17172-57-5Relevant academic research and scientific papers
Synthesis, in vitro and in silico enzymatic inhibition assays, and toxicity evaluations of new 4,5-diphenylimidazole-N-phenylacetamide derivatives as potent α-glucosidase inhibitors
Mohammadi-Khanaposhtani, Maryam,Nikraftar, Atefeh,Asgari, Mohammad Sadegh,Emadi, Mehdi,Mojtabavi, Somayeh,Faramarzi, Mohammad Ali,Rastegar, Hossein,Larijani, Bagher,Mahdavi, Mohammad
, p. 1273 - 1283 (2021/05/26)
α-Glucosidase is responsible for glucose release of oligosaccharides and disaccharides in the intestine and increase postprandial hyperglycemia. Inhibition of this enzyme is a beneficial therapeutic method for glycemic control in diabetes. This study deals with the design and synthesis of 4,5-diphenylimidazole-N-phenylacetamide derivatives 7a–l and the screen of these compounds for their potential for α-glucosidase inhibition. All the synthesized compounds exhibited superior α-glucosidase inhibition (IC50 = 90.0–598.5 μM) as compared to standard inhibitor acarbose (IC50 = 750.0 μM). In contrast, these compounds were inactive against α-amylase. Among the synthesized compounds, compound 7h was the most potent inhibitor of this library and was a competitive inhibitor into α-glucosidase with Ki value = 86.3 μM. Docking study of the most potent compounds was performed to evaluate the binding interactions of these compounds with the active site of enzyme and to determine of binding energies of ligand–enzyme complexes. The results of this in silico study are in complete agreement with the results obtained from in vitro α-glucosidase inhibition assay. Docking study of the most potent compound demonstrated that it interacted with important residues in the active site of α-glucosidase. In vitro cytotoxic activity of the most potent compounds and in silico druglikeness/ADME/toxicity study of these compounds were evaluated.
Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy
Sonawane, Vinay,Mohd Siddique, Mohd Usman,Jadav, Surender Singh,Sinha, Barij Nayan,Jayaprakash, Venkatesan,Chaudhuri, Bhabatosh
, p. 115 - 132 (2019/01/23)
Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G0/G1 phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells’ ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC50 values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC50 value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC50 of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G0/G1 and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.
CYP enzymes, expressed within live human suspension cells, are superior to widely-used microsomal enzymes in identifying potent CYP1A1/CYP1B1 inhibitors: Identification of quinazolinones as CYP1A1/CYP1B1 inhibitors that efficiently reverse B[a]P toxicity and cisplatin resistance
Sonawane, Vinay R.,Siddique, Mohd Usman Mohd,Gatchie, Linda,Williams, Ibidapo S.,Bharate, Sandip B.,Jayaprakash, Venkatesan,Sinha, Barij N.,Chaudhuri, Bhabatosh
, p. 177 - 194 (2019/02/27)
Microsomal cytochrome P450 (CYP) enzymes, isolated from recombinant bacterial/insect/yeast cells, are extensively used for drug metabolism studies. However, they may not always portray how a developmental drug would behave in human cells with intact intracellular transport mechanisms. This study emphasizes the usefulness of human HEK293 kidney cells, grown in ‘suspension’ for expression of CYPs, in finding potent CYP1A1/CYP1B1 inhibitors, as possible anticancer agents. With live cell-based assays, quinazolinones 9i/9b were found to be selective CYP1A1/CYP1B1 inhibitors with IC50 values of 30/21 nM, and > 150-fold selectivity over CYP2/3 enzymes, whereas they were far less active using commercially-available CYP1A1/CYP1B1 microsomal enzymes (IC50, >10/1.3–1.7 μM). Compound 9i prevented CYP1A1-mediated benzo[a]pyrene-toxicity in normal fibroblasts whereas 9b completely reversed cisplatin resistance in PC-3/prostate, COR-L23/lung, MIAPaCa-2/pancreatic and LS174T/colon cancer cells, underlining the human-cell-assays’ potential. Our results indicate that the most potent CYP1A1/CYP1B1 inhibitors would not have been identified if one had relied merely on microsomal enzymes.
Synthesis and cytotoxic evaluation of some 2-{4-[(2-oxo-1,2-dihydro-3h-indol-3-ylidene)methyl] phenoxy}-n-phenylacetamide
Bhadauria, Vivek Singh,Sravanthi, Vishnu,Kumar, Sujeet,Das, Debajyoti,De Clercq, Erik,Schols, Dominique,Tokuda, Harukuni,Karki, Subhas S.
, p. 137 - 145 (2017/01/17)
A series of 2-oxindole derivatives were synthesized and evaluated for cytotoxic activity against different human and murine cancer cell lines and cancer chemopreventive activity. Among the tested compounds VS-06, 08, 12 and 17 displayed cytotoxic activity in the range of 5.0 to 8.5 μM against human T-lymphocyte cells (CEM). Results showed that molecules with electron withdrawing substituent at 4 position of N-phenylacetamide group exhibited an increase in activity against the human tumor cell line CEM. The cancer chemopreventive effect of VS-01 (IC50 = 451 nM) displayed equipotent activity in comparison to standard oleanolic acid (IC50 = 449 nM).
Synthesis and biological evaluation of novel 5-benzylidenethiazolidine-2,4- dione derivatives for the treatment of inflammatory diseases
Ma, Liang,Xie, Caifeng,Ma, Yinghua,Liu, Juan,Xiang, Mingli,Ye, Xia,Zheng, Hao,Chen, Zhizhi,Xu, Qinyuan,Chen, Tao,Chen, Jinying,Yang, Jincheng,Qiu, Neng,Wang, Guangcheng,Liang, Xiaolin,Peng, Aihua,Yang, Shengyong,Wei, Yuquan,Chen, Lijuan
supporting information; experimental part, p. 2060 - 2068 (2011/06/17)
Twenty-two compounds based on thiazolidine-2,4-dione moiety were synthesized and evaluated for the inhibitory potency on the production of nitric oxide (NO), inducible nitric oxide synthase (iNOS) activity, and the generation of prostaglandin E2 (PEG2). (Z)-N-(3-Chlorophenyl)-2-(4- ((2,4-dioxothiazolidin-5-ylidene) methyl) phenoxy) acetamide (3I), superior to the commercial anti-inflammatory drug indomethacin, significantly inhibited iNOS activity (IC50 = 8.66 μM), iNOS-mediated NO, and cyclooxygenase (COX)-2-derived PGE2 production (IC50 = 4.16 and 23.55 μM, respectively) on lipopolysaccharide (LPS)-induced RAW 264.7 cells. Docking study revealed that 3I was perfectly docking into the active site of murine iNOS and suppressed the expression of iNOS protein as evidenced by Western blot analysis. At the dose of 50 mg/kg, oral administration of 3I possessed protective properties in both carrageenan-induced paw edema and adjuvant-induced arthritis rat models.
Synthesis and biological activity of novel barbituric and thiobarbituric acid derivatives against non-alcoholic fatty liver disease
Ma, Liang,Li, Shilin,Zheng, Hao,Chen, Jinying,Lin, Lin,Ye, Xia,Chen, Zhizhi,Xu, Qinyuan,Chen, Tao,Yang, Jincheng,Qiu, Neng,Wang, Guangcheng,Peng, Aihua,Ding, Yi,Wei, Yuquan,Chen, Lijuan
experimental part, p. 2003 - 2010 (2011/06/25)
Forty-four barbituric acid or thiobarbituric acid derivatives were synthesized and evaluated for their effects on adipogenesis of 3T3-L1 adipocytes by measuring the expression of adiponectin in vitro. Four compounds (3a, 3o, 3s, 4t) were found to increase the expression of adiponectin and lower the leptin level in 3T3-L1 adipocytes at respective concentration of 10 μM. Among them, 3s showed the most efficacious. Oral administration of 3s effectively reduced body weight, liver weight, and visceral fat and regulated serum levels of biochemical markers in the high-fat/diet-induced Wistar rats. Histopathological evaluation of liver sections by Oil Red O and H&E staining confirmed 3s as a potent, orally active molecule for reducing fat deposition against non-alcoholic fatty liver disease.
Synthesis, glucose uptake activity and structure-activity relationships of some novel glitazones incorporated with glycine, aromatic and alicyclic amine moieties via two carbon acyl linker
Kumar, B.R. Prashantha,Soni, Mukesh,Kumar, S. Santhosh,Singh, Kuldeep,Patil, Mohan,Baig, R.B. Nasir,Adhikary, Laxmi
experimental part, p. 835 - 844 (2011/04/16)
Three series of novel glitazones were designed and prepared by using appropriate synthetic schemes to incorporate glycine, aromatic and alicyclic amines via two carbon linker. Compounds were synthesized both under conventional and microwave methods. Nineteen out of twenty four synthesized compounds were evaluated for their in vitro glucose uptake activity using isolated rat hemi-diaphragm. Compounds, 6, 9a, 13a, 13b, 13c, 13f and 13h exhibited significant glucose uptake activity. Illustration about their synthesis and in vitro glucose uptake activity is described along with the structure-activity relationships.
Functionalized Congeners of 1,3-Dialkylxanthines: Preparation of Analogues with High Affinity for Adenosine Receptors
Jacobson, Kenneth A.,Kirk, Kenneth L.,Padgett, William L.,Daly, John W.
, p. 1334 - 1340 (2007/10/02)
A series of functionalized congeners of 1,3-dialkylxanthines has been prepared as adenosine receptor antagonists.On the basis of high potency of 8-(p-hydroxyphenyl)-1,3-dialkylxanthines, the parent compounds were 8-phenyl> derivatives of theophylline and 1,3-dipropylxanthine.A series of analogues including esters of ethanol and N-hydroxysuccinimide, amides, a hydrazide, an acylurea, and anilides were prepared.The potency in blocking A1-adenosine receptors (inhibition of binding of N6-cyclohexyladenosine to brain membranes) and A2-adenosine receptors (inhibition of 2-chloroadenosine-elicited accumulations of cyclic AMP in brain slices) was markedly affected by structural changes distal to the primary pharmacophore (8-phenyl-1,3-dialkylxanthine).Potencies in the dipropyl series at the A1 receptor ranged from Ki values of 1.2 nM for a congener with a terminal amidoethyleneamine moiety to a Ki value of 58 nM for the parent carboxylic acid to a Ki of 96 nM for the bulky ureido congener.Certain congeners were up to 145-fold more active at A1 receptors than at A2 receptors.Various derivatives of the congeners should be useful as receptor probes and for radioidodination, avidin binding, and preparation of affinity columns.
