- Construction and activity evaluation of novel benzodioxane derivatives as dual-target antifungal inhibitors
-
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
-
-
- Design, synthesis, and structure-activity relationship studies of L-amino alcohol derivatives as broad-spectrum antifungal agents
-
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)
-
- NOVEL CYP34A-SPECIFIC INHIBITORS AND METHODS OF USING SAME
-
The present invention includes novel compositions inhibiting CYP3 A4. The present invention further includes a novel method of inhibiting CYP3A4 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention. In one embodiment, the subject is further administered at least one additional therapeutic agent.
- -
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Page/Page column 42; 43
(2017/03/28)
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- pH-Controlled recognition of amino acids by urea derivatives of β-cyclodextrin
-
Water soluble amphiphilic urea-substituted β-cyclodextrins were synthesized and applied as amino acid receptors. A great affinity towards nonpolar amino acids was observed, ranging from 2300 M?1 for alanine to 54?800 M?1 for tryptoph
- Stepniak, Pawel,Lainer, Bruno,Chmurski, Kazimierz,Jurczak, Janusz
-
p. 15742 - 15746
(2017/03/22)
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- Structure-Based Inhibitor Design for Evaluation of a CYP3A4 Pharmacophore Model
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Human cytochrome P450 3A4 (CYP3A4) is a key xenobiotic-metabolizing enzyme that oxidizes and clears the majority of drugs. CYP3A4 inhibition may lead to drug-drug interactions, toxicity, and other adverse effects but, in some cases, could be beneficial and enhance therapeutic efficiency of coadministered pharmaceuticals that are metabolized by CYP3A4. On the basis of our investigations of analogs of ritonavir, a potent CYP3A4 inactivator and pharmacoenhancer, we have built a pharmacophore model for a CYP3A4-specific inhibitor. This study is the first attempt to test this model using a set of rationally designed compounds. The functional and structural data presented here agree well with the proposed pharmacophore. In particular, we confirmed the importance of a flexible backbone, the H-bond donor/acceptor moiety, and aromaticity of the side group analogous to Phe-2 of ritonavir and demonstrated the leading role of hydrophobic interactions at the sites adjacent to the heme and phenylalanine cluster in the ligand binding process. The X-ray structures of CYP3A4 bound to the rationally designed inhibitors provide deeper insights into the mechanism of the CYP3A4-ligand interaction. Most importantly, two of our compounds (15a and 15b) that are less complex than ritonavir have comparable submicromolar affinity and inhibitory potency for CYP3A4 and, thus, could serve as templates for synthesis of second generation inhibitors for further evaluation and optimization of the pharmacophore model.
- Kaur, Parminder,Chamberlin, A. Richard,Poulos, Thomas L.,Sevrioukova, Irina F.
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p. 4210 - 4220
(2016/06/01)
-
- METHODS FOR INHIBITING DRUG DEGRADATION
-
Methods of inhibiting cytochrome P450 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450. Pharmaceutical compositions are provided that can act as boosters
- -
-
Paragraph 0249; 0250
(2015/11/02)
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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
-
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
-
-
- A rapid entry to amino acid derived diverse 3,4-dihydropyrazines and dihydro[1,2,3]triazolo[1,5-a]pyrazines through 1,3-dipolar cycloaddition
-
An efficient, general and practical synthesis of diverse 3,4-dihydropyrazines, 6,7-dihydro-[1,2,3]triazolopyrazines and 7,8-dihydro-[1,2,3]triazolodiazepines through intramolecular 1,3-dipolar cycloaddition from amino acid derived common intermediates with high yields is described. Moreover, one-pot access to optically active 3-aryl substituted 6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazines in the palladium-copper co-catalytic system has also been achieved in this work. The easy substrate availability and operational simplicity make the process suitable for further exploration. This journal is the Partner Organisations 2014.
- Bera, Saurav,Panda, Gautam
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p. 3976 - 3985
(2014/06/09)
-
- Synthesis of iron P-N-P' and P-NH-P asymmetric hydrogenation catalysts
-
Complexes of the type mer,trans-[Fe(P-N-P)(CO)2Br]BF4 are known to be precatalysts for the asymmetric direct hydrogenation of ketones and imines. Employing related ligand scaffolds, we successfully generated and tested the series of three new precatalysts [Fe(PCy2CH2CH-NCH(R)CH2PPh2)(CO)2Br]BF4 with chirality derived from (S)-amino alcohols with phenyl, benzyl, and isopropyl substituents (R), yielding fairly active and selective systems. For the reduction of acetophenone to (S)-1-phenylethanol turnover frequencies up to 920 h-1 and up to 74% enantiomeric excess at 50 °C and 5-25 atm of H2 were obtained. We found, however, that placing these large groups R next to nitrogen was found to be deleterious to catalytic activity. Extending the scope of the ligand structure, we then developed a series of six P-N-P and five P-NH-P systems starting with o-diphenylphosphinobenzaldehyde and the phosphine-amines PPh2CHR1CHR2NH2 (R1 = H, Ph, CH2Ph, iPr with R2 = H or R1 = Me, Ph with R2 = Ph) as well as their corresponding [Fe(P-N-P)(NCMe)3][BF4]2 and [Fe(P-NH-P)(NCMe)3][BF4]2 complexes, which were not catalytically active. Finally, we made the new achiral iron complex mer,cis-Fe(PPh2(o-C6H4)CHNCH2CH2PPh2)(CO)Br2, which was active for the direct hydrogenation of acetophenone, achieving turnover frequencies of 800 h-1 at 50°C and 25 atm of H2.
- Sonnenberg, Jessica F.,Lough, Alan J.,Morris, Robert H.
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p. 6452 - 6465
(2015/02/19)
-
- AZAQUINAZOLINE INHIBITORS OF ATYPICAL PROTEIN KINASE C
-
The present invention provides a compound of formula (I) or a salt thereof, wherein R7, R8, R9, G, and X are as defined herein. A compound of formula (I) and its salts have a PKC inhibitory activity, and may be used to treat proliferative disorders.
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-
Page/Page column 222-223
(2014/04/17)
-
- Synthesis of the orthogonally protected amino alcohol Phaol and analogs
-
The development of a multigram synthesis of the orthogonally protected amino acid-derived Phaol [2-{[(2S)-2-amino-3-phenylpropyl]amino}ethanol] is described. The goal of this work is to synthesize an orthogonally protected Phaol in a multigram scale up to
- Nelissen, Jo,Nuyts, Koen,Dehaen, Wim,De Borggraeve, Wim M.
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p. 527 - 532
(2012/05/04)
-
- Syntheis of new chiral 5,6,7,8-tetrahydrotetrazolo[1,5-a]pyrazines from α-amino acid derivatives following "click" chemistry
-
An efficient and practical synthesis of new chiral fused tetrazoles have been synthesized following [3+2] cycloaddition reaction starting from α-amino acid derivatives.
- Mohapatra, Debendra K.,Maity, Pradip K.,Ghorpade, Ravindra V.,Gurjar, Mukund K.
-
scheme or table
p. 865 - 872
(2010/09/16)
-
- HIV PROTEASE INHIBITOR AND CYTOCHROME P450 INHIBITOR COMBINATIONS
-
Compositions and methods of treating viral infections are provided. More particularly, compositions including a combination of protease inhibitors and cytochrome p450 enzyme inhibitors are provided. Methods of using the compositions for treatment of disea
- -
-
Page/Page column 44
(2009/10/18)
-
- COMPOSITIONS AND METHODS FOR INHIBITING CYTOCHROME P450
-
Methods of inhibiting cytochrome P450 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450. Pharmaceutical compositions are provided that can act as boosters
- -
-
Page/Page column 47
(2008/06/13)
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- An organo-catalytic approach to the enantioselective synthesis of (R)-selegiline
-
An efficient enantioselective synthesis of (R)-selegiline has been achieved by two routes, via proline-catalyzed α-aminooxylation as well as α-amination of phenylpropanaldehyde as the key step.
- Talluri, Siva Kumar,Sudalai, Arumugam
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p. 9758 - 9763
(2008/02/12)
-
- Synthesis of new chiral 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines from α-amino acid derivatives under mild conditions
-
A practical and efficient regioselective synthesis of several new chiral 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines is described from α-amino acid derivatives following intramolecular 'click' reaction as the key step. The method obviates product pu
- Mohapatra, Debendra K.,Maity, Pradip K.,Gonnade, Rajesh G.,Chorghade, Mukund S.,Gurjar, Mukund K.
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p. 1893 - 1896
(2008/03/13)
-
- Stereoselective synthesis of 2-alkenylaziridines and 2-alkenylazetidines by palladium-catalyzed intramolecular amination of α- and β-amino allenes
-
Whereas palladium-catalyzed reaction of N-arylsulfonyl-α-amino allenes with an aryl iodide (4 equiv) in the presence of potassium carbonate (4 equiv) in DMF at around 70 °C affords the corresponding 3-pyrroline derivatives, the reaction in refluxing 1,4-dioxane under otherwise identical conditions yields exclusively or most predominantly the corresponding 2-alkenylaziridines bearing an aryl group on the double bond. Similarly, N-arylsulfonyl-β-amino allenes can be also cyclized into the corresponding alkenylazetidines bearing a 2,4-cis-configuration under palladium-catalyzed cyclization conditions in DMF.
- Ohno,Anzai,Toda,Ohishi,Fujii,Tanaka,Takemoto,Ibuka
-
p. 4904 - 4914
(2007/10/03)
-
- New chiral auxiliaries for the construction of quaternary stereocenters by copper-catalyzed Michael reactions
-
The construction of quaternary stereocenters with 95-99% ee at ambient temperatures can be achieved by a copper-catalyzed Michael reaction with the application of α-amino acid amides as chiral auxiliaries [Eq. (1)]. These amides can be obtained in a few steps from the α-amino acids with standard transformations and, after the Michael reaction, they can be quantitatively recovered. Exclusion of water and oxygen is not necessary.
- Christoffers, Jens,Mann, Alexander
-
p. 2752 - 2754
(2007/10/03)
-
- Design and synthesis of a novel cyclo-β-tetrapeptide
-
N-Substituted tetralactams (cyclo-β-tetrapeptides) have been identified as potential molecular scaffolds by computer-aided design; compound 2, arising from L-β-homophenylalanine, has been prepared as a model system and its structure elucidated by single c
- Sutton, Peter W.,Bradley, Adrian,Elsegood, Mark R. J.,Farras, Jaume,Jackson, Richard F. W.,Romea, Pedro,Urpi, Felix,Vilarrasa, Jaume
-
p. 2629 - 2632
(2007/10/03)
-
- Chemoenzymatic synthesis of 4-amino-2-hydroxy acids: A comparison of mutant and wild-type oxidoreductases
-
We describe a new chemoenzymatic synthesis of enantiopure 4-amino-2-hydroxy acids using two biotransformations in a single-pot process in aqueous medium. These compounds are valuable as γ-turn mimics for investigations into the secondary structure of peptides. The enzyme substrates are a series of carbobenzyloxy (CBZ)-protected 4-amino-2-keto esters, prepared efficiently from the L-amino acids, alanine, leucine, phenylalanine, and valine. First, the α-amino acids were converted to the corresponding β-amino acids in a simple five-step procedure. A further one-carbon homologation via ozonolysis of the corresponding β-keto cyanophosphoranes gave the required α-keto esters in good yield. The enzyme catalyzed hydrolyses of all the α-keto esters to the corresponding α-keto acids proceeded smoothly with the lipase from Candida rugosa. Using the same reaction pot, it was found that wild-type lactate dehydrogenases from either Bacillus stearothermophilus CBS-LDH) or Staphylococcus epidermidis (SE-LDH) could be used to specifically reduce the ketone of the alanine-derived α-keto acid 2, giving the (S)- and CR)-2-hydroxy acids, respectively, in good yields. However, the more bulky α-keto acids 3, 4, and 5 (derived from valine, leucine, and phenylalanine) were not substrates for these enzymes. In contrast, the genetically engineered H205Q mutant of D-hydroxyisocaproate dehydrogenase proved to be an ideal catalyst for the reduction of all the α-keto acids 2-5, giving excellent yields of the CBZ-protected (2R,4S)-4-amino2-hydroxy acids as single diastereomers. This genetically engineered oxidoreductase has great potential value in synthesis due to its broad substrate specificity and high catalytic activity. For example, reduction of 1 mmol of N-protected (S)-4-amino-2-oxopentanoic acid 2 took just 4 h with the H205Q mutant giving, after esterification, the CR)-2-alcohol 25 in 85% yield, whereas with SE-LDH the reaction required 4 days to give a 67% yield of 25.
- Sutherland, Andrew,Willis, Christine L.
-
p. 7764 - 7769
(2007/10/03)
-
- Synthesis of novel C2-symmetric and pseudo C2-symmetric based diols, epoxides and dideoxy derivatives of HIV protease inhibitors
-
The Julia's olefination reaction between the sulfone derivative (10) and the aldehyde (13) (both obtained from L-phenylalanine) followed by debenzylation led to the formation (2S,5S,3E)-2,5-bis-[(1,1-dimethyl ethoxy)-carbonyl]amino-1,6-diphenylhex-3-ene (
- Gurjar, Mukund K.,Pal, Shashwati,Rama Rao,Pariza, Richard J.,Chorghade, Mukund S.
-
p. 4769 - 4778
(2007/10/03)
-
- Electrogenerated Superoxide-Activated Carbon Dioxide. A New Mild and Safe Approach to Organic Carbamates
-
The electrochemical reduction of O2 (E = -1.0 V vs SCE) in dipolar aprotic solvents in the presence of CO2 gave a carboxylating reagent (O2·-/CO2) able to convert amines and different types of their derivatives into carbamates. Primary and secondary aliphatic and aromatic amines were converted into the corresponding ethyl carbamates by the addition of EtI to the carbamate anions generated in the first step of the reactions. The yields were dependent on the nucleophilicity of the nitrogen atom ω-Bromoethyl- and propylamine gave 2-oxazolidinone and tetrahydro-l,3-oxazm-2-one in moderate yields. N-Acyl or N-(alkoxycarbonyl)alkylamines bearing a leaving group at the β position of the alkyl substituent were converted into 3-substituted-2-oxazolidinones in high yields. By using chiral substrates, enantiopure 3-alkoxycarbonyl(or acyl)-4-substituted oxazolidin-2-ones (70-85% isolated yields) were obtained. This represents a new mild and safe route to these important auxiliaries for asymmetric synthesis. Some limitations of the process are also evidenced and accounted for.
- Casadei, Maria Antonietta,Moracci, Franco Micheletti,Zappia, Giovanni,Inesi, Achille,Rossi, Leucio
-
p. 6754 - 6759
(2007/10/03)
-
- Synthesis of a novel C2-symmetrical (2S,5S)-2,5-bis-[(1,1 -dimethylethoxy) carbonylamino]-1,6-diphenylhex-3-ene: Applications in the synthesis of potential HIV protease inhibitors
-
The synthesis of a novel and versatile (2S,5S)-2,5-bis-[(1,1′-dimethylethoxy)carbonylamino]-1,6-diphenylhex-3-ene (2) based on Julia's olefination strategy coupled with its application in stereoselective preparations of HIV protease inhibitors has been discussed.
- Rama Rao
-
p. 2505 - 2508
(2007/10/02)
-
- Rationally designed 'dipeptoid' analogues of cholecystokinin (CCK): C-terminal structure-activity relationships of α-methyl tryptophan derivatives
-
This paper outlines the synthesis and C-terminal structure-activity relationships (SAR) of a series of α-methyl tryptophanylphenethylamide analogues of the neuropeptide cholecystokinin (CCK).CCK-B and CCK-A receptor binding affinities of these analogues are described and the contributions of the various side chains on the phenethylamide moiety to binding affinity are discussed.Several of the compounds prepared have CCK-B receptor binding affinities similar to that found with the endogenous neuropeptide CCK-26-33 (sulphated) (CCK-B, IC50 = 0.3 nM) and are highly selective over the CCK-A receptor.Amongst the most potent of the compounds synthesized are *,S*)>-β-3,7>dec-2-yloxy)carbonyl>amino>propyl>amino>benzenebutanoic acid 22, *,S*)>-3,7>dec-2-yloxy)carbonyl>amino>propyl>amino>-3-phenylpropyl>thio>acetic acid 28a and *,S*)>-3,7>dec-2-yloxy)carbonyl>amino>propyl>amino>-3-phenylpropyl>sulfonyl>acetic acid 32 which have CCK-B receptor binding affinities of IC50 = 0.3, 0.3 and 0.2 nM with CCK-A/B ratios of 220, 700 and 1000, respectively.CCK-B receptor selective ligands, 22, 28a and 32 were also shown to be potent anatagonists in blocking pentagastrin-evoked excitation in neurons of the rat hypothalamic ventro-medial nucleus (VMN) with the Ke values of 2.8, 23 and 5.9 nM, respectively. Keywords: cholecystokinin / dipeptoid analogues / structure-affinity relationships / α-methyl-tryptophan derivatives / C-terminal
- Boden, P. R.,Eden, J. M.,Higginbottom, M.,Hill, D. R.,Horwell, D. C.,et al.
-
-
- The Palladium-catalyzed Asymmetric Allylations of Chiral Hydrazones Bearing Phosphine Groups. Stereoelectronic Effects of Allylating Reagents on Asymmetric Induction
-
The palladium-catalyzed allylations of chiral hydrazones bearing phosphine groups were executed successfully under neutral reaction conditions with various allylating reagents, affording optically active α-allyl carbonyl compounds.The systematic and stere
- Hiroi, Kunio,Haraguchi, Mitsuhiro,Masuda, Yoko,Abe, Jun
-
p. 2409 - 2412
(2007/10/02)
-
- Potent and systemically active aminopeptidase N inhibitors designed from active-site investigation
-
Derivatives of amino acids bearing various zinc-coordinating moieties (SH, COOH, CONHOH, and PO3H2) were synthesized and tested for their ability to inhibit aminopeptidase N (APN). Among them, β-amino thiols were found to be the most
- Fournie-Zaluski,Coric,Turcaud,Bruetschy,Lucas,Noble,Roques
-
p. 1259 - 1266
(2007/10/02)
-
- The role of hydroxymethyl function on the biological activity of the antitumor antibiotic sparsomycin
-
The synthesis is described of the sparsomycin analogues 11-14 from the L-amino acids valine, isoleucine, phenylalanine and proline, respectively. The sparsomycin derivative 21 was not prepared in a similar way from glycine, but from cystamine following a different reaction route. These analogues, as well as the O-methylated and O-acetylated derivatives 15 and 16, respectively, were tested in vitro for their protein synthesis inhibitory activity and for their inhibition of colony formation of murine leukemia L1210 cells. The results of these assays indicate that the hydroxymethyl function of 1 is not essential for its biological activity, and that increase of lipophilicity in this 'northern' region of 1 does not noticeably affect the activity of the drug.
- Van den Broek,Fennis,Arevalo,Lazaro,Ballesta,Lelieveld,Ottenheijm
-
p. 503 - 510
(2007/10/02)
-
- Opioid Agonists an Antagonists. Peptides Containing N-Terminal Allyl Groups and/or a Thiomethylene Linkage in Place of a Peptide Bond
-
Peptides containing N-allyl or N,N-diallyl groups at the N-terminus have been synthesized as potential opioid antagonists.A number of analogues with an amine bond replaced by a thiomethylene group have also been prepared.In brain binding assays and in gui
- Balboni, Gianfranco,Salvadori, Severo,Marastoni, Mauro,Tomatis, Roberto,Borea, Pier A.,Bianchi, Clementina
-
p. 1645 - 1652
(2007/10/02)
-