共查询到20条相似文献,搜索用时 0 毫秒
1.
Hubbs JL Zhou H Kral AM Fleming JC Dahlberg WK Hughes BL Middleton RE Szewczak AA Secrist JP Miller TA 《Bioorganic & medicinal chemistry letters》2008,18(1):34-38
Ongoing clinical studies indicate that inhibitors of Class I and Class II histone deacetylase (HDAC) enzymes show great promise for the treatment of cancer. Zolinza (SAHA, Zolinza) was recently approved by the FDA for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma. As a part of an ongoing effort to identify novel small molecules to target these important enzymes, we have prepared several classes of amino acid-derived HDAC1 inhibitors. The design rationale and in vitro activity against the HDAC1 enzyme and HCT116 cell line are described in this letter. 相似文献
2.
Lidia A. Baltina Yan-Ting Tasi Su-Hua Huang Hsueh-Chou Lai Svetlana F. Petrova Marat S. Yunusov Cheng-Wen Lin 《Bioorganic & medicinal chemistry letters》2019,29(20):126645
Dengue virus (DENV) is one of the most geographically distributed pathogenic flaviviruses transmitted by mosquitoes Aedes sps. In this study, the structure-antiviral activity relationships of Glycyrrhizic acid (GL) derivatives was evaluated by the inhibitory assays on the cytopathic effect (CPE) and viral infectivity of DENV type 2 (DENV2) in Vero E6 cells. GL (96% purity) had a low cytotoxicity to Vero E6 cells, inhibited DENV2-induced CPE, and reduced the DENV-2 infectivity with the IC50 of 8.1 μM. Conjugation of GL with amino acids or their methyl esters and the introduction of aromatic acylhydrazide residues into the carbohydrate part strongly influenced on the antiviral activity. Among compounds tested GL conjugates with isoleucine 13 and 11-aminoundecanoic acid 17 were found as potent anti-DENV2 inhibitors (IC50 1.2–1.3 μM). Therefore, modification of GL is a perspective way in the search of new antivirals against DENV2 infection. 相似文献
3.
《Bioorganic & medicinal chemistry letters》2014,24(1):349-352
Employing a genetically modified yeast strain as a screening tool, 4-dimethylaminobenzoic acid (5) was isolated from the marine sediment-derived Streptomyces sp. CP27-53 as a weak yeast sirtuin (Sir2p) inhibitor. Using this compound as a scaffold, a series of disubstituted benzene derivatives were evaluated to elucidate the structure activity relationships for Sir2p inhibition. The results suggested that 4-alkyl or 4-alkylaminobenzoic acid is the key structure motif for Sir2p inhibitory activity. The most potent Sir2p inhibitor, 4-tert-butylbenzoic acid (20), among the tested compounds in this study turned out to be a weak but selective SIRT1 inhibitor. The calculated binding free energies between the selected compounds and the catalytic domain of SIRT1 were well correlated to their measured SIRT1 inhibitory activities. 相似文献
4.
Qian K Kim SY Hung HY Huang L Chen CH Lee KH 《Bioorganic & medicinal chemistry letters》2011,21(19):5944-5947
In this study, 22 new betulinic acid (BA) derivatives were synthesized and tested for their inhibition of the chymotrypsin-like activity of 20S proteasome. From the SAR study, we concluded that the C-3 and C-30 positions are the pharmacophores for increasing the proteasome inhibition effects, and larger lipophilic or aromatic side chains are favored at these positions. Among the BA derivatives tested, compounds 13, 20, and 21 showed the best proteasome inhibition activity with IC(50) values of 1.42, 1.56, and 1.80 μM, respectively, which are three to fourfold more potent than the proteasome inhibition controls LLM-F and lactacystin. 相似文献
5.
6.
Oxana B. Kazakova Gul’nara V. Giniyatullina Emil Yu. Yamansarov Genrikh A. Tolstikov 《Bioorganic & medicinal chemistry letters》2010,20(14):4088-4090
The synthesis of new betulin and ursolic acid derivatives and evaluation of their antiviral activity in vitro is reported. Betulin was modified at positions C-3, C-20 and C-28 to afford the derivatives with nicotinoyl-, methoxycynnamoyl-, alkyne and aminopropoxy-2-cyanoethyl-moieties. The two stage conversion of betulin to the new ursane-type triterpenoid by treatment of allobetulin with Ac2O–HClO4 is suggested. Cyanoethylation of ursonic acid oxime led to cyanoethyloximinoderivative. According to the results of antiviral screening against human papillomavirus type 11 the selectivity index for tested triterpenoids has a range from 10 to 35 with no cellular cytotoxicite, the most remarkable activity was found for 3β,28-di-O-nicotinoylbetulin. 3β,28-Dihydroxy-29-norlup-20(30)-yne was also active against HCV replicon (EC50 1.32; EC90 16.82; IC50 12.41; IC90 >20; SI50 9.4; SI90 >1.19). 28-O-Methoxycynnamoylbetulin was active against influenza type A virus (H1N1) (ЕС50 2; IC50 >200; SI >100). 相似文献
7.
Neres J Bonnet P Edwards PN Kotian PL Buschiazzo A Alzari PM Bryce RA Douglas KT 《Bioorganic & medicinal chemistry》2007,15(5):2106-2119
Benzoic acid and pyridine derivatives inhibit recombinant trans-sialidase from Trypanosoma cruzi with I50 values between 0.4 and 1mM. The best compounds, 4-acetylamino-3-hydroxymethylbenzoic acid and 5-acetylamino-6-aminopyridine-2-carboxylic acid, provide new leads to inhibitors not containing the synthetically complex sialic acid structure. The weak inhibition by such compounds contrasts with their much stronger inhibition of neuraminidase from Influenza virus. 相似文献
8.
Kalgutkar AS Rowlinson SW Crews BC Marnett LJ 《Bioorganic & medicinal chemistry letters》2002,12(4):521-524
This paper describes SAR studies involved in the transformation of the NSAID meclofenamic acid into potent and selective cyclooxygenase-2 (COX-2) inhibitors via neutralization of the carboxylate moiety in this nonselective COX inhibitor. 相似文献
9.
《Bioorganic & medicinal chemistry》2014,22(13):3370-3378
The development of remedies against the Alzheimer’s disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30 μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. 相似文献
10.
Gurulingappa H Buckhalts P Kinzler KW Vogelstein B Khan SR 《Bioorganic & medicinal chemistry letters》2004,14(13):3531-3533
Renal dipeptidase (RDP) is an enzyme overexpressed in benign and malignant colorectal tumors. In an effort to identify potent inhibitors of this enzyme, a series of aminophosphinic acid derivatives were synthesized. Compounds 3a and 3c in which the phenyl ring was para substituted with F and Br and olefin with Z geometry, showed better inhibitory activity against RDP enzyme (IC50 = 5-6 nM). 相似文献
11.
Mauro Marastoni Claudio Trapella Alessandra Scotti Anna Fantinati Valeria Ferretti Erika Marzola 《Journal of enzyme inhibition and medicinal chemistry》2017,32(1):865-877
The ubiquitin-proteasome system has been largely investigated for its key role in protein degradation mechanisms that regulate both apoptosis and cell division. Because of their antitumour activity, different classes of proteasome inhibitors have been identified to date. Some of these compounds are currently employed in the clinical treatment of several types of cancer among which multiple myeloma. Here, we describe the design, chemistry, biological activity and modelling studies of a large series of amino acid derivatives linked to a naphthoquinone pharmacophoric group through variable spacers. Some analogues showed interesting inhibitory potency for the β1 and β5 subunits of the proteasome with IC50 values in the sub-µm range. 相似文献
12.
Yuanchao Xie Bing Huang Kexiang Yu Wenfang Xu 《Bioorganic & medicinal chemistry》2013,21(24):7715-7723
Eight series of compounds, each series containing two to five compounds were prepared by structural modifications of a lead, which was previously discovered as a mild influenza neuraminidase (NA) inhibitor. On the basis of the biological result, a detailed structure–activity relationship (SAR) was derived and discussed. Several caffeic acid derivatives that acted as non-competitive inhibitors were close or superior to the lead and also presented good antiviral activities in cells. Besides, it was interesting to find that modifications of the lead with different strategies could result in selective inhibition against N1 or N2. The preliminary docking analysis indicated that the 150-cavity of the enzymes played an important role in the selective inhibition. 相似文献
13.
Fang Wang Wen Lu Tao Zhang Jinyun Dong Hongping Gao Pengfei Li Sicen Wang Jie Zhang 《Bioorganic & medicinal chemistry》2013,21(22):6973-6980
Histone deacetylase inhibitors (HDACIs) offer a promising strategy for cancer therapy. The discovery of potent ferulic acid-based HDACIs with hydroxamic acid or 2-aminobenzamide group as zinc binding group was reported. The halogeno-acetanilide was introduced as novel surface recognition moiety (SRM). The majority of title compounds displayed potent HDAC inhibitory activity. In particular, FA6 and FA16 exhibited significant enzymatic inhibitory activities, with IC50 values of 3.94 and 2.82 μM, respectively. Furthermore, these compounds showed moderate antiproliferative activity against a panel of human cancer cells. FA17 displayed promising profile as an antitumor candidate. The results indicated that these ferulic acid derivatives could serve as promising lead compounds for further optimization. 相似文献
14.
《Bioorganic & medicinal chemistry letters》2014,24(24):5612-5615
A novel series of elemonic acid derivatives were synthesized and evaluated for their inhibitory activity on Pin1. Five compounds displayed significantly improved ability to inhibit Pin1 activity at micromolar levels. Compound 10 with 2-carboxylmethylene was the most active one with an IC50 value of 0.57 μM. The docking models of Pin1 support that introduction of an acidic group to elemonic acid enhance the Pin1 inhibitory activity. 相似文献
15.
Zhao H Holmes SS Baker GA Challa S Bose HS Song Z 《Journal of enzyme inhibition and medicinal chemistry》2012,27(5):715-721
Betulinic acid is a natural product possessing abundant and favourable biological activity, including anti-cancer, anti-malarial, anti-inflammatory and anti-HIV properties, while causing minimal toxicity to unaffected cells. The full biological potency of betulinic acid cannot be fully unlocked, however, for a number of reasons, a primary one being its limited solubility in aqueous and biologically pertinent organic media. Aiming to improve the water solubility of betulinic acid without disrupting its structurally related bioactivity, we have prepared different ionic derivatives of betulinic acid. Inhibition bioassays on HIV-1 protease-catalysed peptide hydrolysis indicate significantly improved performance resulting from converting the betulinic acid to organic salt form. Indeed, for one particular cholinium-based derivative, its water solubility is improved more than 100 times and the half maximal inhibitory concentration (IC(50)) value (22 μg mL(-1)) was one-third that of wide-type betulinic acid (60 μg mL(-1)). These encouraging results advise that additional studies of ionic betulinic acid derivatives as a therapeutic solution against HIV-1 infection are warranted. 相似文献
16.
Su T Wu Y Doughan B Kane-Maguire K Marlowe CK Kanter JP Woolfrey J Huang B Wong P Sinha U Park G Malinowski J Hollenbach S Scarborough RM Zhu BY 《Bioorganic & medicinal chemistry letters》2001,11(17):2279-2282
A series of glycolic and mandelic acid derivatives was synthesized and investigated for their factor Xa inhibitory activity. These analogues are highly potent and selective inhibitors against fXa. In a rabbit deep vein thrombosis model, compound 26 showed significant antithrombotic effects (81% inhibition of thrombus formation) at 1.1 microM plasma concentration following intravenous administration. 相似文献
17.
Peptide deformylase catalyzes the removal of N-formyl group from the N-formylmethionine of ribosome synthesized polypeptide in eubacteria. Quantitative structure–activity relationship (QSAR) studies have been carried out in a series of β-sulfonyl and β-sulfinyl hydroxamic acid derivatives for their PDF enzyme inhibitory and antibacterial activities against Escherichia coli DC2 and Moraxella catarrhalis RA21 which demonstrate that the PDF inhibitory activity in cell free and whole cell system increases with increase in molar refractivity and hydrophobicity. The comparison of the QSARs between the cell free and whole cell system indicate that the active binding sites in PDF isolated from E. coli and in M. catarrhalis RA21 are similar and the whole cell antibacterial activity is mainly due to the inhibition of PDF. Apart from this the QSARs on some matrixmetelloproteins (COL-1, COL-3, MAT and HME) and natural endopeptidase (NEP) indicate the possibilities of introducing selectivity in these hydroxamic acid derivatives for their PDF inhibitory activity. 相似文献
18.
Zaheer- Ul-Haq Abdul Wadood Reaz Uddin 《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):272-278
Urease (EC 3.5.1.5) serves as a virulence factor in pathogens that are responsible for the development of many diseases in humans and animals. Urease allows soil microorganisms to use urea as a source of nitrogen and aid in the rapid break down of urea-based fertilizers resulting in phytopathiCIT000y. It has been well established that hydroxamic acids are the potent inhibitors of urease activity. The 3D-QSAR studies on thirty five hydroxamic acid derivatives as known urease inhibitors were performed by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods to determine the factors required for the activity of these compounds. The CoMFA model produced statistically significant results with cross-validated (q2) 0.532 and conventional (r2) correlation coefficients 0.969.The model indicated that the steric field (70.0%) has greater influence on hydroxamic acid inhibitors than the electrostatic field (30.0%). Furthermore, five different fields: steric, electrostatic, hydrophobic, H-bond donor and H-bond acceptor assumed to generate the CoMSIA model, which gave q2 0.665 and r2 0.976.This model showed that steric (43.0%), electrostatic (26.4%) and hydrophobic (20.3%) properties played a major role in urease inhibition. The analysis of CoMFA and CoMSIA contour maps provided insight into the possible modification of the hydroxamic acid derivatives for improved activity. 相似文献
19.
Urease (EC 3.5.1.5) serves as a virulence factor in pathogens that are responsible for the development of many diseases in humans and animals. Urease allows soil microorganisms to use urea as a source of nitrogen and aid in the rapid break down of urea-based fertilizers resulting in phytopathicity. It has been well established that hydroxamic acids are the potent inhibitors of urease activity. The 3D-QSAR studies on thirty five hydroxamic acid derivatives as known urease inhibitors were performed by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods to determine the factors required for the activity of these compounds. The CoMFA model produced statistically significant results with cross-validated (q(2)) 0.532 and conventional (r(2)) correlation coefficients 0.969.The model indicated that the steric field (70.0%) has greater influence on hydroxamic acid inhibitors than the electrostatic field (30.0%). Furthermore, five different fields: steric, electrostatic, hydrophobic, H-bond donor and H-bond acceptor assumed to generate the CoMSIA model, which gave q(2) 0.665 and r(2) 0.976.This model showed that steric (43.0%), electrostatic (26.4%) and hydrophobic (20.3%) properties played a major role in urease inhibition. The analysis of CoMFA and CoMSIA contour maps provided insight into the possible modification of the hydroxamic acid derivatives for improved activity. 相似文献
20.
Segall Y Quistad GB Nomura DK Casida JE 《Bioorganic & medicinal chemistry letters》2003,13(19):3301-3303
Arachidonylsulfonyl fluoride (3), reported here for the first time, is similar in potency to its known methyl arachidonylfluorophosphonate (2) analogue as an inhibitor of mouse brain fatty acid amide hydrolase activity (IC(50) 0.1 nM) and cannabinoid CB1 agonist [3H]CP 55,940 binding (IC(50) 304-530 nM). Interestingly, 3 is much more selective than 2 as an inhibitor for fatty acid amide hydrolase relative to acetylcholinesterase, butyrylcholinesterase and neuropathy target esterase. N-(2-Hydroxyethyl)arachidonylsulfonamide (4) is at least 2500-fold less potent than N-(2-hydroxyethyl)arachidonamide (anandamide) (1) at the CB1 agonist site. 相似文献