排序方式: 共有12条查询结果,搜索用时 888 毫秒
1.
A number of structurally related sugar amino acid systems have been examined by chiroptical methods to aid interpretation of their conformational preference. The use of circular dichroism, in addition to NMR and solution IR, has enabled classification of the conformations adopted by sugar amino acid systems as hydrogen-bonded regular, non-hydrogen-bonded regular, and non-hydrogen-bonded irregular. A set of tetrameric SAAs are examined and the effect of change in primary structure related to conformation. 相似文献
2.
Krehan D Frølund B Krogsgaard-Larsen P Kehler J Johnston GA Chebib M 《Neurochemistry international》2003,42(7):561-565
A number of amino acids bioisosterically derived from the specific GABAA agonist, isonipecotic acid, were electrophysiologically characterized as antagonists at GABAC ρ1 receptors expressed in Xenopus oocytes. The phosphinic acid analogue of isonipecotic acid, piperidin-4-ylphosphinic acid (2), was comparable with the standard GABAC antagonist, (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA), in terms of potency and GABAC versus GABAA receptor selectivity. Whereas the phosphonic acid analogue, piperidin-4-ylphosphonic acid (4), was at least an order of magnitude weaker than piperidin-4-ylphosphinic acid as a GABAC antagonist, the seleninic acid analogue, piperidin-4-ylseleninic acid (SEPI, 6), was the most potent and selective GABAC antagonist within the group of isonipecotic acid derived amino acids studied. 相似文献
3.
Heinrich Rueeger Rainer Lueoend Rainer Machauer Siem Jacob Veenstra Laura Helen Jacobson Matthias Staufenbiel Sandrine Desrayaud Jean-Michel Rondeau Henrik Möbitz Ulf Neumann 《Bioorganic & medicinal chemistry letters》2013,23(19):5300-5306
Previous structure based optimization in our laboratories led to the identification of a novel, high-affinity cyclic sulfone hydroxyethylamine-derived inhibitor such as 1 that lowers CNS-derived Aβ following oral administration to transgenic APP51/16 mice. Herein we report SAR development in the S3 and S2′ subsites of BACE1 for cyclic sulfoxide hydroxyethyl amine inhibitors, the synthetic approaches employed in this effort, and in vivo data for optimized compound such as 11d. 相似文献
4.
Mariana Concei??o Souza Tatiana Almeida Padua Natalia Domingos Torres Maria Fernanda de Souza Costa Victor Facchinetti Claudia Regina Brand?o Gomes Marcus Vinícius Nora Souza Maria das Gra?as Henriques 《Memórias do Instituto Oswaldo Cruz》2015,110(4):560-565
A rapid decrease in parasitaemia remains the major goal for new antimalarial drugs
and thus, in vivo models must provide precise results concerning parasitaemia
modulation. Hydroxyethylamine comprise an important group of alkanolamine compounds
that exhibit pharmacological properties as proteases inhibitors that has already been
proposed as a new class of antimalarial drugs. Herein, it was tested the antimalarial
property of new nine different hydroxyethylamine derivatives using the green
fluorescent protein (GFP)-expressing Plasmodium berghei strain. By
comparing flow cytometry and microscopic analysis to evaluate parasitaemia
recrudescence, it was observed that flow cytometry was a more sensitive methodology.
The nine hydroxyethylamine derivatives were obtained by inserting one of the
following radical in the para position: H, 4Cl, 4-Br, 4-F, 4-CH3,
4-OCH3, 4-NO2, 4-NH2 and 3-Br. The antimalarial test showed that the compound that
received the methyl group (4-CH3) inhibited 70% of parasite growth. Our results
suggest that GFP-transfected P. berghei is a useful tool to study the recrudescence
of novel antimalarial drugs through parasitaemia examination by flow cytometry.
Furthermore, it was demonstrated that the insertion of a methyl group at the
para position of the sulfonamide ring appears to be critical for
the antimalarial activity of this class of compounds. 相似文献
5.
McConnell Rose M. Godwin Walter E. Stefan Amy Newton Crystal Myers Nikki Hatfield Susan E. 《International journal of peptide research and therapeutics》2003,10(2):69-78
Summary Cathepsin D, a lysosomal aspartic protease, has been suggested to play a role in the metastatic potential of several types
of cancer. A high activated cathepsin D level in breast tumor tissue has been associated with an increased incidence of relapse
and metastasis. High levels of active cathepsin D have also been found in colon cancer, prostate cancer, uterine cancer and
ovarian cancer. Hydroxyethyl isosteres with cyclic tertiary amine have proven to be clinically useful as inhibitors of aspartyl
proteases similar to cathepsin D in activity, such as the HIV-1 aspartyl protease. The design and the synthesis of (hydroxyethyl)amine
isostere inhibitors with cyclic tertiary amines is described. The IC50 and Ki(app) values for the six cathepsin D inhibitors and pepstatin are reported. Compounds7b,3(S)-[Acetyl-L-valyl-L-phenylalanylamino]-4-phenyl-1-N-piperidine-2(S)-butanol, and7c, 3(S)-[Acetyl-L-leucyl-L-phenylalanylamino]-4-phenyl-1-N-piperidine-2(S)-butanol, showed the most potent inhibition of cathepsin
D hydrolysis of hemoglobin with IC50 values of 3.5 nM and 4.5 nM, respectively. 相似文献
6.
《Bioorganic & medicinal chemistry》2020,28(22):115731
The medicinal chemist toolbox is plenty of (bio)isosteres when looking for a carboxylic acid replacement. However, systematic assessment of acid surrogates is often time consuming and expensive, while prediction of both physicochemical properties (logP and logD) as well as acidity would be desirable at early discovery stages for a better analog design. Herein in this work, to enable decision making on a project, we have synthesized by employing a Diversity-Oriented Synthetic (DOS) methodology, a small library of molecular fragments endowed with acidic properties. By combining in-silico and experimental methodologies these compounds were chemically characterized and, particularly, with the aim to know their physicochemical properties, the aqueous ionization constants (pKa), partition coefficients logD and logP of each fragment was firstly estimated by using molecular modeling studies and then validated by experimental determinations. A face to face comparison between data and the corresponding carboxylic acid might help medicinal chemists in finding the best replacement to be used. Finally, in the framework of Fragment Based Drug Design (FBDD) the small library of fragments obtained with our approach showed good versatility both in synthetic and physico-chemical properties. 相似文献
7.
Hygor M. R. de Souza Jssica S. Guedes Rosana H. C. N. Freitas Luis G. V. Gelves Harold H. Fokoue Carlos Mauricio R. SantAnna Eliezer J. Barreiro Lidia M. Lima 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):718
Esters are one of the major functional groups present in the structures of prodrugs and bioactive compounds. Their presence is often associated with hydrolytic lability. In this paper, we describe a comparative chemical and biological stability of homologous esters and isosteres in base media as well as in rat plasma and rat liver microsomes. Our results provided evidence for the hydrolytic structure lability relationship and demonstrated that the hydrolytic stability in plasma and liver microsome might depend on carboxylesterase activity. Molecular modelling studies were performed in order to understand the experimental data. Taken together, the data could be useful to design bioactive compounds or prodrugs based on the correct choice of the ester subunit, addressing compounds with higher or lower metabolic lability. 相似文献
8.
《Bioorganic & medicinal chemistry》2016,24(9):1993-2010
The use of arginine isosteres is a known strategy to overcome poor membrane permeability commonly associated with peptides or peptidomimetics that possess this highly polar amino acid. Here, we apply this strategy to peptidomimetics that are potent inhibitors of the malarial protease, plasmepsin V, with the aim of enhancing their activity against Plasmodium parasites, and exploring the structure–activity relationship of the P3 arginine within the S3 pocket of plasmepsin V. Of the arginine isosteres trialled in the P3 position, we discovered that canavanine was the ideal and that this peptidomimetic potently inhibits plasmepsin V, efficiently blocks protein export and inhibits parasite growth. Structure studies of the peptidomimetics bound to plasmepsin V provided insight into the structural basis for the enzyme activity observed in vitro and provides further evidence why plasmepsin V is highly sensitive to substrate modification. 相似文献
9.
Yuezhou Zhang Mikael Jumppanen Mirko M. Maksimainen Samuli Auno Zulfa Awol Léo Ghemtio Harikanth Venkannagari Lari Lehtiö Jari Yli-Kauhaluoma Henri Xhaard Gustav Boije af Gennäs 《Bioorganic & medicinal chemistry》2018,26(8):1588-1597
The human O-acetyl-ADP-ribose deacetylase MDO1 is a mono-ADP-ribosylhydrolase involved in the reversal of post-translational modifications. Until now MDO1 has been poorly characterized, partly since no ligand is known besides adenosine nucleotides. Here, we synthesized thirteen compounds retaining the adenosine moiety and bearing bioisosteric replacements of the phosphate at the ribose 5′-oxygen. These compounds are composed of either a squaryldiamide or an amide group as the bioisosteric replacement and/or as a linker. To these groups a variety of substituents were attached such as phenyl, benzyl, pyridyl, carboxyl, hydroxy and tetrazolyl. Biochemical evaluation showed that two compounds, one from both series, inhibited ADP-ribosyl hydrolysis mediated by MDO1 in high concentrations. 相似文献
10.
《Bioorganic & medicinal chemistry letters》2020,30(17):127388
Heroin overdose and addiction remain significant health and economic burdens in the world today costing billions of dollars annually. Moreover, only limited pharmacotherapeutic options are available for treatment of heroin addiction. In our efforts to combat the public health threat posed by heroin addiction, we have developed vaccines against heroin. To expand upon our existing heroin-vaccine arsenal, we synthesized new aryl and alkyl sulfonate ester haptens; namely aryl-mono-sulfonate (HMsAc) and Aryl/alkyl-di-sulfonate (H(Ds)2) as carboxyl-isosteres of heroin then compared them to our model heroin-hapten (HAc) through vaccination studies. Heroin haptens were conjugated to the carrier protein CRM197 and the resulting CRM-immunoconjugates were used to vaccinate Swiss Webster mice following an established immunization protocol. Binding studies revealed that the highest affinity anti-heroin antibodies were generated by the HMsAc vaccine followed by the HAc and H(Ds)2 vaccines, respectively (HMsAc > HAc≫HDs2). However, neither the HMsAc nor H(Ds)2 vaccines were able to generate high affinity antibodies to the psychoactive metabolite 6-acetyl morphine (6-AM), in comparison to the HAc vaccine. Blood brain bio-distribution studies supported these binding results with vaccine efficiency following the trend HAc > HMsAc ≫ H(Ds)2 The work described herein provides insight into the use of hapten-isosteric replacement in vaccine drug design. 相似文献