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1.
《Bioorganic & medicinal chemistry》2016,24(21):5423-5430
A series of (benzimidazol-2-yl)-aniline (1) derivatives has been synthesized and evaluated as glycogen phosphorylase (GP) inhibitors. Kinetics studies revealed that compounds displaying a lateral heterocyclic residue with several heteroatoms (series 3 and 5) exhibited modest inhibitory properties with IC50 values in the 400–600 μM range. Arylsulfonyl derivatives 7 (Ar: phenyl) and 9 (Ar: o-nitrophenyl) of 1 exhibited the highest activity (series 2) among the studied compounds (IC50 324 μM and 357 μM, respectively) with stronger effect than the p-tolyl analogue 8. 相似文献
2.
Sanjeev R. Patil Ashish Asrondkar Vrushali Patil Jaiprakash N. Sangshetti Firoz A. Kalam Khan Manoj G. Damale Rajendra H. Patil Anil S. Bobade Devanand B. Shinde 《Bioorganic & medicinal chemistry letters》2017,27(16):3845-3850
A series of newer 1,2,4-triazole-3-thiol derivatives 5(a–m) and 6(a–i) containing a triazole fused with pyrazine moiety of pharmacological significance have been synthesized. All the synthesized compounds were screened for their in vitro antileishmanial and antioxidant activities. Compounds 5f (IC50 = 79.0 µM) and 6f (IC50 = 79.0 µM) were shown significant antileishmanial activity when compared with standard sodium stibogluconate (IC50 = 490.0 µM). Compounds 5b (IC50 = 13.96 µM) and 6b (IC50 = 13.96 µM) showed significant antioxidant activity. After performing molecular docking study and analyzing overall binding modes it was found that the synthesized compounds had potential to inhibit L. donovani pteridine reductase 1 enzyme. In silico ADME and metabolic site prediction studies were also held out to set an effective lead candidate for the future antileishmanial and antibacterial drug discovery initiatives. 相似文献
3.
Qing-Kun Shen Chuan-Feng Liu Hong-Jian Zhang Yu-Shun Tian Zhe-Shan Quan 《Bioorganic & medicinal chemistry letters》2017,27(21):4871-4875
Two series of xanthotoxin-triazole derivatives were designed, synthesized, and studied for their antiproliferative properties. The in vitro cytotoxicity of the compounds in the AGS cancer cell line and the L02 normal cell line was evaluated via MTT assay. Among the synthesized compounds, 9-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-7H-furo[3,2-g]chromen-7-one (6p) was found to have the greatest antiproliferative activity against AGS cells (IC50 = 7.5 μM) and showed better activity than the lead compound (xanthotoxin, IC50 > 100 μM) and the reference drug (5-fluorouracil, IC50 = 29.6 μM) did. The IC50 value of 6p in L02 cells was 13.3 times higher than that in the AGS cells. Therefore, the compound exhibited better therapeutic activity and specificity compared with the positive control 5-fluorouracil. Cell cycle analysis revealed that compound 6p inhibited cell growth via the induction of S/G2 phase arrest in AGS cells. Compound 6p was identified as a promising lead compound for the further development and identification of 1,2,3-triazole-based anticancer agents. 相似文献
4.
《Bioorganic & medicinal chemistry》2014,22(1):468-477
A series of new 1,3,4-oxadiazole derivatives (6a–6x) containing pyridine and acylhydrazone moieties were synthesized and developed as potential telomerase inhibitors. The bioassay tests demonstrated that compounds 6n, 6o, 6q, 6s and 6t exhibited significant broad-spectrum anticancer activity with IC50 range from 0.76 to 9.59 μM against the four cancer cell lines (HEPG2, MCF7, SW1116 and BGC823). Moreover, all the title compounds were assayed for telomerase inhibition using the TRAP-PCR-ELISA assay. Compound 6s showed the highest anticancer activity with IC50 of 0.76–1.54 μM against the tested cancer cell lines and exhibited the most potent telomerase inhibitory activity with IC50 of 1.18 ± 0.14 μM. The docking simulation was carried out to investigate a possible binding mode of compound 6s into the active site of telomerase (pdb. 3DU6) while the QSAR model was built to check the previous work as well as to introduce new directions. 相似文献
5.
Mura Reddy Gudisela N. Srinivasu Chaitanya Mulakayala Praveen Bommu M.V. Basaveswara Rao Naveen Mulakayala 《Bioorganic & medicinal chemistry letters》2017,27(17):4140-4145
Novel N-(1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl derivatives were designed, synthesized and their chemical structures were confirmed by 1H NMR, 13C NMR and Mass spectra. The anticancer activities of the newly synthesized compounds were evaluated in vitro against three human cancer cell lines including K562, Colo-205 and MDA-MB 231 by MTT assay. The screening results showed that five compounds (16b, 16d, 16i, 16p and 16q) exhibited potent cytotoxic activities with IC50 values between 20 and 40 μM. Further in vitro studies revealed that inhibition of sirtuins could be the possible mechanism of action of these molecules. 相似文献
6.
Chi N. Nguyen Binh T.D. Trinh Toan B. Tran Le-Thu T. Nguyen Anna K. Jäger Lien-Hoa D. Nguyen 《Bioorganic & medicinal chemistry letters》2017,27(15):3301-3304
An ethyl acetate extract the bark of Garcinia xanthochymus exhibited strong inhibition towards α-glucosidase and PTP1B with IC50 values of 0.3 ± 0.1 μg/mL and 2.3 ± 0.4 μg/mL, respectively. Chemical constituents of the extract were therefore examined, and two new compounds, xanthochymusxanthones A (1) and B (2), along with ten known xanthones (3–12), were isolated. Their structures were determined using spectroscopic methods, mainly 1D and 2D NMR. Inhibitory activity of the isolated compounds was then tested, and subelliptenone F (12) showed significant effect towards α-glucosidase with IC50 value of 4.1 ± 0.3 μM (compared with acarbose, IC50 = 900.0 ± 3.0 μM) whilst xanthochymusxanthone B (2) exhibited remarkable activity towards PTP1B with IC50 value of 8.0 ± 0.6 μM (compared with RK682, IC50 = 4.4 ± 0.3 μM). 相似文献
7.
Ting-jian Zhang Song-ye Li Wei-yan Yuan Qing-xia Wu Lin Wang Su Yang Qi Sun Fan-hao Meng 《Bioorganic & medicinal chemistry letters》2017,27(4):729-732
A series of (1H-1,2,3-triazol-4-yl)methoxybenzaldehyde derivatives containing an anthraquinone moiety were synthesized and identified as novel xanthine oxidase inhibitors. Among them, the most promising compounds 1h and 1k were obtained with IC50 values of 0.6 μM and 0.8 μM, respectively, which were more than 10-fold potent compared with allopurinol. The Lineweaver-Burk plot revealed that compound 1h acted as a mixed-type xanthine oxidase inhibitor. SAR analysis showed that the benzaldehyde moiety played a more important role than the anthraquinone moiety for inhibition potency. The basis of significant inhibition of xanthine oxidase by 1h was rationalized by molecular modeling studies. 相似文献
8.
Firoz A. Kalam Khan Zahid Zaheer Jaiprakash N. Sangshetti Rajendra H. Patil Mazahar Farooqui 《Bioorganic & medicinal chemistry letters》2017,27(3):567-573
A new series of bis(indolyl)-pyridine derivatives 6(a–m) were synthesized by Chichibabin reaction process and evaluated for antileishmanial and antibacterial activities to establish structure–activity relationship. The synthesis was carried out through one-pot multicomponent reaction of 3-acetylindole, aromatic aldehydes, and ammonium acetate in the presence of camphor-10-sulfonic acid as a catalyst. The compounds 6d (IC50 = 102.47 μM) and 6f (IC50 = 99.49 μM) had shown promising antileishmanial against L. donovani promastigotes when compared with standard sodium stibogluconate (IC50 = 490.00 μM). All the synthesized compounds (MIC range = 41.35–228.69 μg/mL) had shown potent antibacterial activity than standard ampicillin (MIC range = 100.00–250.00 μg/mL) against all the tested bacterial strains. In silico ADME and metabolic site prediction studies were also held out to set an effective lead candidate for the future antileishmanial and antibacterial drug discovery initiatives. 相似文献
9.
10.
Guangcheng Wang Xin Li Jing Wang Zhenzhen Xie Luyao Li Ming Chen Shan Chen Yaping Peng 《Bioorganic & medicinal chemistry letters》2017,27(5):1115-1118
A novel series of 2-((5,6-diphenyl-1,2,4-triazin-3-yl)thio)-N-arylacetamides 5a–5q have been synthesized and evaluated for their α-glucosidase inhibitory activity. All newly synthesized compounds exhibited potent α-glucosidase inhibitory activity in the range of IC50 = 12.46 ± 0.13–72.68 ± 0.20 μM, when compared to the standard drug acarbose (IC50 = 817.38 ± 6.27 μM). Among the series, compound 5j (12.46 ± 0.13 μM) with strong electron-withdrawing nitro group on the arylacetamide moiety was identified as the most potent inhibitor of α-glucosidase. Molecular docking study was carried out to explore the binding interactions of these compounds with α-glucosidase. Our study identifies a novel series of potent α-glucosidase inhibitors for further investigation. 相似文献
11.
Ahmed S. Aboraia Sook Wah Yee Mohamed Sayed Gomaa Nikhil Shah Anna C. Robotham Bart Makowski David Prosser Andrea Brancale Glenville Jones Claire Simons 《Bioorganic & medicinal chemistry》2010,18(14):4939-4946
A series of N-(2-(1H-imidazol-1-yl)-2-phenylethyl)arylamides were prepared, using an efficient three- to five-step synthesis, and evaluated for their inhibitory activity against human cytochrome P450C24A1 (CYP24A1) hydroxylase. Inhibition ranged from IC50 0.3–72 μM compared with the standard ketoconazole IC50 0.52 μM, with the styryl derivative (11c) displaying enhanced activity (IC50 = 0.3 μM) compared with the standard, providing a useful preliminary lead for drug development. 相似文献
12.
Yong-Ling Wu De-Long Wang En-Hui Guo Shuang Song Jun-Tao Feng Xing Zhang 《Bioorganic & medicinal chemistry letters》2017,27(5):1284-1290
Thirty-six new α-benzylidene-γ-lactone compounds based α-methylene-γ-butyrolactone substructure were prepared and characterized by spectroscopic analysis. All compounds were evaluated for antifungal activities in vitro against six plant pathogenic fungi and the half maximal inhibitory concentration (IC50) against Botrytis cinerea and Colletotrichum lagenarium were investigated. Compounds 5c-3 and 5c-5 with the halogen atom exhibited excellent fungicidal activity against B. cinerea (IC50 = 22.91, 18.89 μM). The structure-activity relationships (SARs) analysis indicated that the derivatives with electron-withdrawing substituents at the meta- or para-positions improves the activity. Via the heuristic method, the generated quantitative structure-activity relationship (QSAR) model (R2 = 0.961) revealed a strong correlation of antifungal activity against B. cinerea with molecular structures of these compounds. Meanwhile, the cytotoxicity of 20 representative derivatives was tested in the human tumor cells line (HepG2) and the hepatic L02 cells line, the result indicated that the synthesized compounds showed significant inhibitory activity and limited selectivity. Compound 5c-5 has the highest fungicidal activity with IC50 = 18.89 μM (against B. cinerea.) but low cytotoxicity with IC50 = 35.4 μM (against HepG2 cell line) and IC50 = 68.8 μM (against Hepatic L02 cell line). These encouraging results can be providing an alternative, promising use of α-benzylidene-γ-lactone through the design and exploration of eco-friendly fungicides with low toxicity and high efficiency. 相似文献
13.
Linhong He Da Li Chufeng Zhang Peng Bai Lijuan Chen 《Bioorganic & medicinal chemistry letters》2017,27(17):4171-4175
Described as a Btk inhibitor, ibrutinib also potently inhibits Bmx and EGFR, two good targets for lung cancer. Owing to its high CLogP (4.07) and low aqueous solubility (<0.01 mg/ml), resulting in unfavorable bioavailability, ibrutinib requires high dosages to achieve good clinical response in the treatment of non-small cell lung cancer (NSCLC). In our effort to improve the CLogP of ibrutinib by structural optimization led to the discovery of a potent anti-cancer agent B6, with beneficial physicochemical parameters (CLogP = 2.56, solubility in water ≈ 0.1 mg/ml) meeting the principles of oral drugs. B6 exhibited anti-proliferation activities against EGFR-expressing cells, especially the mutant ones, such as H1975 (L858R/T790M, IC50 = 0.92 ± 0.19 μM) and HCC827 (Del119 IC50 = 0.014 ± 0.01 μM). Moreover, B6 significantly slowed down H1975 tumor growth with anti-tumor rate of 73.9% (p < 0.01). Enzyme potencies assay demonstrated B6 moderately selectively inhibited Bmx (IC50 = 35.7 ± 0.1 nM) over other kinases. So, as a potent Bmx inhibitor, B6 has the potential to be an efficacious treatment for NSCLC with acquired drug resistance. 相似文献
14.
Chao Ding Shaopeng Chen Cunlong Zhang Guangnan Hu Wei Zhang Lulu Li Yu Zong Chen Chunyan Tan Yuyang Jiang 《Bioorganic & medicinal chemistry》2017,25(1):27-37
By merging the critical pharmacophore of EGFR/HER2 and HDAC inhibitors into one compound, a novel series of EGFR, HER-2, and HDAC multitarget inhibitors were synthesized. Compounds 9a–l contained 4-anilinoquinazolines with C-6 triazole-linked long alkyl chains of hydroxamic acid and displayed excellent inhibition against these enzymes (compound 9d exhibited the best inhibitory potency on wild-type EGFR, HDAC1, and HDAC6 with IC50 values 0.12 nM, 0.72 nM and 3.2 nM individually). Furthermore, compounds 9b and 9d potently inhibited proliferation of five human cancer cell lines (with IC50 values between 0.49 and 8.76 μM). Further mechanistic study revealed that compound 9d also regulated the phosphorylation of EGFR and HER2 and histone H3 hyperacetylation on the cellular level and induced remarkable apoptosis in BT-474 cells. Therefore, our study suggested that a system network-based multi-target drug design strategy might provided an alternate drug design method, by taking into account the synergy effect of EGFR, HER-2 and HDAC. 相似文献
15.
Khang D.H. Nguyen Phu H. Dang Hai X. Nguyen Mai T.T. Nguyen Suresh Awale Nhan T. Nguyen 《Bioorganic & medicinal chemistry letters》2017,27(13):2902-2906
A new lignan, 9′-methoxypinoresinol (1), and two new glycosylated 5-hydroxymethylfurfurals, calofurfuralside A (2), and calofurfuralside B (3), together with nine known compounds (4–12) have been isolated from the active fractions, CHCl3 (IC50, 0.32 μg mL?1) and EtOAc (IC50, 0.55 μg mL?1) fractions of the leaves of Calotropis gigantea. Their structures were elucidated based on NMR and MS data. Among the isolated compounds, compounds 1 and 9 exhibited potent cytotoxicity against PANC-1 human pancreatic cancer cell line under the normoglycemic condition with IC50 values of 3.7 and 3.3 μM, respectively. 9′-Methoxypinoresinol (1) significantly inhibited the colony formation of PANC-1 cells in a concentration-dependent manner. 相似文献
16.
《Bioorganic & medicinal chemistry》2014,22(4):1487-1495
A novel series of N-(3-((7H-purin-6-yl)thio)-4-hydroxynaphthalen-1-yl)-sulfonamides were designed and synthesized. Biological characterization revealed that several compounds exerted enhanced anti-proliferative activity against human umbilical vein endothelial cells (HUVECs) and several cancer cell lines and high specific protein kinase and angiogenesis inhibitory activities. Compared with our previously synthesized compounds, the substitution of sulfonamide structure for amide fragment played an essential role for the advance of inhibitory activities. In addition, the replacement of 1H-1,2,4-triazole ring by 7H-purine did not result in obvious decrease of inhibition efficacy, indicating that the sulfonamide structure contributes even more to the inhibition efficacy than the 1H-1,2,4-triazole ring. Among these compounds, compound 9n demonstrated comparable in vitro antiangiogenic activities to pazopanib in both HUVEC tube formation assay and the rat thoracic aorta rings (TARs) test. Meanwhile, compound 9n was identified to inhibit Akt1 (IC50 = 1.73 μM) and Abl tyrosine kinase (IC50 = 1.53 μM) effectively. 相似文献
17.
Violina T. Angelova Violeta Valcheva Tania Pencheva Yulian Voynikov Nikolay Vassilev Rositsa Mihaylova Georgi Momekov Boris Shivachev 《Bioorganic & medicinal chemistry letters》2017,27(13):2996-3002
A new convenient method for preparation of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b–g and coumarin containing hydrazide-hydrazone analogues 4a–e was presented. The antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and cytotoxicity against the human embryonic kidney cell line HEK-293 were tested in vitro. All compounds demonstrated significant minimum inhibitory concentrations (MIC) ranging 0.28–1.69 μM, which were comparable to those of isoniazid. The cytotoxicity (IC50 > 200 µM) to the “normal cell” model HEK-293T exhibited by 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b–e, was noticeably milder compared to that of their hydrazone analogues 4a–e (IC50 33–403 µM). Molecular docking studies on compounds 4a–e and 5b–g were also carried out to investigate their binding to the 2-trans-enoyl-ACP reductase (InhA) enzyme involved in M. tuberculosis cell wall biogenesis. The binding model suggested one or more hydrogen bonding and/or arene-H or arene-arene interactions between hydrazones or pyrazole-fused coumarin derivatives and InhA enzyme for all synthesized compounds. 相似文献
18.
Attar Salahuddin Afreen Inam Robyn L. van Zyl Donovan C. Heslop Chien-Teng Chen Fernando Avecilla Subhash M. Agarwal Amir Azam 《Bioorganic & medicinal chemistry》2013,21(11):3080-3089
A new series of 4-aminochloroquinoline based sulfonamides were synthesized and evaluated for antiamoebic and antimalarial activities. Out of the eleven compounds evaluated (F1–F11), two of them (F3 and F10) showed good activity against Entamoeba histolytica (IC50 <5 μM). Three of the compounds (F5, F7 and F8) also displayed antimalarial activity against the chloroquine-resistant (FCR-3) strain of Plasmodium falciparum with IC50 values of 2 μM. Compound F7, whose crystal structure was also determined, inhibited β-haematin formation more potently than quinine. To further understand the action of hybrid molecules F7 and F8, molecular docking was carried out against the homology model of P. falciparum enzyme dihydropteroate synthase (PfDHPS). The complexes showed that the inhibitors place themselves nicely into the active site of the enzyme and exhibit interaction energy which is in accordance with our activity profile data. Application of Lipinski ‘rule of five’ on all the compounds (F1–F11) suggested high drug likeness of F7 and F8, similar to quinine. 相似文献
19.
Hua Sun Weina Ding Xiaotong Song Dong Wang Mingzhu Chen Kaili Wang Yazhou Zhang Peng Yuan Ying Ma Runling Wang Robert H. Dodd Yongmin Zhang Kui Lu Peng Yu 《Bioorganic & medicinal chemistry letters》2017,27(15):3226-3230
A series of 6-hydroxyaurones and their analogues have been synthesized and evaluated for their in vitro α-glucosidase inhibitory and glucose consumption-promoting activity. These compounds exhibited varying degrees of α-glucosidase inhibitory activity, 11 of them showing higher potency than that of the control standard acarbose (IC50 = 50.30 μM). Surprisingly, analogues devoid of a substituent at C-2 but having an aryl group at C-5 were found to be highly active (e.g., 7f, IC50 = 9.88 μM). Docking analysis substantiated these findings. The kinetic analysis of compound 7f, the most potent α-glucosidase inhibitor of this study, revealed that it inhibited α-glucosidase in an irreversible and mixed competitive mode. In addition, compounds 7f and 10c exhibited significant glucose consumption promoting activity at 1 μM. 相似文献
20.
Ting-jian Zhang Qing-xia Wu Song-ye Li Lin Wang Qi Sun Yi Zhang Fan-hao Meng Hua Gao 《Bioorganic & medicinal chemistry letters》2017,27(16):3812-3816
This study mainly focused on the modification of the X2 position in febuxostat analogs. A series of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives (1a-s) with an N atom occupying the X2 position was designed and synthesized. Evaluation of their inhibitory potency in vitro on xanthine oxidase indicated that these compounds exhibited micromolar level potencies, with IC50 values ranging from 0.21 µM to 26.13 μM. Among them, compound 1s (IC50 = 0.21 μM) showed the most promising inhibitory effects and was 36-fold more potent than allopurinol, but was still 13-fold less potent than the lead compound Y-700, which meant that a polar atom fused at the X2 position could be unfavorable for potency. The Lineweaver-Burk plot revealed that compound 1s acted as a mixed-type xanthine oxidase inhibitor. Analysis of the structure-activity relationships demonstrated that a more lipophilic ether tail (e.g., meta-methoxybenzoxy) at the 4′-position could benefit the inhibitory potency. Molecular modeling provided a reasonable explanation for the structure–activity relationships observed in this study. 相似文献