- Optically active helical substituted polyacetylenes as chiral seeding for inducing enantioselective crystallization of racemic N -(tert -butoxycarbonyl)alanine
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Helical substituted polyacetylenes were investigated for inducing enantioselective crystallization of racemic N-(tert-butoxycarbonyl)alanine (BOC-alanine) enantiomers. For this purpose, helical substituted polyacetylenes [(R)-PSA and (S)-PSA)] were dissolved in supersaturated racemic BOC-alanine solutions. Upon cooling the solutions, (R)-PSA preferentially induced BOC-l-alanine to crystallize, while (S)-PSA facilitated the enantioselective crystallization of BOC-d-alanine, according to the characterizations by circular dichroism, XRD, SEM, and optical rotation analyses. As expected, no enantioselective crystallization was observed in such cases: racemic BOC-alanine enantiomers in the absence of optically active helical PSA and racemic BOC-alanine enantiomers in the presence of equal amount of (R)-PSA and (S)-PSA. The present study provides the first direct evidence for the role of artificially synthetic helical polymers in inducing efficiently enantioselective crystallization.
- Chen, Bo,Deng, Jianping,Cui, Xin,Yang, Wantai
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- Metal-induced supramolecular chirality inversion of small self-assembled molecules in solution
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A non-covalent self-assembled chiral alanyl aminopyridine ligand exhibits supramolecular chirality in solution, independent of the organic solvent used. The supramolecular chirality of the assemblies is completely inverted by complexation to zinc ions. To date, such a supramolecular metal-ligand system has not been reported in the literature.
- Kokan, Zoran,Peri?, Berislav,Vazdar, Mario,Marini?, ?eljko,Viki?-Topi?, Dra?en,Me?trovi?, Ernest,Kirin, Sre?ko I.
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- HIGH PRESSURE APPROACH TO THE TOTAL SYNTHESIS OF 6-EPI-D-PURPUROSAMIN B
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Methyl 2,6-di-N-acetyl-6-epi-α-D-purpurosaminide B (11) was synthesized from L-alanine by an eleven-step reaction sequence.Eu(fod)3-mediated high-pressure (4+2)cycloaddition of 1-methoxybuta-1,3-diene (2) to α-amino aldehyde 3, easily available from L-alanine (4), is the key step in the synthetic sequence.
- Golebiowski, Adam,Jacobsson, Ulla,Jurczak, Janusz
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- Copolymerization of chiral amino acid-based acetylenes and helical conformation of the copolymers
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The present study deals with the copolymerization of an amino acid-based acetylene, N-(tert-butoxycarbonyl)-L-alanine N′-propargylamide (L-1A) with the optical isomer (D-1A), achiral hexanoic acid N-propargylamide (2A), and pivalic acid N-propargylamide (3A), and chiroptical properties of the copolymers. The copolymerization catalyzed by (nbd)Rh+[η6-C6H5B- (C6H5)3] afforded copolymers with number-average molecular weights over 104 in good yields. Nonlinear relationships were observed in the specific rotation and CD and UV-vis spectroscopies with respect to the L-1A content in feed. For instance, poly(L-1A-co-D-1A)s incorporated with 12.5% of either optical isomer (75% ee) exhibited almost the same optical properties as those of the homopolymers. Chiral amplification was observed in the copolymerization of L-1A with the achiral monomers. The specific rotation of poly(L-1A-co-2A) with 45% L-1A unit was practically the same as that of poly(L-1A). The copolymers of L-1A and 3A with an L-1A content in feed as low as 12% exhibited nearly the same helix content as the homopolymer of L-1A did.
- Gao, Guangzheng,Sanda, Fumio,Masuda, Toshio
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- Pinensins: The First Antifungal Lantibiotics
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Lantibiotics (lanthionine-containing antibiotics) from Gram-positive bacteria typically exhibit activity against Gram-positive bacteria. The activity and structure of pinensin A (1) and B (2), lantibiotics isolated from a native Gram-negative producer Chitinophaga pinensis are described. Surprisingly, the pinensins were found to be highly active against many filamentous fungi and yeasts but show only weak antibacterial activity. To the best of our knowledge, lantibiotic fungicides have not been described before. An in-depth bioinformatic analysis of the biosynthetic gene cluster established the ribosomal origin of these compounds and identified candidate genes encoding all of the enzymes required for post-translational modification. Additional encoded functions enabled us to build up a hypothesis for the biosynthesis, export, sensing, and import of this intriguing lantibiotic.
- Mohr, Kathrin I.,Volz, Carsten,Jansen, Rolf,Wray, Victor,Hoffmann, Judith,Bernecker, Steffen,Wink, Joachim,Gerth, Klaus,Stadler, Marc,Müller, Rolf
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- Efficient, non-acidolytic method for the selective cleavage of N-Boc amino acid and peptide phenacyl esters linked to a polystyrene resin
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An efficient, non-acidolytic method for the selective cleavage of phenacyl esters of N-Boc-amino acids and -peptides linked to a polystyrene resin by (CH3)3SnOH (TMTOH) or [(n-C4H9)3Sn]2O (BBTO) is described. We highly recommend the use of trimethyltin hydroxide for the selective cleavage of carboxylic esters based on its favourable properties. The method is compatible with an N-Boc/O-Bn (benzyl ether) strategy and yields enantiomerically pure N-Boc-peptides useful for further manipulation, for segment condensations or for cyclization strategies. A mechanism for the cleavage of methyl phenylacetate in solution by TMTOH is postulated.
- Furlan, Ricardo L. E.,Mata, Ernesto G.,Mascaretti, Oreste A.
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- Biocatalytic resolution of Boc-dl-alanine methyl ester by a newly isolated Bacillus amyloliquefaciens WZZ002
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A new esterase-producing strain (Bacillus amyloliquefaciens WZZ002) that exhibits high hydrolytic activity, excellent enantioselectivity, and high substrate tolerance on Boc-dl-Alanine methyl ester was isolated from soil samples. The reaction temperature, pH, and neutralizer optima of the cell-mediated biocatalysis were 35 °C, pH 8.0, and NH3·H2O, respectively. The optimal substrate concentration was 2 M, with a biocatalyst loading of 50 g/L. Results showed that the enantiomeric excess values of substrate and product were both greater than 99%. Thus, bioprocessing with the use of the isolated strain is a promising route for the commercial production of Boc-d-Ala-OMe.
- Zheng, Jian-Yong,Wang, Yu-Qiang,Luo, Wei-Feng,Zhou, Sha-Sha,Zhu, Qing,Ying, Xiang-Xian,Wang, Zhao
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- Significant enantioselectivity in alanine ester hydrolysis catalyzed by imidazole attached β-cyclodextrins
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Imidazole-appended β-cyclodextrins, 3-deoxy-3=imidazolyl-β-cyclodextrin (3Im-βCyD) and 6-deoxy-6-imidazolyl-β-cyclodextrin (6Im-βCyD) were synthesized as substrate selective enzyme mimics. 6Im-βCyD shows marked enantioselectivity in the hydrolysis of Boc-alanine p-nitrophenyl ester rather than 3Im-βCyD.This selectivity could be interpreted by transition stability theory.
- Hamasaki, Keita,Ueno, Akihiko
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- Self-assembly of β-turn forming synthetic tripeptides into supramolecular β-sheets and amyloid-like fibrils in the solid state
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We have described here the self-assembling properties of the synthetic tripeptides Boc-Ala(1)-Aib(2)-Val(3)-OMe 1, Boc-Ala(1)-Aib(2)-Ile(3)-OMe 2 and Boc-Ala(1)-Gly(2)-Val(3)-OMe 3 (Aib=α-amino isobutyric acid, β-Ala=β-alanine) which have distorted β-turn conformations in their respective crystals. These turn-forming tripeptides self-assemble to form supramolecular β-sheet structures through intermolecular hydrogen bonding and other noncovalent interactions. The scanning electron micrographs of these peptides revealed that these compounds form amyloid-like fibrils, the causative factor for many neurodegenerative diseases including Alzheimer's disease, Huntington's disease and Prion-related encephalopathies.
- Maji, Samir Kumar,Haldar, Debasish,Drew, Michael G. B.,Banerjee, Arijit,Das, Apurba Kumar,Banerjee, Arindam
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- Adrenocorticotropin. 48. Synthesis and biological activity of [15,16 D lysine, 17,18 D arginine] adrenocorticotropin (1 19) and an all D retropeptide related to the amino terminal octadecapeptide of adrenocorticotropin
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The peptide [15, 16-D-lysine, 17, 18-D-arginine]-adrenocorticotropin -(1-19) and an all-D-retropeptide related to the amino terminal octadecapeptide of adrenocorticotropin have been synthesized by the solid-phase method. The nonadecapeptide was shown to p
- Blake,Li
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- Enantioselective hydrolysis of amino acid esters by non-chiral copper complexes equipped with bis (β-cyclodextrin)s
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Two non-chiral copper(II) complexes equipped with bis(β-cyclodextrin)s (bisCDs) were explored as hydrolase models for the enantioselective hydrolysis of two pairs of alkyl chain-possessing amino acid ester enantiomers. The two bisCD complexes are pyridine-linked with different CD cavity orientations, denoted as CuL1 (L1?=?2,6-bis(6-mono-amino-β-cyclodextrin-methyl)-pyridine) and CuL2 (L2?=?2,6-bis(3-mono-amino-β-cyclodextrin-methyl)-pyridine). Kinetic studies indicated that the “back-to-back” bisCD complex CuL1 showed higher catalytic efficiency and more pronounced enantioselectivity for all substrates than the “face-to-face” bisCD complex CuL2. Overall preference of L-isomers was observed for both complexes. In the presence of CuL1, the formation of catalyst-substrate Michaelis complexes during the hydrolysis was demonstrated by saturation kinetic study and Electrospray ionization mass spectrometry (ESI–MS) analysis. Enantiomer selectivity (vmaxL/vmaxD) value for N-Boc-N'-Boc-Lysine 4-nitrophenyl esters (Boc-Lys(Boc)-ONp), the longer alkyl-chain analogs, is twice of that for N-Boc-Alanine 4-nitrophenyl esters (Boc-Ala-ONp). The enantioselective hydrolysis of Boc-Lys(Boc)-ONp promoted by CuL1 was confirmed by chiral high-performance liquid chromatography (HPLC) analysis. The participation of CD cavities during enantioselective hydrolysis was investigated through inhibition assay. The enantioselectivity in hydrolyzing different amino acid esters promoted by CuL1 was compared. The mechanism involved in the cooperation of two adjacent CD cavities of bisCD was proposed.
- Xue, Shan-Shan,Zhao, Meng,Lan, Jing-Xing,Ye, Rui-Rong,Li, Yi,Ji, Liang-Nian,Mao, Zong-Wan
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- Novel synthesis and biological evaluation of enigmols as therapeutic agents for treating prostate cancer
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Enigmol is a synthetic, orally active 1-deoxysphingoid base analogue that has demonstrated promising activity against prostate cancer. In these studies, the pharmacologic roles of stereochemistry and N-methylation in the structure of enigmols were examined. A novel enantioselective synthesis of all four possible 2S-diastereoisomers of enigmol (2-aminooctadecane-3,5-diols) from l-alanine is reported, which features a Liebeskind-Srogl cross-coupling reaction between l-alanine thiol ester and (E)-pentadec-1-enylboronic acid as the key step. In vitro biological evaluation of the four enigmol diastereoisomers and 2S,3S,5S-N-methylenigmol against two prostate cancer cell lines (PC-3 and LNCaP) indicates that all but one diastereomer demonstrate potent oncolytic activity. In nude mouse xenograft models of human prostate cancer, enigmol was equally effective as standard prostate cancer therapies (androgen deprivation or docetaxel), and two of the enigmol diastereomers, 2S,3S,5R-enigmol and 2S,3R,5S-enigmol, also caused statistically significant inhibition of tumor growth. A pharmacokinetic profile of enigmol and N-methylenigmol is also presented.
- Garnier-Amblard, Ethel C.,Mays, Suzanne G.,Arrendale, Richard F.,Baillie, Mark T.,Bushnev, Anatoliy S.,Culver, Deborah G.,Evers, Taylor J.,Holt, Jason J.,Howard, Randy B.,Liebeskind, Lanny S.,Menaldino, David S.,Natchus, Michael G.,Petros, John A.,Ramaraju, Harsha,Reddy, G. Prabhakar,Liotta, Dennis C.
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- Monofunctional platinum complexes showing potent cytotoxicity against human liver carcinoma cell line BEL-7402
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Three novel Pt(II) complexes [PtL1′Cl] I (L1′ = glycine-N′-8-quinolylamide), [PtL2′Cl] II (L2′= L-alanine-N′-8-quinolylamide), and [PtL3Cl] III [L3 = N-(tert-butoxycarbonyl)-L-methionine-N′-8-quinolylamide] have been synthesized and characterized. The crystal structure of complexes II and III showed that the ligands are three-coordinated with only one Cl- as the leaving group. Complex II crystallized in the monoclinic system with space group P2(1), a = 9.502(2) ?, b = 4.724(1) ?, c = 14.800(3) ?, while complex III crystallized in the orthorhombic system with space group P2(1)2(1)2(1), a = 5.441(1) ?, b = 12.978(3) ?, c = 29.438(6) ?. These complexes have been tested against a wide range of tumor cell lines including BEL-7402, HCT-116, SPC-A4, MOLT-4, P388, HL-60, A-549, SGC-7901, MKN-28, and HO-8910. Complex III is highly cytotoxic against the HCT-116 (IC50 = 0.38 μM), SPC-A4 (IC50 = 0.43 μM), BEL-7402 (IC50 = 0.43 μM), and MOLT-4 (IC50 = 0.61 μM) cell lines. The cell line most sensitive to III is human liver carcinoma cell line BEL-7402, which has a response rate of 75.1% at 6.6 × 10-7 M, nearly 6 times higher than that of cisplatin.
- Zhang, Junyong,Wang, Xiaoyong,Tu, Chao,Lin, Jun,Ding, Jian,Lin, Liping,Wang, Zheming,He, Cheng,Yan, Chunhua,You, Xiaozeng,Guo, Zijian
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- SPIRO-LACTAM COMPOUNDS AND METHODS OF TREATING VIRAL INFECTIONS USING THE SAME
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Disclosed are compounds, and pharmaceutically acceptable salts thereof, that can ameliorate or treat a viral infection in a subject in need thereof. The disclosure also includes conjugates of such compounds with a protease.
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Page/Page column 100; 106
(2021/12/28)
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- Highly Stable Zr(IV)-Based Metal-Organic Frameworks for Chiral Separation in Reversed-Phase Liquid Chromatography
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Separation of racemic mixtures is of great importance and interest in chemistry and pharmacology. Porous materials including metal-organic frameworks (MOFs) have been widely explored as chiral stationary phases (CSPs) in chiral resolution. However, it remains a challenge to develop new CSPs for reversed-phase high-performance liquid chromatography (RP-HPLC), which is the most popular chromatographic mode and accounts for over 90% of all separations. Here we demonstrated for the first time that highly stable Zr-based MOFs can be efficient CSPs for RP-HPLC. By elaborately designing and synthesizing three tetracarboxylate ligands of enantiopure 1,1′-biphenyl-20-crown-6, we prepared three chiral porous Zr(IV)-MOFs with the framework formula [Zr6O4(OH)8(H2O)4(L)2]. They share the same flu topological structure but channels of different sizes and display excellent tolerance to water, acid, and base. Chiral crown ether moieties are periodically aligned within the framework channels, allowing for stereoselective recognition of guest molecules via supramolecular interactions. Under acidic aqueous eluent conditions, the Zr-MOF-packed HPLC columns provide high resolution, selectivity, and durability for the separation of a variety of model racemates, including unprotected and protected amino acids and N-containing drugs, which are comparable to or even superior to several commercial chiral columns for HPLC separation. DFT calculations suggest that the Zr-MOF provides a confined microenvironment for chiral crown ethers that dictates the separation selectivity.
- Jiang, Hong,Yang, Kuiwei,Zhao, Xiangxiang,Zhang, Wenqiang,Liu, Yan,Jiang, Jianwen,Cui, Yong
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supporting information
p. 390 - 398
(2021/01/13)
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- Membrane transport inspired hydrolysis of non-activated esters at near physiological pH
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A positively charged micelle loaded with substrates was transported selectively to the reaction site (cathode) to promote the proximity and localization of the reactants (ester and hydroxide). The guided vehicular delivery coupled with electrolysis allows the hydrolysis of non-activated esters at near physiological pH with significant yields along with recyclability.
- Mandal, Raki,Mahanty, Kingshuk,Mandal, Subhendu,De Sarkar, Suman,Tarafdar, Pradip K.
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supporting information
p. 11088 - 11091
(2021/10/30)
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- PRODRUGS OF ABIRATERONE
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The present invention relates to compounds of formula (I), or their isotopic forms, stereoisomers, tautomers, or pharmaceutically acceptable salt(s) thereof as prodrugs of abiraterone. The present invention also describes method of making such compounds, pharmaceutical compositions comprising such compounds and the use of the compounds of formula (I).
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Page/Page column 20
(2021/05/29)
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- Design, synthesis, and biological evaluation of novel Bcr-AblT315I inhibitors incorporating amino acids as flexible linker
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Despite the success of imatinib in CML therapy through Bcr-Abl inhibition, acquired drug resistance occurs over time in patients. In particular, the resistance caused by T315I mutation remains a challenge in clinic. Herein, we embarked on a structural optimization campaign aiming at discovery of novel Bcr-Abl inhibitors toward T315I mutant based on previously reported dibenzoylpiperazin derivatives. We proposed that incorporation of flexible linker could achieve potent inhibition of Bcr-AblT315I by avoiding steric clash with bulky sidechain of Ile315. A library of 28 compounds with amino acids as linker has been developed and evaluated. Among them, compound AA2 displayed the most potent activity against Bcr-AblWT and Bcr-AblT315I, as well as toward Bcr-Abl driven K562 and K562R cells. Further investigations indicated that AA2 could induce apoptosis of K562 cells and down regulate phosphorylation of Bcr-Abl. In summary, the compounds with amino acid as novel flexible linker exhibited certain antitumor activities, providing valuable hints for the discovery of novel Bcr-Abl inhibitors to overcome T315I mutant resistance, and AA2 could be considered as a candidate for further optimization.
- Li, Yanchen,Li, Zilong,Liu, Nanxin,Pan, Xiaoyan,Shan, YuanYuan,Wang, Kai,Zhang, Jie,Zhang, Qingqing
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- The Mechanism of Dehydrating Bimodules in trans-Acyltransferase Polyketide Biosynthesis: A Showcase Study on Hepatoprotective Hangtaimycin
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A bioassay-guided fractionation led to the isolation of hangtaimycin (HTM) from Streptomyces spectabilis CCTCC M2017417 and the discovery of its hepatoprotective properties. Structure elucidation by NMR suggested the need for a structural revision. A putative HTM degradation product was also isolated and its structure was confirmed by total synthesis. The biosynthetic gene cluster was identified and resembles a hybrid trans-AT PKS/NRPS biosynthetic machinery whose first PKS enzyme contains an internal dehydrating bimodule, which is usually found split in other trans-AT PKSs. The mechanisms of such dehydrating bimodules have often been proposed, but have never been deeply investigated. Here we present in vivo mutations and in vitro enzymatic experiments that give first and detailed mechanistic insights into catalysis by dehydrating bimodules.
- Deng, Zixin,Dickschat, Jeroen S.,Dong, Yulu,Lu, Junlei,Luo, Minghe,Qi, Miaomiao,Shen, Kun,Sun, Guo,Sun, Yuhui,Tang, Lingjie,Xiang, Jin,Xu, Houchao,Yin, Zhiyong
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supporting information
p. 19139 - 19143
(2021/08/03)
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- Sensing of the Induced Helical Chirality by the Chiroptical Response of the Ferrocene Chromophore
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The experimental (infrared, nuclear magnetic resonance, circular dichroism) and computational (density functional theory) methods allowed us to demonstrate the potential of the ferrocene chromophore to translate chiral information stored at N-terminally attached l-Ala, and transmitted through achiral (Aib)n sequence (n=1 to 3), into a characteristic signal in circular dichroism spectra near 470 nm. The sufficiently long tetrapeptide forms a robust and highly organized 310 helices capable of perturbing the environment of the highly symmetric ferrocene chromophore in an asymmetric manner. The origin of the sign in the circular dichroism spectra of the ferrocene chromophore (near the 470 nm) strongly correlates with the sign of the dihedral angle χ, accounting for a rotation of a substituent attached to the cyclopentadienyl ring that depends on the helicity of peptide sequence. These observations may help us in the design of future ferrocene-based probes for the assignment of the screw-sense preference of short peptides.
- ?utalo, Petar,Kodrin, Ivan,Nuskol, Marko,Semen?i?, Mojca ?aki?
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- Amino acid amide hydrochloride without inorganic ammonium salt and synthesis method thereof
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The present invention discloses an amino acidamide hydrochloride without inorganic ammonium salts and a synthesis method thereof, comprising the following steps: S1, the amino acid under alkaline conditions, added di-tert-butyl dicarbonate to prepare tert-butoxycarbonyl - amino acid; S2, to the prepared tert-butoxycarbonyl - amino acid and then add di-tert-butyl dicarbonate, in the presence of N- methyl morpholine, ammonium bicarbonate, the preparation of tert-butoxycarbonyl - amino acid amide; S3, the tert-butoxycarbonyl - amino acid amide placed in the ethyl acetate / hydrogen chloride solution system, Crystallization is obtained immediately. The present invention is twice added di-tert-butyl dicarbonate, prepared under different conditions to give a high purity tert-butoxycarbonyl - amino acid amide, and finally in the ethyl acetate / hydrogen chloride solution conditions to obtain the final product, the present invention solves the problem of inorganic ammonium salts in the production of amino acid amide hydrochloride difficult to separate, reducing the amount of organic solvent.
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Paragraph 0021-0023; 0026-0028; 0031-0033; 0043-0045
(2022/01/10)
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- PEPTIDE AMIDE COMPOUND AND PREPARATION METHOD AND MEDICAL USE THEREOF
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The invention provides a peptide amide compound represented by the general general formula (I), a preparation method thereof, and a medical application thereof. The compound has a novel structure, better biological activity, and better analgesic effect.
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Paragraph 0228
(2020/06/15)
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- Cytotoxic activity of synthetic chiral amino acid derivatives
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Cancer is a chronic degenerative disease considered one of the most important causes of death worldwide. In this context, a series of dual-protected amino acid derivatives was synthesized and evaluated as potential novel anticancer agents. The 40 derivatives were prepared in up to three reaction steps. The cytotoxic activities were screened in vitro against a panel of tumor and non-tumor cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among the synthesized derivatives, three of them showed promising activity against cancer cells with half-maximal inhibitory concentration (IC50) ranging between 1.7-6.1 μM. The most promising derivative, bearing both a lipophilic N-alkyl diamine moiety and a protected amino acid scaffold showed a selectivity index of 3.4 towards tumor cells. The N-alkyl diamine moiety seems to play a crucial role in the enhancement of the anticancer activity. On the other hand, the incorporation of an amino acid scaffold resulted in increase in the selectivity towards cancer cell lines.
- de Castro, Pedro P.,Siqueira, Raoni P.,Conforte, Luiza,Franco, Chris H.J.,Bressan, Gustavo C.,Amarante, Giovanni W.
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p. 193 - 200
(2019/12/28)
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- Synthesis, in vitro and in vivo biological evaluation of dihydroartemisinin derivatives with potential anti-Toxoplasma gondii agents
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In this study, four series of dihydroartemisinin derivatives were designed, synthesized, and evaluated for anti-toxoplasma gondii activity, and calculated the selectivity index (SI). It was the higher the SI, the better the effect of this compound against Toxoplasma gondii. Our goal was to filter out compounds that were bigger SI than the lead compound. The compound with the highest SI was selected for the anti-toxoplasmosis test in mice in vivo. Among the synthesized compounds, the (3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyl-decahydro-12H-3,12-epoxy[1,2]di-oxepino[4,3 -i]isochromen-10-yl-(te-rt-butoxycarbonyl)-L-alaninate (A2) exhibited the most potent anti-T. gondii activity and low cytotoxicity (SI: 6.44), yielding better results than the lead compound DHA (SI: 1.00) and the clinically used positive-control drug spiramycin (SI: 0.72) in vitro. Furthermore, compound A2 had better growth inhibitory effects on T. gondii in vivo than spiramycin did and significantly reduced the number of tachyzoites in the peritoneal cavity of mice (P 0.01). The evaluation of the data generated in the T. gondii mouse infection model indicates that compound A2 treatment was a good inhibitor of T. gondii in vivo and that it was effective in relieving the liver damage induced by T. gondii. In addition, the results of a docking study revealed that A2 could become a better T. gondii calcium-dependent protein kinase1 (TgCDPK1) inhibitor. For this reason, compound A2 has potential as an anti-parasitic drug. Further studies are required to elucidate the mechanism of the action of compound A2, as well as to develop drug delivery systems for patients.
- Deng, Hao,Huang, Xing,Jin, Chun-Mei,Jin, Chunmei,Quan, Zhe-Shan
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- Structure-Activity Relationship Study of Majusculamides A and B and Their Analogues on Osteogenic Activity
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We discovered that majusculamide A (1) and majusculamide B (2), isolated from a marine cyanobacterium collected in Okinawa, induced osteoblast differentiation in MC3T3-E1 cells. Although majusculamide A (1) has a different configuration only at the C-19 stereocenter, bearing a methyl group, compared to majusculamide B (2), the effect of 1 was stronger than that of 2. We synthesized some analogues of the majusculamides (3-15) and evaluated osteogenic activities of these analogues. The structure-activity relationship study of majusculamide analogues suggested that the number of methyls and configuration at C-19 and the nature of the substituent at C-20 of majusculamide A (1) may be important for the osteoblast differentiation-inducing effect of 1.
- Nakajima, Daisuke,Natsume, Noriyuki,Ozaki, Kaori,Teruya, Toshiaki,Yokoshima, Satoshi
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supporting information
p. 2477 - 2482
(2020/10/02)
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- Synthesis of pyrimidine nucleoside and amino acid conjugates
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The synthesis of novel pyrimidine nucleoside bioconjugates with amino acids is presented. The N4-amino acid-acylated 2′-deoxycytidine analogues, modified with various amino acids, were synthesized using a three-step synthesis and obtained in moderate overall yields. Novel amino acid-alkylated 2′-deoxycytidine derivatives were obtained during the rearrangement of amino acid-acylated derivatives that occurred during Boc deprotection.
- Koplūnait?, Martyna,Butkut?, Kamil?,Me?kys, Rolandas,Taurait?, Daiva
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supporting information
(2020/11/13)
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- GLUCOPYRANOSYL DERIVATIVE AND USE THEREOF
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Provided are a glucopyranosyl derivative as a sodium-dependent glucose transporters inhibitor, especially as a SGLT1 inhibitor, a pharmaceutically acceptable salt or a stereoisomer thereof, a pharmaceutical composition thereof, and the uses of the compound and pharmaceutical composition thereof in the preparation of drugs for the treatment of diabetes and diabetes-related diseases.
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Paragraph 00227; 00283
(2019/08/12)
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- Alanine derivative and preparation method and application thereof
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The invention discloses an alanine derivative and a preparation method and application thereof. The preparation comprises the following steps: taking biphenylpyridine as a hinge region binding fragment, introducing L-alanine as a flexible linker by adopting a fragment drug design strategy to construct a compound library with kinase inhibitory activity, and discovering a tyrosine kinase inhibitor with Bcr-Abl kinase inhibitory activity through ADP-Glo kinase activity screening. The compound can be used for preparing anti-tumor (chronic myelogenous leukemia) drugs, inhibits kinase activity of Bcr-Abl and Bcr-AblT315I, and has the activity of inhibiting cell proliferation of K562 cells. The introduction of an alanine structure has an important effect on the inhibitory activity of the compound, the structural diversity of the kinase inhibitor can be expanded, and the activity result shows that the structure can be used as a Linker pharmacodynamic fragment of the Bcr-Abl tyrosine kinase inhibitor.
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Paragraph 0044; 0048
(2019/07/04)
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- INHIBITORS OF FIBROBLAST ACTIVATION PROTEIN
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Compounds and compositions for modulating fibroblast activation protein (FAP) are described. The compounds and compositions may find use as therapeutic agents for the treatment of diseases, including hyperproliferative diseases.
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Paragraph 1047-1048
(2019/07/03)
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- Engineered Substrate for Cyclooxygenase-2: A Pentapeptide Isoconformational to Arachidonic Acid for Managing Inflammation
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Beyond the conventional mode of working of anti-inflammatory agents through enzyme inhibition, herein, COX-2 was provided with an alternate substrate. A proline-centered pentapeptide isoconformational to arachidonic acid, which exhibited appreciable selectivity for COX-2, overcoming acetic acid- and formalin-induced pain in rats to almost 80%, was treated as a substrate by the enzyme. Remarkably, COX-2 metabolized the pentapeptide into small fragments consisting mainly of di- and tripeptides that ensured the safe breakdown of the peptide under in vivo conditions. The kinetic parameter Kcat/Km for COX-2-mediated metabolism of the peptide (6.3 × 105 M-1 s-1) was quite similar to 9.5 × 105 M-1 s-1 for arachidonic acid. Evidenced by the molecular dynamic studies and the use of Y385F COX-2, it was observed that the breakage of the pentapeptide has probably been taken place through H-bond activation of the peptide bond by the side chains of Y385 and S530.
- Kaur, Baljit,Kaur, Manpreet,Kaur, Navjot,Garg, Saweta,Bhatti, Rajbir,Singh, Palwinder
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p. 6363 - 6376
(2019/07/08)
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- Rhamnolipid inspired lipopeptides effective in preventing adhesion and biofilm formation of Candida albicans
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Rhamnolipids are biodegradable low toxic biosurfactants which exert antimicrobial and anti-biofilm properties. They have attracted much attention recently due to potential applications in areas of bioremediation, therapeutics, cosmetics and agriculture, however, the full potential of these versatile molecules is yet to be explored. Based on the facts that many naturally occurring lipopeptides are potent antimicrobials, our study aimed to explore the potential of replacing rhamnose in rhamnolipids with amino acids thus creating lipopeptides that would mimic or enhance properties of the parent molecule. This would allow not only for more economical and greener production but also, due to the availability of structurally different amino acids, facile manipulation of physico-chemical and biological properties. Our synthetic efforts produced a library of 43 lipopeptides revealing biologically more potent molecules. The structural changes significantly increased, in particular, anti-biofilm properties against Candida albicans, although surface activity of the parent molecule was almost completely abolished. Our findings show that the most active compounds are leucine derivatives of 3-hydroxy acids containing benzylic ester functionality. The SAR study demonstrated a further increase in activity with aliphatic chain elongation. The most promising lipopeptides 15, 23 and 36 at 12.5 μg/mL concentration allowed only 14.3%, 5.1% and 11.2% of biofilm formation, respectively after 24 h. These compounds inhibit biofilm formation by preventing adhesion of C. albicans to abiotic and biotic surfaces.
- Jovanovic, Milos,Radivojevic, Jelena,O'Connor, Kevin,Blagojevic, Stevan,Begovic, Biljana,Lukic, Vera,Nikodinovic-Runic, Jasmina,Savic, Vladimir
-
supporting information
p. 209 - 217
(2019/03/23)
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- Mandelic acid aminoacid aminopeptidase N inhibitor and synthesis method
-
The invention relates to a mandelic acid aminoacid aminopeptidase N inhibitor, the general chemical formula of which is in the drawing (The formula is shown in the description.), wherein R1, R2, R3 and R4 are H, F, Cl, Br, NO2, OCH3, CH3 or CH(CH3)3; and R5 is CH3 or CH2CH(CH3)2. Thiosemicarbazide and substituted benzoic acid are utilized to carry out condensation reaction, so that a substituted phenylthiadiazole derivative is produced, the substituted phenylthiadiazole derivative is connected with Boc-protected amino acid by acylation reaction, the protecting group is then removed under the effect of strong acid, and finally, after acylation with trimethylsiloxylphenylacetyl chloride, the target compound is obtained. The route of the synthesis process is short, the raw materials are easyto obtain, and the production cost is low.
- -
-
Paragraph 0037; 0038
(2018/07/15)
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- Synthesis and molecular simulation study of furoic peptidomimetic derivatives as potent aminopeptodase N inhibitors
-
The aminopeptidase N (APN) plays a critical role in angiogenesis and is over-expressed in tumor cells. In this paper, we report the synthesis and enzyme inhibition assay of furoic peptidomimetic compounds. These new compounds exhibit potent inhibitory ability toward APN with IC50 values lying in the micromolar level. The binding mode of inhibitors in APN active site was explained by a molecular simulation study. These data reveal that ligand coordinating with the catalytic Zn-ion is very important for inhibitory activities.
- Gao, Min,He, Junhua,Xu, Weidong,Lai, Xiaoping,Liu, Fen,Tu, Guogang
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p. 123 - 127
(2018/03/25)
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- Amine compound for inhibiting SSAO/VAP-1 and application thereof in medicines
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The present invention relates to an amine compound for inhibiting SSAO/VAP-1 and application thereof in medicines. In particular, the present invention relates to an amine compound for inhibiting a semicarbazide-sensitive oxidase (SSAO) and/or vascular adhesion protein-1 (VAP-1) inhibitor, or a pharmaceutically acceptable salt thereof, a stereoisomer or an/a E/Z isomer, further relates to a pharmaceutical composition containing the amine compound. The invention further relates to the application of the amine compound and the pharmaceutical composition in manufacture of the medicines for treatment of inflammation, inflammation-related diseases and immune diseases.
- -
-
Paragraph 0317; 0319; 0320; 0321
(2018/09/08)
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- Synthesis method for nitro group-containing natural product chrysamides B and diastereoisomer-compound thereof
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The invention belongs to the technical fields of medicinal chemistry and organic synthesis, and relates to a synthesis method for a nitro group-containing natural product chrysamides B, a chrysamidesB diastereoisomer-compound and a synthesis method and application thereof. According to the invention, a convergent synthesis method is adopted to condense chiral epoxy carboxylic acid and chiral dimethylpiperazine ring, and thereby the nitro group-containing natural product chrysamides B with a symmetrical structure and the chrysamides B diastereoisomer-compound are easily and efficiently synthesized. By three-step continuous oxidation, chiral epoxy carboxylic acid is prepared from p-nitrobenzaldehyde which is easy to obtain commercially, and dimethylpiperazine ring is prepared by reduction after alanine dimerization. The compound shows inhibitory activity on pasteurella multocida. Such a convergent synthesis route can be applied to the chemical synthesis of compounds with the similar structure and related derivatives, opening up a broad development space for novel antibiotic drugs.
- -
-
Paragraph 0026; 0027
(2018/11/22)
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- Synthesis and characterization of some atypical sphingoid bases
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Sphingolipids are ubiquitous and abundant components of all eukaryotic and some prokaryotic organisms. Sphingolipids show a large structural variety not only between the different species, but also within an individual cell. This variety is not limited to alterations in the polar headgroups of e.g. glycosphingolipids, but also affects the lipophilic anchors comprised of different fatty acids on the one hand and different sphingoid bases on the other hand. The structural variations within different sphingoid bases e.g. in pathogens can be used to identify novel biomarkers and drug targets and the specific change in the profile of common and uncommon sphingolipids are associated with pathological conditions like diabetes or cancer. Therefore, the emerging field of sphingolipidomics is dedicated to collect data on the sphingolipidome of a cell and hence to assign changes therein to certain states of a cell or to pathological conditions. This powerful tool however is still limited by the availability of structural information about the individual lipid species as well as by the availability of appropriate internal standards for quantification. Herein we describe the synthesis of a variety of 1-deoxy-sphingoid bases. 1-DeoxySphingolipids have recently acquired significant attention due to its pathological role in the rare inherited neuropathy, HSAN1 but also as predictive biomarkers in diabetes type II. Some of the compounds synthesized and characterized herein, have been used and will be used to elucidate the correct structure of these disease-related lipids and their metabolites.
- Saied, Essa M.,Le, Thuy Linh-Stella,Hornemann,Arenz, Christoph
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supporting information
p. 4047 - 4057
(2018/06/30)
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- Synthesis and bioactivities study of new antibacterial peptide mimics: The dialkyl cationic amphiphiles
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The emergence of infectious diseases caused by pathogenic bacteria is widespread. Therefore, it is urgently required to enhance the development of novel antimicrobial agents with high antibacterial activity and low cytotoxicity. A series of novel dialkyl cationic amphiphiles bearing two identical length lipophilic alkyl chains and one non-peptidic amide bond were synthesized and tested for antimicrobial activities against both Gram-positive and Gram-negative bacteria. Particular compounds synthesized showed excellent antibacterial activity toward drug-sensitive bacteria such as S. aureus, E. faecalis, E. coli and S. enterica, and clinical isolates of drug-resistant species such as methicillin-resistant S. aureus (MRSA), KPC-producing and NDM-1-producing carbapenem-resistant Enterobacteriaceae (CRE). For example, the MIC values of the best compound 4g ranged from 0.5 to 2 μg/mL against all these strains. Moreover, these small molecules acted rapidly as bactericidal agents, and functioned primarily by permeabilization and depolarization of bacterial membranes. Importantly, these compounds were difficult to induce bacterial resistance and can potentially combat drug-resistant bacteria. Thus, these compounds can be developed into a new class of antibacterial peptide mimics against Gram-positive and Gram-negative bacteria, including drug-resistant bacterial strains.
- Zhang, En,Bai, Peng-Yan,Cui, De-Yun,Chu, Wen-Chao,Hua, Yong-Gang,Liu, Qin,Yin, Hai-Yang,Zhang, Yong-Jie,Qin, Shangshang,Liu, Hong-Min
-
p. 1489 - 1509
(2017/11/13)
-
- Synthesis of Histidine-Containing Oligopeptides via Histidine-Promoted Peptide Ligation
-
Histidine-containing peptides are valuable therapeutic agents for a treatment of neurodegenerative diseases. However, the synthesis of histidine-containing peptides is not trivial due to the potential of imidazole sidechain of histidine to act as a nucleophile if unprotected. A peptide ligation method utilizing the imidazole sidechain of histidine has been developed. The key imidazolate intermediate that acts as an internal acyl transfer catalyst during ligation is generated by deprotonation. Transesterification with amino acids or peptides tethered with C-terminal thioester followed by N→N acyl shifts led to the final ligated products. A range of histidine-containing dipeptides could be synthesized in moderate to good yields via this method without protecting the imidazole sidechain. The protocol was further extended to tripeptide synthesis via a long-range N→N acyl transfer, and tetrapeptide synthesis.
- Huang, Kai-Jin,Huang, Yi-Chen,Lin, Yuya A.
-
supporting information
p. 400 - 403
(2018/02/21)
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- Antiplasmodial activity of hydroxyethylamine analogs: Synthesis, biological activity and structure activity relationship of plasmepsin inhibitors
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Malaria, particularly in endemic countries remains a threat to the human health and is the leading the cause of mortality in the tropical and sub-tropical areas. Herein, we explored new C2 symmetric hydroxyethylamine analogs as the potential inhibitors of Plasmodium falciparum (P. falciparum; 3D7) in in-vitro cultures. All the listed compounds were also evaluated against crucial drug targets, plasmepsin II (Plm II) and IV (Plm IV), enzymes found in the digestive vacuole of the P. falciparum. Analog 10f showed inhibitory activities against both the enzymes Plm II and Plm IV (Ki, 1.93 ± 0.29 μM for Plm II; Ki, 1.99 ± 0.05 μM for Plm IV). Among all these analogs, compounds 10g selectively inhibited the activity of Plm IV (Ki, 0.84 ± 0.08 μM). In the in vitro screening assay, the growth inhibition of P. falciparum by both the analogs (IC50, 2.27 ± 0.95 μM for 10f; IC50, 3.11 ± 0.65 μM for 10g) displayed marked killing effect. A significant growth inhibition of the P. falciparum was displayed by analog 12c with IC50 value of 1.35 ± 0.85 μM, however, it did not show inhibitory activity against either Plms. The hemolytic assay suggested that the active compounds selectively inhibit the growth of the parasite. Further, potent analogs (10f and 12c) were evaluated for their cytotoxicity towards mammalian HepG2 and vero cells. The selectivity index (SI) values were noticed greater than 10 for both the analogs that suggested their poor toxicity. The present study indicates these analogs as putative lead structures and could serve as crucial for the development of new drug molecules.
- Kumar Singh, Amit,Rajendran, Vinoth,Singh, Snigdha,Kumar, Prashant,Kumar, Yogesh,Singh, Archana,Miller, Whelton,Potemkin, Vladimir,Poonam,Grishina, Maria,Gupta, Nikesh,Kempaiah, Prakasha,Durvasula, Ravi,Singh, Brajendra K.,Dunn, Ben M.,Rathi, Brijesh
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p. 3837 - 3844
(2018/07/13)
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- Dual-protected amino acid derivatives as new antitubercular agents
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Tuberculosis is an infectious disease with high incidence and growing drug-resistant rates. In an attempt to develop new antitubercular agents, 35 compounds were synthesized, most of them bearing a carbamate and enantiopure amino acid moiety. These compounds had their activity evaluated toward a Mycobacterium tuberculosis strain (ATCC 27294) and cytotoxicity against fibroblast MRC-5 cells (ATCC CCL-171). Three of the prepared derivatives presented a good antimicrobial inhibition and two of them a moderate cytotoxicity. The lipophilicity seems to play a vital role in the cell growth activity, with best results for the derivatives with a higher logP.
- de Castro, Pedro P.,Campos, Débora L.,Pavan, Fernando R.,Amarante, Giovanni W.
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p. 1576 - 1580
(2018/06/06)
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- Antiviral nucleoside phosphoramidate and pharmaceutical composition and applications thereof
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The invention provides an antiviral nucleoside phosphoramidate and a pharmaceutical composition and applications thereof. The nucleoside phosphoramidate compound is prepared by connecting nucleoside with phosphate through phosphorus-oxygen bonds. The structural formulas of the nucleoside phosphoramidate compound are represented by a, a1, a2, b, b1, and b2. The invention also discloses stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, or crystals of the nucleoside phosphoramidate compound. The anti-hepatitis C activity of the provided novel nucleoside phosphoramidate is obviously better than that of sofosbuvir used in clinic. On the saccharide ring, the fluorine atoms are replaced by chlorine atoms, and the cytotoxicity of measure cell lines is prominently reduced. By systematically modifying and optimizing the basic groups, saccharide rings, and prodrugs, the anti-hepatitis C activity of partial synthesized compounds is 2 to 10 times higher than that of sofosbuvir. At the same time, the key parts of metabolism are optimized, the metabolism stability and chemical stability of synthesized compounds in plasma are better, compared with those of sofosbuvir.
- -
-
Paragraph 0092-0095
(2017/05/06)
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- New reagent for the introduction of Boc protecting group to amines: Boc-OASUD
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A new reagent, tert-butyl (2,4-dioxo-3-azaspiro [5,5] undecan-3-yl) carbonate (Boc-OASUD) for the preparation of N-Boc-amino acids is described. The Boc-OASUD reacts with amino acids and their esters at room temperature in the presence of a base and gives N-Boc-amino acids and their esters in good yields and purity. Introduction of the Boc group takes place without racemization. The Boc-OASUD, being a solid and more stable, is a better alternative to di-tert-butyl dicarbonate which is low melting and has to be dispensed in plastic containers than glass because of its poor stability.
- Maheswara Rao, B. Leela,Nowshuddin, Shaik,Jha, Anjali,Divi, Murali K.,Rao
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p. 2127 - 2132
(2017/10/31)
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- Desyl and phenacyl as versatile, photocatalytically cleavable protecting groups: A classic approach in a different (visible) light
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A highly efficient, catalytic strategy for the deprotection of classical phenacyl (Pac) as well as desyl (Dsy) protection groups has been developed using visible light photoredox catalysis. The deliberate use of a neutral two-phase acetonitrile/water mixture with K3PO4 applying catalytic amounts of [Ru(bpy)3](PF6)2 in combination with ascorbic acid is the key to this truly catalytic deprotection of Pac- and Dsy-protected carboxylic acids. Our mild yet robust protocol allows for fast and selective liberation of the free carboxylic acids in very good to quantitative yields, while only low catalyst loadings (1 mol %) are required. Both Pac and Dsy, easily introduced from commercially available precursors, can be applied for the direct protection of carboxylic acids and amino acids, offering orthogonality to a great variety of other common protecting groups. We further demonstrate the general applicability and versatility of these formerly underrated protecting groups in combination with our catalytic cleavage conditions, as underscored by the gained high functional group tolerance. Moreover, this method could successfully be adapted to the requirements of solidphase synthesis. As a proof of principle for an efficient visible light, photocatalytic linker cleavage, a Boc-protected tripeptide was split off from commercially available brominated Wang resin.
- Speckmeier, Elisabeth,Zeitler, Kirsten
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p. 6821 - 6826
(2017/11/06)
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- NOVEL SUBSTITUTED AMIDES OF TRITERPENE DERIVATIVES AS HIV INHIBITORS
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The present invention relates to compounds of novel substituted amides of triteripene derivatives of formula (I); or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, tautomers, stereoisomers, prodrugs, compositions or combination thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, X, Y, Z1, Z2, Z3 and formula (II) are as defined herein. The present invention also relates to,, and pharmaceutical compositions comprising compounds of formula (I) useful for the treatment of viral diseases and particularly HIV mediated diseases.
- -
-
Page/Page column 21
(2017/02/28)
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- A (S)- N - methoxy - methyl -2 - (tetrahydro-pyrrolyl) propionamide and its preparation method and application
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The invention discloses a (S)-N-methoxy-methyl-2-(pyrrolidine) propionamide shown as a formula (5). A preparation method is as follows: subjecting a starting material L-alanine to amino protection, reaction with N,O-dimethyl hydroxylamine hydrochloride, removal of amino protecting group, and alkylation; and subjecting the prepared compound shown as (5) to addition elimination and reduction to obtain an Efavirenz chiral ligand shown as the formula (7). The synthetic method of Efavirenz chiral ligand provided by the invention has the advantages of mild reaction conditions, simple operation, high yield and low production cost, and is suitable for industrialized production.
- -
-
Paragraph 0035; 0036
(2017/08/25)
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- Efficient near infrared fluorescence detection of elastase enzyme using peptide-bound unsymmetrical squaraine dye
-
Extended wavelength analyte-responsive fluorescent probes are highly desired for the imaging applications owing to their deep tissue penetration, and minimum interference from autofluorescence by biomolecules. Near infra-red (NIR) sensitive and self-quenching fluorescent probe based on the dye-peptide conjugate (SQ 1 PC) was designed and synthesized by facile and efficient one-pot synthetic route for the detection of Elastase activity. In the phosphate buffer solution, there was an efficient quenching of fluorescence of SQ 1 PC (86%) assisted by pronounced dye-dye interaction due to H-aggregate formation. Efficient and fast recovery of this quenched fluorescence of SQ 1 PC (> 50% in 30 s) was observed on hydrolysis of this peptide-dye conjugate by elastase enzyme. Presently designed NIR sensitive self-quenching substrate offers the potential application for the detection of diseases related to proteases by efficient and fast detection of their activities.
- Saikiran, Maryala,Sato, Daisuke,Pandey, Shyam S.,Hayase, Shuzi,Kato, Tamaki
-
supporting information
p. 4024 - 4029
(2017/08/23)
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- Enantioselective Synthesis of Quaternary Δ4- and Δ5-Dehydroprolines Based on a Two-Step Formal [3+2] Cycloaddition of α-Aryl and α-Alkyl Isocyano(thio)acetates with Vinyl Ketones
-
A divergent synthesis of optically active quaternary Δ4- and Δ5-dehydro prolines is developed based on the first catalytic enantioselective conjugate addition of α-substituted isocyano(thio)acetates to vinyl ketones that is general for both α-aryl and α-alkyl isocyano(thio)acetates. The new tetrasubstituted C?N stereocenter is formed without the need of any metal salt due to a bifunctional tertiary amine/squaramide catalyst, featuring a bulky polyaryl sidearm and an unusually short squaramide diamide H???H interatomic distance in the solid state.
- Odriozola, Amaiur,Oiarbide, Mikel,Palomo, Claudio
-
supporting information
p. 12758 - 12762
(2017/09/25)
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- PROPYL CATIONIC PEPTIDE LIPIDS, SYNTHESIS METHOD THEREOF, AND APPLICATION THEREOF
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A class of propyl cationic peptide lipids is propyl cationic peptide lipid compounds having a general formula structure as follows. After the propyl cationic peptide lipids are dispersed in water, a cationic liposome with a particle size of approximately 100 nm is obtained. The cationic liposome can carry plasmid DNA (pDNA) or small interfering RNA (siRNA) into cells to realize the function of gene delivery, and is almost non-toxic to the cells.
- -
-
Paragraph 0065; 0081
(2018/01/13)
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- Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters
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Background and Purpose: 4-Methyl-N-methylcathinone (mephedrone) is a synthetic stimulant that acts as a substrate-type releaser at transporters for dopamine (DAT), noradrenaline (NET) and 5-HT (SERT). Upon systemic administration, mephedrone is metabolized to several phase I compounds: the N-demethylated metabolite, 4-methylcathinone (nor-mephedrone); the ring-hydroxylated metabolite, 4-hydroxytolylmephedrone (4-OH-mephedrone); and the reduced keto-metabolite, dihydromephedrone. Experimental Approach: We used in vitro assays to compare the effects of mephedrone and synthetically prepared metabolites on transporter-mediated uptake and release in HEK293 cells expressing human monoamine transporters and in rat brain synaptosomes. In vivo microdialysis was employed to examine the effects of i.v. metabolite injection (1 and 3?mg·kg?1) on extracellular dopamine and 5-HT levels in rat nucleus accumbens. Key Results: In cells expressing transporters, mephedrone and its metabolites inhibited uptake, although dihydromephedrone was weak overall. In cells and synaptosomes, nor-mephedrone and 4-OH-mephedrone served as transportable substrates, inducing release via monoamine transporters. When administered to rats, mephedrone and nor-mephedrone produced elevations in extracellular dopamine and 5-HT, whereas 4-OH-mephedrone did not. Mephedrone and nor-mephedrone, but not 4-OH-mephedrone, induced locomotor activity. Conclusions and Implications: Our results demonstrate that phase I metabolites of mephedrone are transporter substrates (i.e. releasers) at DAT, NET and SERT, but dihydromephedrone is weak in this regard. When administered in vivo, nor-mephedrone increases extracellular dopamine and 5-HT in the brain whereas 4-OH-mephedrone does not, suggesting the latter metabolite does not penetrate the blood–brain barrier. Future studies should examine the pharmacokinetics of nor-mephedrone to determine its possible contribution to the in vivo effects produced by mephedrone.
- Mayer,Wimmer,Dillon-Carter,Partilla,Burchardt,Mihovilovic,Baumann,Sitte
-
supporting information
p. 2657 - 2668
(2016/10/19)
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- SPIROCYCLIC HAT INHIBITORS AND METHODS FOR THEIR USE
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Compounds having a structure of Formula (IX) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b, R3a, R3b, R4a, R4b, Q1----Q2, R6, R7, A, B, W, x, and y are as defined herein and are provided. Pharmaceutical compositions comprising such compounds and methods for treating various HAT-related conditions or diseases, including cancer, by administration of such compounds are also provided.
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Page/Page column 698
(2016/04/10)
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- Efinaconazole intermediate and preparation method thereof
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The invention provides an efinaconazole intermediate compound (VI) and a preparation method thereof and relates to the field of pharmaceutical technology. The preparation method comprises the following steps: a compound (V) reacts with trimethylsulfoxonium iodide to obtain a compound (VV); and the compound (VV) experiences a ring-opening reaction with 1,2,4-triazole to obtain the compound (VI). The method has the advantages of easiness in operation, low production cost and good product quality and is suitable for industrial production.
- -
-
Paragraph 0046; 0047; 0048
(2016/10/10)
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- Design and synthesis of novel HDAC8 inhibitory 2,5-disubstituted-1,3,4-oxadiazoles containing glycine and alanine hybrids with anti cancer activity
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Oxadiazole is a heterocyclic compound containing an oxygen atom and two nitrogen atoms in a five-membered ring. Of the four oxadiazoles known, 1,3,4-oxadiazole has become an important structural motif for the development of new drugs and the compounds containing 1,3,4-oxadiazole cores have a broad spectrum of biological activity. Herein, we describe the design, synthesis and biological evaluation of a series of novel 2,5-disubstituted 1,3,4-oxadiazoles (10a–10j) as class I histone deacetylase (HDAC) inhibitors. The compounds were designed and evaluated for HDAC8 selectivity using in silico docking software (Glide) and the top 10 compounds with high dock score and obeying Lipinski's rule were synthesized organically. Further the biological HDAC inhibitory and selectivity assays and anti-proliferative assays were carried out. In in silico and in vitro studies, all compounds (10a–10j) showed significant HDAC inhibition and exhibited HDAC8 selectivity. Among all tested compounds, 10b showed substantial HDAC8 inhibitory activity and better anticancer activity which is comparable to the positive control, a FDA approved drug, vorinostat (SAHA). Structural activity relation is discussed with various substitutions in the benzene ring connected on 1,3,4-oxadizole and glycine/alanine. The study warranted further investigations to develop HDAC8-selective inhibitory molecule as a drug for neoplastic diseases. Novel 1,3,4-oxadizole substituted with glycine/alanine showed HDAC8 inhibition.
- Pidugu, Vijaya Rao,Yarla, Nagendra Sastry,Pedada, Srinivasa Rao,Kalle, Arunasree M.,Satya, A. Krishna
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p. 5611 - 5617
(2016/10/24)
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- Bisindolyl maleimide derivative and preparation method and application thereof
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The invention provides a bisindolyl maleimide derivative and a preparation method and application thereof. The bisindolyl maleimide derivative has an excellent alpha-glucosidase inhibition effect and can be used for preventing and treating diabetes.
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-
Paragraph 0280; 0281; 0287; 0288
(2017/01/02)
-
- Bisindolylmaleimide derivative, and preparation method and use thereof
-
The invention provides a bisindolylmaleimide derivative, and a preparation method and a use thereof. The bisindolylmaleimide derivative has a good tumor treatment effect, especially has a good treatment effect on some drug-resistant tumors, and can realize accurate treatment of the drug-resistant tumors.
- -
-
Paragraph 0284; 0285; 0291; 0292
(2017/04/03)
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- Efficient N-Boc protection of amines by a reusable heterogeneous solid acid nanocatalyst at room temperature
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An efficient and rapid protocol for chemoselective N-Boc protection of various structurally different aryl, aliphatic, and heterocyclic amines is reported with (Boc)2O using mesoporous silica phenylsulfonic acid (SBA-15-Ph-SO3H) as a recyclable and heterogeneous solid acid nanocatalyst under solvent-free condition at ambient temperature. The catalyst can be easily recovered and reused for ten reaction cycles for protection of amines without considerable loss of activity. The advantages of this green method are simplicity, easy workup, chemoselectivity, short reaction time, and excellent yield.
- Veisi, Hojat,Sedrpoushan, Alireza,Ghazizadeh, Habibollah,Hemmati, Saba
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p. 1451 - 1461
(2016/04/26)
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- Paliperidone amino acid ester and its preparation method
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The invention discloses a preparation method of a paliperidone amino-acid ester compound or medicinal salt thereof used for treating mental disease, wherein the structural formula of the compound is shown as a formula (I) (described in the specification). The compound can be an optical isomer and also can be a racemic mixture. The paliperidone amino-acid ester can be metabolized and converted into paliperidone (II) with pharmacological activity in vivo after being ingested in a human body, the paliperidone (II) is taken as an antagonist for neurotransmission substance to play a pesticide effect, and the paliperidone (II) is used for treating related mental diseases such as schizophrenia.
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-
Paragraph 0022; 0023; 0024
(2017/01/12)
-
- Study of the Paternò–Büchi type photolabile protecting group and application to various acids
-
An efficient photolabile protecting group, thiochromone S,S-dioxides with the diazomethyl group for phosphate derivatives, amino acids and sulfonic acids was developed. Protection and photodeprotection reactions proceeded smoothly under mild conditions without any catalyst.1H NMR and HPLC spectra studies demonstrated the photolysis properties of the photolabile protecting group and gave an exact quantification of the released substrates. Specially, the photoproduct derived from the thiochromone derivatives following Paternò–Büchi type photo-cycloaddition showed high fluorescence intensity. This fluorescent characteristic demonstrated the photodeprotection progress also can be monitored by fluorescence spectra.
- Zhang, Youlai,Zhang, Huan,Ma, Chi,Li, Junru,Nishiyama, Yasuhiro,Tanimoto, Hiroki,Morimoto, Tsumoru,Kakiuchi, Kiyomi
-
supporting information
p. 5179 - 5184
(2016/11/13)
-
- Carbon-Nanotube-Mediated Electrochemical Transition in a Redox-Active Supramolecular Hydrogel Derived from Viologen and an l -Alanine-Based Amphiphile
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A two-component hydrogelator (16-A)2-V2+, comprising an l-alanine-based amphiphile (16-A) and a redox-active viologen based partner (V2+), is reported. The formation the hydrogel depended, not only on the acid-to-amine stoichiometric ratio, but on the choice of the l-amino acid group and also on the hydrocarbon chain length of the amphiphilic component. The redox responsive property and the electrochemical behavior of this two-component system were further examined by step-wise chemical and electrochemical reduction of the viologen nucleus (V2+/V+ and V+/V0). The half-wave reduction potentials (E1/2) associated with the viologen ring shifted to more negative values with increasing amine component. This indicates that higher extent of salt formation hinders reduction of the viologen moiety. Interestingly, the incorporation of single-walled carbon nanotubes in the electrochemically irreversible hydrogel (16-A)2-V2+ transformed it into a quasi-reversible electrochemical system.
- Datta, Sougata,Bhattacharya, Santanu
-
supporting information
p. 7524 - 7532
(2016/05/24)
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- The role of disulfide-bridge on the activities of H-shape gemini-like cationic lipid based siRNA delivery
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In our previous study, a H-shape gemini-like cationic lipid (ssGLCL, formerly named as CLD), composed of two hydrophilic lysine heads and two hydrophobic oleyl alcohol tails with a bridge of the redox-active disulfide-bond, had been synthesized and used as a nanocarrier for delivering small interfering RNAs (siRNAs) into cells. In order to further elucidate the role of disulfide ( - S - S - ) bridge on the activity of ssGLCL based siRNA delivery, a comparable ccGLCL bridged with a non-reducible carbon-carbon bond was synthesized and used as control in this study. Both two H-shape GLCL molecules could individually self-assemble into cationic nanoparticles in water phase and complex with negatively-charged siRNA into nanoplexes with particle size of ~ 200 nm and zeta potential of ~ + 30 mV, and exhibit effective siRNA delivery both in vitro and in vivo. Investigation of internalization pathway displayed that both ssGLCL/siRNA and ccGLCL/siRNA nanoplexes were predominantly internalized into MCF-7 cells by the clathrin-mediated endocytosis pattern. Although a lower cellular uptake of siRNA was found in the human breast cancer MCF-7 cells, the ssGLCL/siRNA nanoplexes could exhibit similar or even stronger down-regulation effects on the targeted EGFR mRNA and protein in MCF-7 cells when compared to the ccGLCL/siRNA nanoplexes. Furthermore, mechanistic study showed that the enhanced down-regulation effects of ssGLCL/siRNA nanoplexes on targeted mRNA and protein were probably attributed to the increased release of siRNA from lysosomes to cytoplasm following the cleavage of redox-active disulfide-bridge in ssGLCL. Therefore, we believed that the redox-active H-shape ssGLCL could be a potential nanocarrier towards improving siRNA delivery.
- Ma, Xiao-Fei,Sun, Jing,Qiu, Chong,Wu, Yi-Fan,Zheng, Yi,Yu, Min-Zhi,Pei, Xi-Wei,Wei, Lin,Niu, Yu-Jie,Pang, Wen-Hao,Yang, Zhen-Jun,Wang, Jian-Cheng,Zhang, Qiang
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- PROCESS FOR THE PREPARATION OF INTERMEDIATES USEFUL IN THE SYNTHESIS OF ELUXADOLINE
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The invention relates to an improved process for preparing [(S)-1-(4-phenyl-1-H-imidazol-2- yl)-ethyl]-amine. The process involves formation of the novel intermediate crystalline compound[(S)-1-(4-phenyl-1-H-imidazol-2-yl)-ethyl]-carbamic acid tert-butyl ester oxalate.
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Page/Page column 8
(2017/05/28)
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- Design, synthesis, and in vitro antiplasmodial activity of 4-aminoquinolines containing modified amino acid conjugates
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Abstract: A new series of side chain-modified 4-aminoquinolines were synthesized and screened for in vitro antiplasmodial activity against both chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. Among the series, compounds 30 and 31 showed significant inhibition of parasite growth against K1 strain of P. falciparum with IC50 values 0.28 and 0.31?μM, respectively, whereas compounds 34, 35, and 38 exhibited superior activity against K1 strain with IC50 values 0.18, 0.22, and 0.17?μM, respectively, as compared to 0.255?μM for chloroquine (CQ). All the compounds displayed good resistance factor between 1.54 and >34.48 as against 51.0 for CQ. All these analogues were found to form strong complex with hematin and inhibited the β-hematin formation in vitro, suggesting that this class of compounds act on a heme polymerization target. Overall results suggest that present series of compounds appear to be promising for further lead optimization to obtain compounds active against drug-resistant parasites. Graphical Abstract: [Figure not available: see fulltext.]
- Srinivasarao, Kondaparla,Agarwal, Pooja,Srivastava, Kumkum,Haq,Puri, Sunil K.,Katti
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p. 1148 - 1162
(2016/07/06)
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