 (VEEV TrD, EC50= 2.4 μM (HeLa), 1.6 μM (Vero E6)). These results may facilitate the evolution of the compounds into selective and broad-spectrum anti-alphaviral drug leads.
- Zhang, Huaisheng,Harmon, Moeshia,Radoshitzky, Sheli R.,Soloveva, Veronica,Kane, Christopher D.,Duplantier, Allen J.,Ogungbe, Ifedayo Victor
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supporting information
p. 2139 - 2145
(2020/12/17)
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- Synthesis and photophysics of benzazole based triazoles with amino acid-derived pendant units. Multiparametric optical sensors for BSA and CT-DNA in solution
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Herein we report the synthesis of a series of amino acid-derived triazoles by an organocatalytic cycloaddition reaction between azides and carbonyl compounds, catalyzed by a simple amine. These compounds present absorption maxima located in the UV-B ascribed to fully spin and symmetry allowed electronic transitions and a main fluorescence emission in the UV-A (~380 nm) with a relatively large Stokes shift (5700 cm?1). No significant solvatochromism was observed in both ground and excited states. Unexpectedly, the benzoxazole derivatives presented much higher fluorescence quantum yield values (40–80%) of compared to the sulfur analogues (3–6%). In addition, the DNA binding assays indicated that these compounds presented strong interaction with CT-DNA, which could be attributed to π-stacking and intermolecular hydrogen-bonding. The interaction of the benzazoles with bovine serum albumin (BSA) was also investigated, where a suppression mechanism was observed. In each case, docking was performed to better understand the observed interactions.
- Debia, Natalí P.,Rodríguez, Juan J.P.,da Silveira, Carolina H.,Chaves, Otavio A.,Iglesias, Bernardo A.,Rodembusch, Fabiano S.,Lüdtke, Diogo S.
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- O-Alkyl S-(Pyridin-2-yl)carbonothiolates: Operationally Simple and Highly Nitrogen-Selective Reagents for Alkoxy Carbonylation of Amino Groups
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Amino groups are selectively protected in good yields by reaction with O-Alkyl S-(pyridin-2-yl)carbonothiolates in an appropriate solvent at room temperature in air. Even glucosamine, which contains multiple hydroxyl groups, is selectively N-protected in methanol.
- Hashimoto, Yoshimitsu,Morita, Nobuyoshi,Suzuki, Tomoyuki,Tamura, Osamu,Tanaka, Kosaku
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p. 899 - 902
(2020/05/28)
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- Nascent-HBr-Catalyzed Removal of Orthogonal Protecting Groups in Aqueous Surfactants
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Organic reactions in the aqueous environment have recently emerged as a promising research area. The generation of nascent-HBr from the slow hydrolysis of the dispersed catalyst, benzyl bromide, with the interior water present in the hydrophobic core of the confined micellar medium in aqueous surfactant is described for the first time. The sustained-release nascent-HBr enabled the chemoselective cleavages of acid-sensitive orthogonal functionalities present in carbohydrates, amino alcohols, and hydroxylated acyclic compounds in good to excellent yields.
- Bera, Smritilekha,Gupta, Shilpi,Mondal, Dhananjoy
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- Borinic Acid Mediated Hydrosilylations: Reductions of Carbonyl Derivatives
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4-Fluoro-2-chlorophenylborinic acid acts as a precatalyst in the presence of phenylsilane for the facile reduction of ketones, aldehydes and imines. Notably, synergistic mediation of a tertiary amine was found essential to trigger silicon to boron hydride transfer to generate a key amine–diarylhydroborane Lewis complex.
- Chardon, Aurélien,Rouden, Jacques,Blanchet, Jér?me
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supporting information
p. 995 - 998
(2018/12/13)
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- NOVEL AMINOPYRIDINEMETHANOL COMPOUNDS AND THEIR USE
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The present invention is directed to novel compounds of Formula (I): pharmaceutically acceptable salts or solvates thereof, and their use, in particular in the treatment or prevention of malaria.
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Page/Page column 45; 73; 74
(2019/05/22)
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- COMPOSITION FOR TREATMENT AND/OR PREVENTION OF PERIPHERAL NERVE DISORDER
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The present invention provides a means for treating and/or preventing peripheral nerve disorder by facilitating regeneration of peripheral nerves. Specifically, the present invention provides a composition for treating and/or preventing peripheral nerve d
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Paragraph 0184
(2019/10/29)
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- Design, synthesis, and structure-activity relationship studies of L-amino alcohol derivatives as broad-spectrum antifungal agents
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To discover broad spectrum antifungal agents, two strategies were applied, and a novel class of L-amino alcohol derivatives were designed and synthesized. 3-F substituted compounds 14i, 14n, 14s and 14v exhibited excellent antifungal activities with broad antifungal spectra against C. albicans and C. tropicalis, with MIC values in the range of 0.03–0.06 μg/mL, and against A. fumigatus and C. neoformans, with MIC values in the range of 1–2 μg/mL. Notably, Compounds 14i, 14n, 14s and 14v also displayed moderate activities against fluconazole-resistance strains 17# and CaR that were isolated from AIDS patients. Moreover, only compounds in the S-configuration showed antifungal activity. Preliminary mechanistic studies showed that the potent antifungal activity of compound 14v stemmed from inhibition of C. albicans CYP51. Compounds 14n and 14v were almost nontoxic to mammalian A549 cells, and their stability in human plasma was excellent.
- Zhao, Liyu,Tian, Linfeng,Sun, Nannan,Sun, Yin,Chen, Yixuan,Wang, Xinran,Zhao, Shizhen,Su, Xin,Zhao, Dongmei,Cheng, Maosheng
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p. 374 - 385
(2019/06/05)
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- Asymmetric kinetic resolution of sulfides for the construction of unsymmetric sulfides and chiral 3,3-disubstituted oxindoles
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A range of 3,3-disubstituted oxindoles accessed using para-quinone methides derived from isatins with thiols were used for the formation of unsymmetrical disulfides, and 3,3-disubstituted oxindoles with a chiral quaternary carbon center and unsymmetric di
- Wang, Kaiye,Xiang, Yanan,Shi, Zhujun,Wang, Hongyu,Li, Na,Tang, Bo
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supporting information
p. 6351 - 6354
(2019/07/10)
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- Evaluation of in-batch and in-flow synthetic strategies towards the stereoselective synthesis of a fluorinated analogue of retro-thiorphan
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A stereoselective synthetic strategy for the preparation of trifluoromethylamine mimics of retro-thiorphan, involving a diastereoselective, metal-free catalytic step, has been studied in batch and afforded the target molecule in good yields and high diast
- Pirola, Margherita,Puglisi, Alessandra,Raimondi, Laura,Forni, Alessandra,Benaglia, Maurizio
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supporting information
(2019/07/31)
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- Tetrahydro-4 H-(pyrrolo[3,4- d]isoxazol-3-yl)methanamine: A Bicyclic Diamino Scaffold Stabilizing Parallel Turn Conformations
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A tetrahydro-4H-(pyrrolo[3,4-d]isoxazol-3-yl)methanamine scaffold was designed as a diamino derivative to stabilize parallel turn conformations. Its synthesis took advantage of a [1,3]-dipolar cycloaddition reaction between the nitrile oxide derived from
- Bucci, Raffaella,Giofré, Sabrina,Clerici, Francesca,Contini, Alessandro,Pinto, Andrea,Erba, Emanuela,Soave, Raffaella,Pellegrino, Sara,Gelmi, Maria Luisa
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supporting information
p. 11493 - 11501
(2018/09/27)
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- [3 + 3] Cycloaddition of azides with in situ formed azaoxyallyl cations to synthesize 1,2,3,4-Tetrazines
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A formal [3 + 3] cycloaddition reaction between azides and in situ formed azaoxyallyl cations has been realized. This reaction provided an efficient and practical pathway to synthesize 1,2,3,4-tetrazines in good yields under mild conditions. Biologically active molecules could also be well compatible, highlighting the potential value of this reaction.
- Xu, Xiaoying,Zhang, Kaifan,Li, Panpan,Yao, Hequan,Lin, Aijun
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supporting information
p. 1781 - 1784
(2018/04/14)
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- Regioselective Fluorination of α-Hydroxy-β-aminophosphonates by Using PyFluor
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We report a simple protocol for the synthesis of α-fluoro-β-aminophosphonates by the regioselective fluorination of α-hydroxy-β-aminophosphonates under mild conditions. The fluorination reactions were mediated by the PyFluor reagent and occurred with the retention of configuration. The main products of this reaction were a series of α-fluoro-β-aminophosphonates, which can be used as precursors in the preparation of medicinally important compounds (e.g., dipeptide analogues).
- Ka?mierczak, Marcin,Kubicki, Maciej,Koroniak, Henryk
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p. 3844 - 3852
(2018/07/31)
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- NOVEL PROCESS FOR THE PREPARATION OF 1,3-THIAZOL-5-YLMETHYL [(2R,5R)-5- CARBAMOYL) AMINO] -4-(MORPHOLIN-4-YL)BUTANOYL]AMINO}-1,6-DIPHENYLHEXAN-2-YL]CARBAMATE
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The present invention relates to novel processes for the preparation 1,3-Thiazol-5-ylmethyl[(2R,5R)-5-{[(2S)-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl} carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl] carbamate having the following structural formula-1 and it's intermediates thereof.
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- Synthesis, biological evaluation, and molecular modeling studies of chiral chloroquine analogues as antimalarial agents
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In a focused exploration, we designed, synthesized, and biologically evaluated chiral conjugated new chloroquine (CQ) analogues with substituted piperazines as antimalarial agents. In vitro as well as in vivo studies revealed that compound 7c showed potent activity (in vitro 50% inhibitory concentration, 56.98 nM for strain 3D7 and 97.76 nM for strain K1; selectivity index in vivo [up to at a dose of 12.5 mg/kg of body weight], 3,510) as a new lead antimalarial agent. Other compounds (compounds 6b, 6d, 7d, 7h, 8c, 8d, 9a, and 9c) also showed moderate activity against a CQ-sensitive strain (3D7) and superior activity against a CQ-resistant strain (K1) of Plasmodium falciparum. Furthermore, we carried out docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of all in-house data sets (168 molecules) of chiral CQ analogues to explain the structure-activity relationships (SAR). Our new findings specify the significance of the H-bond interaction with the side chain of heme for biological activity. In addition, the 3D-QSAR study against the 3D7 strain indicated the favorable and unfavorable sites of CQ analogues for incorporating steric, hydrophobic, and electropositive groups to improve the antimalarial activity.
- Kondaparla, Srinivasarao,Debnath, Utsab,Dola, Vasantha Rao,Sinha, Manish,Katti, Seturam B.,Soni, Awakash,Srivastava, Kumkum,Puri, Sunil K.
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- Fluorocyclisation via I(I)/I(III) catalysis: A concise route to fluorinated oxazolines
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Herein, we describe a catalytic fluorooxygenation of readily accessible N-allylcarboxamides via an I(I)/I(III) manifold to generate 2-oxazolines containing a fluoromethyl group. Catalysis is conditional on the oxidation competence of Selectfluor, whilst HF serves as both a fluoride source and Br?nsted acid activator. The C(sp3)–F bond of the mono-fluoromethyl unit and the C(sp3)–O bond of the ring are aligned in a synclinal relationship thereby engaging in stabilising hyperconjugative interactions with vicinal, electron-rich σ-bonds (σC–C→σ*C–F and σC–H→σ*C–O). This manifestation of the stereoelectronic gauche effect was established by X-ray crystallographic analysis of a representative example. Given the importance of fluorine in drug discovery, its ability to modulate conformation, and the prevalence of the 2-oxazoline scaffold in Nature, this strategy provides a rapid entry into an important bioisostere class.
- Daniliuc, Constantin G.,Gilmour, Ryan,Kehr, Gerald,Meyer, Stephanie,Scheidt, Felix,Thiehoff, Christian,Yilmaz, Gülay
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supporting information
p. 1021 - 1027
(2020/05/06)
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- Staudinger/aza-Wittig reaction to access Nβ-protected amino alkyl isothiocyanates
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A unified approach to access Nβ-protected amino alkyl isothiocyanates using Nβ-protected amino alkyl azides through a general strategy of Staudinger/aza-Wittig reaction is described. The type of protocol used to access isothiocyanates depends on the availability of precursors and also, especially in the amino acid chemistry, on the behavior of other labile groups towards the reagents used in the protocols; fortunately, we were not concerned about both these factors as precursor-azides were prepared easily by standard protocols, and the present protocol can pave the way for accessing title compounds without affecting Boc, Cbz and Fmoc protecting groups, and benzyl and tertiary butyl groups in the side chains. The present strategy eliminates the need for the use of amines to obtain title compounds and thus, this method is step-economical; additional advantages include retention of chirality, convenient handling and easy purification. A few hitherto unreported compounds were also prepared, and all final compounds were completely characterized by IR, mass, optical rotation, and 1H and 13C NMR studies.
- Santhosh,Durgamma,Shekharappa,Sureshbabu, Vommina V.
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p. 4874 - 4880
(2018/07/15)
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- IDO inhibitors
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The invention discloses novel compounds used as indoleeamine-pyrrole-2,3-dioxygenase (IDO) inhibitors, and specifically discloses the compounds represented by a formula (I) shown in the description and pharmaceutically-acceptable salts of the compounds. The invention also discloses an application of the compounds represented by the formula (I) and the pharmaceutically-acceptable salts of the compounds in preparation of a medicament for treating tumors.
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Paragraph 0121-0123
(2019/01/05)
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- Synthesis of Enantiomerically Pure 3-Substituted Piperazine-2-acetic Acid Esters as Intermediates for Library Production
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The piperazine heterocycle is broadly exploited in FDA-approved drugs and biologically active compounds, but its chemical diversity is usually limited to ring nitrogen substitutions, leaving the four carbon atoms underutilized. Using an efficient six-step synthesis, chiral amino acids were transformed into 3-substituted piperazine-2-acetic acid esters as diastereomeric mixtures whose cis and trans products (dr 0.56 a? 2.2:1, respectively) could be chromatographically separated. From five amino acids (both antipodes) was obtained a complete matrix of 20 monoprotected chiral 2,3-disubstituted piperazines, each as a single absolute stereoisomer, all but one in multigram quantities. In keeping with our overall purpose of constructing more Csp3-enriched compound libraries for drug discovery, these diverse and versatile piperazines can be functionalized on either nitrogen atom, allowing them to be used as scaffolds for parallel library synthesis and as intermediates for the production of novel piperazine compounds.
- Reddy Guduru, Shiva Krishna,Chamakuri, Srinivas,Raji, Idris O.,MacKenzie, Kevin R.,Santini, Conrad,Young, Damian W.
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p. 11777 - 11793
(2018/09/27)
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- Stereoselective Synthesis of 1,2-trans-Diamines Using the Three-Component Borono-Mannich Condensation – Reaction Scope and Mechanistic Insights
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The Petasis borono-Mannich (PBM) process with easily accessible N-protected α-amino aldehydes produces 1,2-trans-diamines diastereoselectively with an enantiomeric excess up to 98 %. The protecting group on the nitrogen atom had a decisive influence on bo
- Norsikian, Stéphanie,Beretta, Margaux,Cannillo, Alexandre,Auvray, Marie,Martin, Amélie,Retailleau, Pascal,Iorga, Bogdan I.,Beau, Jean-Marie
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p. 1940 - 1951
(2017/04/21)
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- A new family of 1,2,3-oxathiazolidine-2,2-dioxide phosphonate derivatives: Synthesis, characterization and anticancer evaluation
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An efficient synthesis of a new series of organophosphorus compounds having a cyclic sulfamidates moiety is described. The cyclic sulfamidate precursors were prepared from α-amino acids after four steps (Reduction, N-Boc protection, cyclization and cleavage). The novel organophosphonates were synthesized within two steps starting from the cyclic sulfamidate (chloroacetylation following by phosphorylation via Arbuzov reaction). A particular compound 7-a (diethyl phosphonate {2-[(4S)-4-benzyl-1,2,3-oxathiazolidin-3-yl-2,2-dioxyde]-2-oxoethyl}) was essayed for their in vitro cytotoxic activities against a panel of four cell lines (Jurkat, K562, U266, and A431). For all of these cells, the synthesized compound showed low cytotoxicity, even at high concentration levels (4?mM).
- K'tir, Hacène,Aouf, Zineb,Souk, Tan Otea,Zerrouki, Rachida,Berredjem, Malika,Aouf, Nour-Eddine
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p. 555 - 559
(2017/05/01)
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- Synthesis and stereochemical assignment of geraniol- and nerol-derived Cygerol enantiomers
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The enantiomers (up to 99% ee) of both geraniol- and nerol-derived 2-cyclohexyl-5,9-dimethyldeca-4,8-dienoic acid, the active ingredient of the wound healing medication Cygerol, were prepared via a low-temperature alkylation, basic hydrolysis, derivatization with (S)-4-benzyloxazolidin-2-one and chromatographic separation steps. The absolute configuration of stereocenters in the antipodes having an (E)- or (Z)-geometry of the internal double bond was determined based on characteristic 1H NMR signals of the corresponding (S)-4-benzyloxazolidin-2-one-derived imides and on conversion to the known diethyl (S)-2-cyclohexylsuccinate and (S)-2-cyclohexylbutane-1,4-diol with reported specific rotations.
- Sukhanova, Anna A.,Puchkin, Ilya A.,Vasil'ev, Andrei A.,Zlotin, Sergei G.
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supporting information
p. 1834 - 1841
(2017/11/20)
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- Enantioselective Conjunctive Cross-Coupling of Bis(alkenyl)borates: A General Synthesis of Chiral Allylboron Reagents
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Palladium-catalyzed conjunctive cross-coupling is used for the synthesis of enantioenriched allylboron reagents. This reaction employs nonsymmetric bis(alkenyl)borates as substrates and appears to occur by a mechanism that involves selective activation of the less substituted alkene followed by migration of the more substituted alkene during the course of a Pd-induced metalate rearrangement.
- Edelstein, Emma K.,Namirembe, Sheila,Morken, James P.
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supporting information
p. 5027 - 5030
(2017/05/04)
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- Synthesis and evaluation of chirally defined side chain variants of 7-chloro-4-aminoquinoline to overcome drug resistance in malaria chemotherapy
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A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methyl-piperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile.
- Dola, Vasantha Rao,Soni, Awakash,Agarwal, Pooja,Ahmad, Hafsa,Raju, Kanumuri Siva Rama,Rashid, Mamunur,Wahajuddin, Muhammad,Srivastava, Kumkum,Haq,Dwivedi,Puri,Katti
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- A method for preparing may compared to the department he intermediate and intermediate thereof and use thereof
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The invention relates to the field of medicinal chemical synthesis, in particular to a cobicistat intermediate preparing method, an intermediate and application thereof. The cobicistat intermediate (a compound (4)) preparing method includes the steps that a compound (5) is prepared into an organic metal compound (5'), and the compound (5') reacts with a compound (6) to prepare the compound (4) (see the reaction process in the description). The new reaction raw material compound (5) or (6) is provided to obtain the new compound (4) preparing method, the overall yield of the reaction can be increased, usage of toxic reagents is avoided, side reactions are reduced, and the cobicistat intermediate preparing method is suitable for industrial production. Further, the compound (4) is used as the intermediate for preparing a compound (1), by-products in the prior art are avoided, usage of toxic reagents is avoided, cost is saved, and the intermediate is beneficial for environment maintenance and suitable for industrial production.
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Paragraph 0073-0075
(2017/11/16)
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- Synthesis and Superpotent Anticancer Activity of Tubulysins Carrying Non-hydrolysable N-Substituents on Tubuvaline
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Synthetic tubulysins 24 a–m, containing non-hydrolysable N-substituents on tubuvaline (Tuv), were obtained in high purity and good overall yields using a multistep synthesis. A key step was the formation of differently N-substituted Ile-Tuv fragments 10 b
- Sani, Monica,Lazzari, Paolo,Folini, Marco,Spiga, Marco,Zuco, Valentina,De Cesare, Michelandrea,Manca, Ilaria,Dall'Angelo, Sergio,Frigerio, Massimo,Usai, Igor,Testa, Andrea,Zaffaroni, Nadia,Zanda, Matteo
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supporting information
p. 5842 - 5850
(2017/04/28)
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- Synthesis and biological activity of cyclolinopeptide A analogues modified with γ4-bis(homo-phenylalanine)
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Cyclolinopeptide A (CLA), an immunosuppressive nonapeptide derived from linen seeds, was modified with S or R-γ4-bis(homo-phenylalanine) in positions 3 or 4, or both 3 and 4. These modifications changed the flexibility of new analogues and distribution of intramolecular hydrogen bonds. Analogues 11 c(Pro1-Pro2-Phe3-S-γ4-hhPhe4-Leu5-Ile6-Ile7-Leu8-Val9), 13 c(Pro1-Pro2-S-γ4-hhPhe3-R-γ4-hhPhe4-Leu5-Ile6-Ile7-Leu8-Val9) and 15 c(Pro1-Pro2-R-γ4-hhPhe3-Phe4-Leu5-Ile6-Ile7-Leu8-Val9) existed as a mixture of stable cis/trans isomers of Pro-Pro peptide bond. The comparison of the relative spatial orientations in crystal state of the two carbonyl groups, neighboring γ-amino acids, revealed conformational similarities to α-peptides. The addition of two -CH2- groups in γ-amino acids led to a more rigid conformation, although a more flexible one was expected. A significant difference in the relative orientation of the carbonyl groups was found for cyclic γ-peptides with a dominance of an antiparallel arrangement. As carbonyl groups may be engaged in the interactions with plausible receptors through hydrogen bonds, a similar biological activity of the modified peptides was expected. Our biological studies showed that certain cyclic, but not the corresponding linear peptides, lowered the viability of peripheral blood mononuclear cells (PBMC) at 100?μg/mL concentration. The proliferation of PBMC induced by phytohemagglutinin A (PHA) was strongly inhibited by cyclic peptides only, in a dose-dependant manner. On the other hand, lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α) production in whole blood cell cultures was inhibited by both linear and cyclic peptides. Peptide 15 c(Pro1-Pro2-R-γ4-hhPhe3-Phe4-Leu5-Ile6-Ile7-Leu8-Val9) blocked the expression of caspase-3, inhibited the expression of caspases-8 and -9 in 24?h culture of Jurkat cells, and caused DNA fragmentation in these cells, as an indicator of apoptosis. Thus, we revealed a new mechanism of immunosuppressive action of a nonapeptide.
- J?drzejczak, Karol,Hrynczyszyn, Pawe?,Szczesio, Ma?gorzata,Artym, Jolanta,Jastrz?bek, Tomasz,Koci?ba, Maja,G?ówka, Marek,Huben, Krzysztof,Kochanowska, Iwona,Zimecki, Micha?,Zabrocki, Janusz,Jankowski, Stefan,Kolesińska, Beata
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p. 4265 - 4276
(2017/07/22)
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- Lissencephaly therapeutic agent
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An object of the present invention is to provide a medicament and method for treating lissencephaly patients. The present invention provides a lissencephaly therapeutic or preventive agent comprising a compound represented by the general formula (I): wher
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Page/Page column 34
(2016/07/27)
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- Chemo- and Diastereoselective N-Heterocyclic Carbene-Catalyzed Cross-Benzoin Reactions Using N-Boc-α-amino Aldehydes
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N-Boc-α-amino aldehydes are shown to be excellent partners in cross-benzoin reactions with aliphatic or heteroaromatic aldehydes. The chemoselectivity of the reaction and the facial selectivity on the amino aldehyde allow cross-benzoin products to be obtained in good yields and good diastereomeric ratios. The developed method is utilized as the key step in a concise total synthesis of d-arabino-phytosphingosine.
- Haghshenas, Pouyan,Gravel, Michel
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supporting information
p. 4518 - 4521
(2016/09/28)
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- Acylaminoimidazole derivative and use thereof
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The invention belongs to the technical field of medicines and relates to an acylaminoimidazole derivative shown in the general formula I and its stereisomer and pharmaceutical acceptable salt, hydrate, solvate or prodrug. In the formula I, substituents R, R1, Ar, M and X are defined in the specification. The invention also relates to a method for preparing the compound shown in the formula I, a medicinal composition containing the compound and a use of the compound and the medicinal composition in preparation of drugs for treating and/or preventing cancers and other skin proliferative diseases. An antifungal experiment proves that the compound has strong resistance to shallow and deep fungi and can be used for preparation of an antibacterial drug.
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Paragraph 0445; 0450; 0451
(2016/10/07)
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- Enantioselective Synthesis of β-Hydrazino Alcohols Using Alcohols and N-Boc-Hydrazine as Substrates
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An enantioselective approach for the synthesis of α-hydrazino aldehydes is described that utilizes alcohols and N-Boc hydrazine instead of the conventional combination of aldehydes with azodicarboxylates. This protocol is enabled by merging in situ aerobic dual oxidation with asymmetric organocatalysis. This reaction also exhibits a high tolerance for varieties of substituents on the alcohol component. This approach features excellent enantiocontrol, cheap starting materials, operational simplicity, and scalability. The corresponding chiral β-hydrazino alcohols were obtained by sequential reduction with excellent enantioselectivity (up to 98% ee).
- Cui, Zhihao,Du, Da-Ming
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supporting information
p. 5616 - 5619
(2016/11/17)
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- Synthesis and antimalarial activity of new 4-aminoquinolines active against drug resistant strains
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In the present study we have synthesized a new class of 4-aminoquinoline derivatives via replacement of the diethylamine functionality of chloroquine (CQ) with acyclic and/or cyclic amine groups containing basic tertiary terminal nitrogen and bioevaluated them for antimalarial activity against Plasmodium falciparum in vitro (CQ-sensitive strain-3D7 & CQ-resistant strain-K1) and Plasmodium yoelii in vivo (N-67 strain). Among the series, thirteen compounds showed superior antimalarial activity against K1 strain as compared to CQ. In addition, all these analogs showed 100% suppression of parasitaemia on day 4 in the in vivo mouse model against N-67 strain when administered orally. Further, biophysical studies suggest that these compounds act on the heme polymerization target.
- Kondaparla, Srinivasarao,Soni, Awakash,Manhas, Ashan,Srivastava, Kumkum,Puri, Sunil K.,Katti
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p. 105676 - 105689
(2016/11/18)
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- 5 - thiazole amides and biological applications
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The invention relates to a 5-thiazole amide compound and biology application thereof. The 5-thiazole amide compound has a general formula (I) described in the specification and is used for targeting an AKT/PKB kinase (ATP binding site). Experiments prove that a thiazole amide AKT inhibitor can remarkably inhibit the activity of the AKT kinase in vitro and has strong proliferation inhibition function on various tumor cells with high AKT activity, which indicate that the 5-thiazole amide compound can be used for preparing drugs for resisting tumors.
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Paragraph 0123-0126
(2018/09/26)
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- Asymmetric Multicomponent Sulfa-Michael/Mannich Cascade Reaction: Synthetic Access to 1,2-Diamino-3-Organosulfur Compounds and 2-Nitro Allylic Amines
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A novel catalytic asymmetric three-component intermolecular sulfa-Michael/Mannich cascade reaction has been developed using a chiral multifunctional catalyst. This reaction provides facile access to 1-amino-2-nitro-3-organosulfur compounds bearing three c
- Hou, Wenduan,Wei, Qi,Liu, Guisheng,Chen, Jing,Guo, Jing,Peng, Yungui
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supporting information
p. 4870 - 4873
(2015/10/12)
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- A General, Practical Triethylborane-Catalyzed Reduction of Carbonyl Functions to Alcohols
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A combination of the abundant and low-cost triethylborane and sodium alkoxide generates a highly efficient catalyst for reduction of esters, as well as ketones and aldehydes, to alcohols using an inexpensive hydrosilane under mild conditions. The catalyst system exhibits excellent chemoselectivity and a high level of functional group tolerance. Mechanistic studies revealed a resting state of sodium triethylalkoxylborate that is the product of the reaction of BEt3 with sodium alkoxide. This borate species reacts with hydrosilane to form NaBEt3H, which rapidly reduces esters.
- Peng, Dongjie,Zhang, Mintao,Huang, Zheng
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supporting information
p. 14737 - 14741
(2015/10/19)
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- Synthesis of enantioenriched 1,2-trans-diamines using the borono-Mannich reaction with N-protected α-amino aldehydes
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The three-component Petasis borono-Mannich reaction starting with easily accessible N-protected α-amino aldehydes produces efficiently and diastereoselectively 1,2-trans-diamines with an enantiomeric excess of up to 98%.
- Norsikian, Stéphanie,Beretta, Margaux,Cannillo, Alexandre,Martin, Amélie,Retailleau, Pascal,Beau, Jean-Marie
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supporting information
p. 9991 - 9994
(2015/06/22)
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- A concise enantioselective synthesis of (R)-selegiline, (S)-benzphetamine and formal synthesis of (R)-sitagliptin via electrophilic azidation of chiral imide enolates
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A concise and high yielding enantioselective synthesis of (R)-selegiline, an anti-Parkinson's drug, (S)-benzphetamine, an anti-obesity agent, and (S)-sitagliptin, an anti-diabetic drug has been described starting from commercially available starting materials employing Evans' electrophilic azidation of chiral imide enolates as a key chiral inducing step, which proceeds in a highly diastereoselective manner (>99%).
- Dey, Soumen,Sudalai, Arumugam
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- Anaerobic nitroxide-catalyzed oxidation of alcohols using the NO +/NO· redox pair
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A new method for alcohol oxidation using TEMPO or AZADO in conjunction with BF3·OEt2 or LiBF4 as precatalysts and tert-butyl nitrite as a stoichiometric oxidant has been developed. The system is based on a NO+/NO· pair for nitroxide reoxidation under anaerobic conditions. This allows the simple, high-yielding conversion of various achiral and chiral alcohols to carbonyl compounds without epimerization and no formation of nonvolatile byproducts.
- Holan, Martin,Jahn, Ullrich
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supporting information
p. 58 - 61
(2014/01/23)
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- Novel enantioselective fluorescent sensors for malate anion based on acridine
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The compounds L-1 and L-2 were synthesized and the interactions of all of the compounds with malate anion were studied by fluorescent titration and 1H NMR experiments. The Sensors L-1 and L-2 were found to present good enantioselective fluorescent sensing ability to malate anion. The results indicated that sensors L-1 and L-2 were very promising to be used as fluorescent sensors in determining malate anion in CH3CN.
- Li, Qian,Xu, Kuoxi,Song, Pan,Dai, Yanpeng,Yang, Li,Pang, Xiaobin
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p. 169 - 174
(2014/06/23)
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- Novel enantioselective fluorescent sensors for malate anion based on acridine
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The compounds L-1 and L-2 were synthesized and the interactions of all of the compounds with malate anion were studied by fluorescent titration and 1H NMR experiments. The Sensors L-1 and L-2 were found to present good enantioselective fluorescent sensing ability to malate anion. The results indicated that sensors L-1 and L-2 were very promising to be used as fluorescent sensors in determining malate anion in CH3CN.
- Li, Qian,Xu, Kuoxi,Song, Pan,Dai, Yanpeng,Yang, Li,Pang, Xiaobin
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p. 163 - 168
(2014/06/23)
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