共查询到20条相似文献,搜索用时 31 毫秒
1.
Kovac A Wilson RA Besra GS Filipic M Kikelj D Gobec S 《Journal of enzyme inhibition and medicinal chemistry》2006,21(4):391-397
Four new sulfonates were prepared as potential inhibitors of antigen 85C, a mycolyl transferase involved in the biosynthesis of the mycobacterial cell wall being designed on the basis of the proposed catalytic mechanism and antigen 85C crystal structure. The inhibitors contained a sulfonate moiety, 3-phenoxybenzyl alcohol or N-(hydroxyethyl)phthalimide as trehalose mimetics, and an alkyl chain of different length mimicking either the mycolate (alpha-chain or the mycolic acid (beta-branch. One compound displayed promising activity in a mycolyltransferase inhibition assay (compound 2b, IC50 = 4.3 microM). The two compounds containing a phthalimide moiety (compounds 3a and 3b) showed significant and selective cytotoxicity against the breast cancer cell line MDA-MB231. 相似文献
2.
Ahmed Malki Hayam M. A. Ashour Doaa A. E. Issa Hassan A. Aziz Xiaozhuo Chen 《Journal of enzyme inhibition and medicinal chemistry》2016,31(6):1286-1299
Novel 1,5-diphenyl-6-substituted-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones were synthesized and characterized. All compounds were screened for their anti-proliferative activities in five different cancer cell lines. The results showed that compounds 7a and 7b comprising aminoguanidino or guanidino moiety at position 6 inhibited proliferation of RKO colon cancer cells with IC50 of 8 and 4?μM, respectively. Compounds 7a and 7b induced apoptosis in RKO cells, which was confirmed by TUNEL and annexin V-FITC assays. Flow cytometric analysis indicated that compounds 7a and 7b arrested RKO cells in the G1 phase and the most active compound 7b increased levels of p53, p21, Bax, ERK1/2 and reduced levels of Bcl2 and Akt. Compound 7b also activates release of cytochrome c, which is consistent with activation of caspase-9. Additionally, compound 7b increased caspase-3 activity and cleaved PARP-1 in RKO cells. Collectively, these findings could establish a molecular basis for the development of new anti-cancer agents. 相似文献
3.
Morgane Lardic Cedric Patry Muriel Duflos Jean Guillon Stephane Massip Francisco Cruzalegui 《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):313-325
New series of 2(or 3)-arylmethylenenaphtho[2,1-b]furan-3(or 2)-ones were synthesized, characterized and tested for anticancer properties in vitro. The target compounds were prepared by Knoevenagel coupling between the naphthofuranones 3, 28–30 and formyl derivatives. 2-(4-Oxo-1-benzopyran-3-ylmethylene)naphtho[2,1-b]furan-3-one 36 was the most active compound (IC50 (L1210) = 1.6 μM). These compounds were also evaluated, in an independent manner, as inhibitors of Src protein tyrosine kinase, but only minor activity was observed. 相似文献
4.
Jufeng Sun Suwen Wang Hongjuan Li Wenguo Jiang Guige Hou Feng Zhao 《Journal of enzyme inhibition and medicinal chemistry》2016,31(3):495-502
Novel N-aroyl-α,β-unsaturated piperidones, series 1, series 2 and series 3 (featuring 2-bromo-4,5-dimethoxybenzylidene, 4-dimethylaminobenzylidene and 4-trifluoromethylbenzylidene, respectively), were synthesized as candidate cytotoxins. Most of the compounds displayed potent cytotoxicity against the human neoplastic cell lines SK-BR-3, PG-BE1, NCI-H460, MIA PaCa-2 and SW1990 in vitro, and approximately 64% of the IC50 values were lower than 5?μM. Among those tested, compound 1b of series 1, 3a, 3d and 3e of series 3 proved to be the most active. Importantly, 1b displayed marked inhibitory effects on tumor growth in vivo and had no apparent toxicity to mice; this was evaluated by a nude mouse PG-BE1 xenograft model. In addition, the fluorescent properties of compounds series 1–3 were investigated. The interesting fluorescence exhibited by these compounds could be useful for their visualization in tumor cells, permitting further studies on these α,β-unsaturated piperidones as candidates for novel fluorescent antitumor agents. 相似文献
5.
Bassem H. Naguib 《Journal of enzyme inhibition and medicinal chemistry》2016,31(6):1718-1725
Three series of 5-bromo-thieno[2,3-b]pyridines bearing amide or benzoyl groups at position 2 were prepared as pim-1 inhibitors. All the prepared compounds were tested for their pim-1 enzyme inhibitory activity. Two compounds (3c and 5b) showed moderate pim-1 inhibitory activity with IC50 of 35.7 and 12.71?μM, respectively. Three other compounds (3d, 3g and 6d) showed poor pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on five cell lines [MCF7, HEPG2, HCT116, A549 and PC3]. Compound 3g was the most potent cytotoxic agent on almost all the cell lines tested. 相似文献
6.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(4):717-726
Aminopeptidase N (APN/CD13) is one of the essential proteins for tumour invasion, angiogenesis and metastasis as it is over-expressed on the surface of different tumour cells. Based on our previous work that L-isoserine dipeptide derivatives were potent APN inhibitors, we designed and synthesized L-isoserine tripeptide derivatives as APN inhibitors. Among these compounds, one compound 16l (IC50?=?2.51?±?0.2 µM) showed similar inhibitory effect compared with control compound Bestatin (IC50?=?6.25?±?0.4 µM) and it could be used as novel lead compound for the APN inhibitors development as anticancer agents in the future. 相似文献
7.
Adel S. El-Azab Alaa A.-M. Abdel-Aziz Laila A. Abou-Zeid Walaa M. El-Husseiny Ahmad M. El_Morsy Manal A. El-Gendy 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):989-998
A new series of NSAID thioesters were synthesized and evaluated for their in vitro antitumor effects against a panel of four human tumor cell lines, namely: HepG2, MCF-7, HCT-116 and Caco-2, using the MTT assay. Compared to the reference drugs 5-FU, afatinib and celecoxib, compounds 2b, 3b, 6a, 7a, 7b and 8a showed potent broad-spectrum antitumor activity against the selected tumour cell lines. Accordingly, these compounds were selected for mechanistic studies about COX inhibition and kinase assays. In vitro COX-1/COX-2 enzyme inhibition assay results indicated that compounds 2b, 3b, 6a, 7a, 7b, 8a and 8?b selectively inhibited the COX-2 enzyme (IC50?=?~0.20–0.69?μM), with SI values of (>72.5–250) compared with celecoxib (IC50?=?0.16?μM, COX-2 SI:?>?312.5); however, all the tested compounds did not inhibit the COX-1 enzyme (IC50?>?50?μM). On the other hand, EGFR, HER2, HER4 and cSrc kinase inhibition assays were evaluated at a 10?μM concentration. The selected candidates displayed limited activities against the various tested kinases; the compounds 2a, 3b, 6a, 7a, 7b and 8a showed no activity to weak activity (% inhibition?=?~0–10%). The molecular docking study revealed the importance of the thioester moiety for the interaction of the drugs with the amino acids in the active sites of COX-2. The aforementioned results indicated that thioester based on NSAID scaffolds derivatives may serve as new antitumor compounds. 相似文献
8.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(4):853-862
New furanone derivatives incorporating the indolin-2-one moiety 3 were prepared via the Perkin reaction of isatins 1 with aroylpropionic acids 2 under conventional conditions or microwave irradiation. A series of functionally heterocyclic derivatives (e.g., pyridazines, pyrroles, and sulfonamides) incorporating the indolin-2-one moiety was achieved via reaction of 3 with different reagents under microwave irradiation conditions. The newly synthesized compounds were characterized on the basis of FTIR, 1H, 13C NMR and mass spectral studies. Some of the new synthesized compounds were screened for antibacterial activity against Gram-positive bacteria (Staphylococcus aureus and Bacillus cereus), Gram-negative bacteria (Escherichia coli and Shigilla flexneri) and antifungal activity against Aspergillus flavus and Candida albicans. Compound 8 j was equipotent to chloramphenicol in inhibiting the growth of E. coli minimum inhibitory concentration (MIC 2.5 μg/mL). Compound 8j may possibly be used as a lead compound for developing a new antibacterial agents. The antibacterial activity is expressed as the corresponding MIC (μg/mL) values. 相似文献
9.
Mange R. Yadav Anil K. Shinde Bishram S. Chouhan Rajani Giridhar Robert Menard 《Journal of enzyme inhibition and medicinal chemistry》2013,28(2):190-197
Cathepsins have been found to have important physiological roles. The implication of cathepsin L in various types of cancers is well established. In a search for selective cathepsin L inhibitors as anticancer agents, a series of 2-cyanoprrolidine peptidomimetics, carrying a nitrile group as warhead, were designed. Two series of compounds, one with a benzyl moiety and a second with an isobutyl moiety at P2 position of the enzyme were synthesized. The synthesized compounds were evaluated for inhibitory activity against human cathepsin L and cathepsin B. Although, none of the compounds showed promising inhibitory activity, (E)N-{(S)1-[(S)2-cyano-1-pyrrolidinecarbonyl]-3-methylbutyl}-2,3-diphenylacrylamide (24) with an isobutyl moiety at P2 was found to show selectivity as a cathepsin L inhibitor (Ki 5.3 μM for cathepsin L and Ki > 100 μM for cathepsin B). This compound could act as a new lead for the further development of improved inhibitors within this inhibitor type. 相似文献
10.
Wissam H. Faour Mohamed Mroueh Costatantine F. Daher Hanan M. Ragab Asser I. Ghoneim 《Journal of enzyme inhibition and medicinal chemistry》2016,31(6):1079-1094
Four series of new bipyrazoles comprising the N-phenylpyrazole scaffold linked to polysubstituted pyrazoles or to antipyrine moiety through different amide linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory and analgesic activities. In vitro COX-1/COX-2 inhibition study revealed that compound 16b possessed the lowest IC50 value against both COX-1 and COX-2. Moreover, the effect of the most promising compounds on inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) protein expression in lipopolysaccharide (LPS)-activated rat monocytes was also investigated. The results revealed that some of the synthesized compounds showed anti-inflammatory and/or analgesic activity with less ulcerogenic potential than the reference drug diclofenac sodium and are well tolerated by experimental animals. Moreover, they significantly inhibited iNOS and COX-2 protein expression induced by LPS stimulation. Compounds 16b and 18 were proved to display anti-inflammatory activity superior to diclofenac sodium and analgesic activity equivalent to it with minimal ulcerogenic potential. 相似文献
11.
Ashraf F. Zaher Suzan M. Abuel-Maaty Samir A.S. Amer Tamer M. Abdelghany 《Journal of enzyme inhibition and medicinal chemistry》2016,31(6):145-153
AbstractThree series of benzothiophene derivatives were designed and synthesized as cytotoxic agents. The compounds were subjected to in vitro antitumor screening at the National Cancer Institute (NCI), Bethesda, MD. The results of the single dose screening indicated that only the benzothieno[3,2-b]pyran series 3a–f exhibited potent and broad spectrum cytotoxic activity and was subjected to five dose cytotoxic screening. The most active compound in this study was 2-amino-6-bromo-4-(4-nitrophenyl)-4H-[1]benzothieno[3,2-b]pyran-3-carbonitrile (3e) with MG-MID GI50, TGI, and LC50 values of 0.11, 7.94 and 42.66?μM, respectively. Compound 3e exhibited broad spectrum anticancer activity against a panel of 59 cell lines. To elucidate the underlying mechanism of compound 3e cytotoxic activity, we examined its effect on cell cycle progression and its ability to induce apoptosis using human colon adenocarcinoma cell line (HCT-116). The effect of compound 3e on the cell cycle progression indicated that exposure of HCT-116 cells to compound 3e for 24 and 48?h, induced a significant disruption in the cell cycle profile including time dependent decrease in cell population at G1 phase with concomitant increase in pre-G and G2/M cell population. Moreover, compound 3e induced time dependent increase in the percentage of early and late apoptotic and necrotic cell population. In conclusion, we were able to successfully design a new series of benzothieno[3,2-b]pyran derivatives with potent cytotoxic activity and their mechanism of cytotoxicity was examined. 相似文献
12.
Phoebe F. Lamie John N. Philoppes Amany A. Azouz Nesreen M. Safwat 《Journal of enzyme inhibition and medicinal chemistry》2017,32(1):805-820
Nineteen new compounds containing tetrazole and/or cyanamide moiety have been designed and synthesised. Their structures were confirmed using spectroscopic methods and elemental analyses. Anti-inflammatory activity for all the synthesised compounds was evaluated in vivo. The most active compounds 4c, 5a, 5d–f, 8a and b and 9a and b were further investigated for their ulcerogenic liability and analgesic activity. Pyrazoline derivatives 9b and 8b bearing trimethoxyphenyl part and SO2NH2 or SO2Me pharmacophore showed equal or nearly the same ulcerogenic liability (UI: 0.5, 0.75, respectively), to celecoxib (UI: 0.50). Most of tested compounds showed potent central and/or peripheral analgesic activities. Histopathological investigations were done to evaluate test compounds effect on rat's gastric tissue. The obtained results were in consistent with the in vitro data on COX evaluation. Docking study was also done for all the target compounds inside COX-2-active site. 相似文献
13.
Zhiqiang Ge Chunyan Chen Qin Liao Hualong Wu Xiaofei Liu 《Journal of enzyme inhibition and medicinal chemistry》2016,31(2):219-228
A series of novel 3-substituted amino-4-hydroxycoumarin derivatives have been designed and synthesized as chitin synthase (CHS) inhibitors. All the synthesized compounds have been screened for their CHS inhibition activity and antimicrobial activity in vitro. The enzymatic assay indicated that most of the compounds have good inhibitory activity against CHS, in which compound 6o with IC50 of 0.10?mmol/L had stronger activity than that of polyoxins B, which acts as control drug with IC50 of 0.18?mmol/L. As far as the antifungal activity is concerned, most of the compounds possessed moderate to excellent activity against some representative pathogenic fungi. Especially, compound 6b was found to be the most potent agent against Cryptococcus neoformans with minimal inhibitory concentration (MIC) of 4?μg/mL. Moreover, the results of antibacterial screening showed that these compounds have negligible actions to some tested bacteria. Therefore, these compounds would be promising to develop selective antifungal agents. 相似文献
14.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):767-776
Dual cyclooxygenase/lipoxygenase (COX/LOX) inhibitors constitute a valuable alternative to classical nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors for the treatment of inflammatory diseases. A series of 3-(5-phenyl/phenylamino-[1,3,4]oxadiazol-2-yl)-chromen-2-one and N-[5-(2-oxo-2H-chromen-3-yl)-[1,3,4]oxadiazol-2-yl]-benzamide derivatives were synthesized and screened for anti-inflammatory, analgesic activity. All the derivatives prepared are active in inhibiting oedema induced by carrageenan. Compound 4e was found more potent with 89% of inhibition followed by compound 4b (86%). Compounds with >70% of anti-inflammatory activity were tested for analgesic, ulcerogenic, and lipid peroxidation profile. Selected compounds were also evaluated for inhibition of COXs (COX-1 and COX-2) and LOXs (LOX-5, LOX-12, and LOX-15). Compound 4e was comparatively selective for COX-2, LOX-5, and LOX-15. Study revealed that these derivatives were more effective than ibuprofen with reduced side effects. It can be suggested that these derivatives could be used to develop more potent and safer NSAIDs. 相似文献
15.
Carlotta Granchi Flavio Rizzolio Vittorio Bordoni Isabella Caligiuri Clementina Manera Marco Macchia 《Journal of enzyme inhibition and medicinal chemistry》2016,31(1):137-146
This study reports on a preliminary structure–activity relationship exploration of 4-aryliden-2-methyloxazol-5(4H)-one-based compounds as MAGL/FAAH inhibitors. Our results highlight that this scaffold may serve for the development of selective MAGL inhibitors. A 69-fold selectivity against MAGL over FAAH was achieved for compound 16b (MAGL and FAAH IC50?=?1.6 and 111?µM, respectively). Furthermore, the best compound behaved as a reversible ligand and showed promising antiproliferative activity in cancer cells. 相似文献
16.
Fatih Sonmez Belma Zengin Kurt Isil Gazioglu Aydan Dag Valentina Cappello 《Journal of enzyme inhibition and medicinal chemistry》2017,32(1):285-297
New coumaryl-thiazole derivatives with the acetamide moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and in vitro tested as acetylcholinesterase (AChE) inhibitors. 2-(diethylamino)-N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)acetamide (6c, IC50 value of 43?nM) was the best AChE inhibitor with a selectivity index of 4151.16 over BuChE. Kinetic study of AChE inhibition revealed that 6c was a mixed-type inhibitor. Moreover, the result of H4IIE hepatoma cell toxicity assay for 6c showed negligible cell death. Molecular docking studies were also carried out to clarify the inhibition mode of the more active compounds. Best pose of compound 6c is positioned into the active site with the coumarin ring wedged between the residues of the CAS and catalytic triad of AChE. In addition, the coumarin ring is anchored into the gorge of the enzyme by H-bond with Tyr130. 相似文献
17.
《Bioscience, biotechnology, and biochemistry》2013,77(12):2351-2358
A series of polyphenolic curcumin analogs were synthesized and their inhibitory effects on mushroom tyrosinase and the inhibition of 1,1-diphenyl-2-picryl-hydrazyl (DPPH) free radical formation were evaluated. The results indictated that the analogs possessing m-diphenols and o-diphenols exhibited more potent inhibitory activity on tyrosinase than reference compound rojic acid, and that the analogs with o-diphenols exhibited more potent inhibitory activity of DPPH free-radical formation than reference compound vitamin C. The inhibition kinetics, analyzed by Lineweaver–Burk plots, revealed that compounds B2 and C2 bearing o-diphenols were non-competitive inhibitors, while compounds B11 and C11 bearing m-diphenols were competitive inhibitors. In particular, representative compounds C2 and B11 showed no side effects at a dose of 2,000 mg/kg in a preliminary evaluation of acute toxicity in mice. These results suggest that such polyphenolic curcumin analogs might serve as lead compounds for further design of new potential tyrosinase inhibitors. 相似文献
18.
B. K. Sharma P. Singh R. Kumar Susheela Sharma 《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):50-55
Abstract GPR119 is a promising target for discovery of anti-type 2 diabetes mellitus agents. We described the optimisation of a novel series of pyrimido[5,4-b][1,4]oxazine derivatives as GPR119 agonists. Most designed compounds exhibited good agonistic activities. Among them, compound 10 and 15 demonstrated the potent EC50 values (13 and 12?nM, respectively) and strong inherent activities. Moreover, significant hypoglycaemic effect of compound 15 was observed by reducing the blood glucose AUC0–2h at the dose of 30?mg/kg, which is stronger than Vildagliptin (23.4% reduction vs. 17.9% reduction). 相似文献
19.
Igor A. Mikhailopulo Grigorii G. Sivets Tamara I. Pricota Nicolai E. Poopeiko Jan Balzarini Erik De Clercq 《Nucleosides, nucleotides & nucleic acids》2013,32(8):1743-1757
Abstract The oxidation of methyl 5–0-benzyl-3-deoxy-3-fluoro-α-D-arabi-nofuranoside (1) with DMSO/Ac2o afforded a ~ 2:1 mixture of 2-keto derivatives with erythro and threo configuration resulting from isomerization at C3. Successive treatment of the above mixture with MeONH2, LiA1H4, and S-ethyl trifluoroacetate followed by silica gel chromatography afforded methyl 5–0-benzyl-2, 3-dideoxy-3-fluoro-2-(trifluoroacetamido)-α-D-ribofuranoside (6b) and its lyxo isomer 7b in a total yield of 25% and 5%, respectively. The arabino analogue 25 was prepared from 6b. Compounds 6b, 7b and 25 were converted to the corresponding 5–0-benzoyl derivatives 8a, 9 and 26. A series of 2′-amino-2′, 3′-dideoxy-3′-fluoro-β-D-ribo- and-α-D-lyxofuranosides of natural heterocyclic bases have been synthesized starting from 8a and 9. None of the test compounds had any antiviral activity. 3′-Fluoro-2′-amino-2′, 3′-dideoxycytidine (16) was the only compound showing inhibition of murine L1210 and human Molt/4F cell proliferation (50% effective concentration: 39–42μg/m1). 相似文献
20.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(4):598-602
In this study, a series of novel 3-(substituted phenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]isoxazole analogues were synthesized and evaluated for antimycobacterial activity against Mycobacterium tuberculosis (MTB) H37Rv and isoniazid resistant M. tuberculosis (INHR-MTB). All the newly synthesized compounds were showing moderate to high inhibitory activities. The compound 6,7-dimethoxy-3-(4-chloro phenyl)-4H-indeno[1,2-c]isoxazole (4b) was found to be the most promising compound, active against MTB H37Rv and INHR-MTB with minimum inhibitory concentrations of 0.22 and 0.34 μM. 相似文献