- Design, synthesis, antitrypanosomal activity, DNA/RNA binding and in vitro ADME profiling of novel imidazoline-substituted 2-arylbenzimidazoles
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Novel imidazoline benzimidazole derivatives containing diversely substituted phenoxy moieties were synthesized with the aim of evaluating their antitrypanosomal activity, DNA/RNA binding affinity and in vitro ADME properties. The presence of the diethylaminoethyl subunit in 18a–18c led to enhanced antitrypanosomal potency, particularly for 18a and 18c, which contain unsubstituted and methoxy-substituted phenoxy moieties. They were found to be > 2-fold more potent against African trypanosomes than nifurtimox. Fluorescence and CD spectroscopy, thermal denaturation assays and computational analysis indicated a preference of 18a–18c toward AT-rich DNA and their minor groove binding mode. Replacement of the amidine group with less basic and ionisable nitrogen-containing moieties failed to improve membrane permeability of the investigated compounds. Due to structural diversification, the compounds displayed a range of physico-chemical features resulting in variable in vitro ADME properties, leaving space for further optimization of the biological profiles.
- Kelly, John M.,Taylor, Martin C.,Baji?, Miroslav,Bokuli?, Ana,Jeli?, Dubravko,Ko?trun, Sanja,Krstulovi?, Luka,Popov, Andrea Bistrovi?,Rai?-Mali?, Silvana,Stojkovi?, Marijana Radi?,Zonji?, Iva
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- Bronchospasmolytic activity and adenosine receptor binding of some newer 1,3-dipropyl-8-phenyl substituted xanthine derivatives
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The aldehyde derivatives of 1,3-dipropyl xanthines as described in this paper, constitutes a new series of selective adenosine ligands displaying bronchospasmolytic activity. The effect of substitution at third- and fourth-position of 8-phenyl xanthine ha
- Gumber, Divya,Yadav, Divya,Yadav, Rakesh,Kachler, Sonja,Klotz, Karl Norbert
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p. 600 - 609
(2020/03/23)
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- Silver(i) complexes of 3-methoxy-4-hydroxybenzaldehyde thiosemicarbazones and triphenylphosphine: structural, cytotoxicity, and apoptotic studies
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Novel silver(i) complexes of the type [AgCl(PPh3)2(L)] {PPh3 = triphenylphosphine; L = VTSC = 3-methoxy-4-hydroxybenzaldehyde thiosemicarbazone (1); VMTSC = 3-methoxy-4-[2-(morpholine-1-yl)ethoxy]benzaldehyde thiosemicarbazone (2); VPTSC = 3-methoxy-4-[2-
- Silva, Débora E. S.,Becceneri, Amanda B.,Santiago, Jo?o V. B.,Gomes Neto, José A.,Ellena, Javier,Cominetti, Márcia R.,Pereira, José C. M.,Hannon, Michael J.,Netto, Adelino V. G.
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p. 16474 - 16487
(2020/12/03)
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- Chalcone and flavone derivatives adopted as aurora kinase inhibitor
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The present invention relates to design and synthesis of a class of chalcone and flavone derivatives represented by formulas I (I-1 and I-2) and II (II-1 and II-2), and inhibition effects of the derivatives on aurora kinase A. According to the present inv
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Paragraph 0079; 0080; 0092; 0093
(2017/08/02)
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- Synthesis of different heterocycles-linked chalcone conjugates as cytotoxic agents and tubulin polymerization inhibitors
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A series of new heterocycles-linked chalcone conjugates has been designed and synthesized by varying different alkane spacers. These conjugates were tested for their in vitro cytotoxic potential against a panel of selected human cancer cell lines namely,
- Shankaraiah, Nagula,Nekkanti, Shalini,Brahma, Uma Rani,Praveen Kumar, Niggula,Deshpande, Namrata,Prasanna, Daasi,Senwar, Kishna Ram,Jaya Lakshmi, Uppu
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p. 4805 - 4816
(2017/10/05)
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- Design and synthesis of 4′-O-alkylamino-tethered-benzylideneindolin-2-ones as potent cytotoxic and apoptosis inducing agents
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A series of new 4′-O-alkylamino-tethered-benzylideneindolin-2-one derivatives has been synthesized and evaluated for their anti-proliferative activity against selected human cancer cell lines of lung (A549), prostate (DU-145), breast (BT549 and MDA-MB-231) and normal breast epithelial cells (MCF-10A). Gratifyingly, the compounds 5j, 5o and 5r exhibited potent cytotoxicity against breast cancer cell lines (BT549 and MDA-MB-231) with IC50values in the range of 1.26–2.77?μM, and are found to be safer with lesser cytotoxicity on normal breast epithelial cells (MCF-10A). Further, experiments were conducted with these compounds 5j, 5o and 5r on MDA-MB-231 cancer cells to study the mechanism of growth inhibition and apoptosis inducing effect. Treatment of MDA-MB-231 cells with test compounds resulted in inhibition of cell migration through disorganization and disruption of F-actin capping protein. The flow-cytometry analysis results showed that the compound 5o arrested MDA-MB-231 cells in G0/G1 phase of cell cycle in a dose dependent manner. Hoechst staining study revealed that the test compounds inhibited tumor cell proliferation through induction of apoptosis. In addition, the mitochondrial membrane potential (DΨm) was affected and the increased level of reactive oxygen species (ROS) was noted in MDA-MB-231 cells.
- Senwar, Kishna Ram,Reddy, T. Srinivasa,Thummuri, Dinesh,Sharma, Pankaj,Bharghava, Suresh K.,Naidu,Shankaraiah, Nagula
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p. 4061 - 4069
(2016/08/01)
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- Synthesis and Evaluation of a New Series of 8-(2-Nitroaryl)Xanthines as Adenosine Receptor Ligands
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(Table presented.). A new series of 1,3-dimethylxanthine derivatives bearing 8-(2-nitroaryl) residue was synthesized and evaluated for affinity for recombinant human adenosine receptors subtypes. Nitrate esters of 7-substituted-1,3-dimethyl-8-phenylxanthines were also synthesized and tested. Introducing a nitro substituent at the 2-position of the 8-substituted phenyl ring resulted in generally low affinity for adenosine receptors (ARs), selectivity toward the A2A subtype was enhanced in some of the compounds. 8-(4-Cyclopentyloxy-5-methoxy-2-nitrophenyl)-1,3-dimethylxanthine (9e) proved to be a potent compound among the 2-nitrophenyl substituted xanthines exhibiting a Ki = 1 μM at human A2A ARs with at least 30 fold selectivity versus human A1 and A2B ARs. Replacement of 8-chloropropoxy phenyl with 8-nitrooxypropoxy phenyl resulted in a negligible change in binding affinity of the 8-substituted xanthines for various AR subtypes. Drug Dev Res 77 : 241–250, 2016.
- Bansal, Ranju,Kumar, Gulshan,Rohilla, Suman,Klotz, Karl-Norbert,Kachler, Sonja,Young, Louise C.,Harvey, Alan L.
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p. 241 - 250
(2016/08/28)
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- Indolinone based LRRK2 kinase inhibitors with a key hydrogen bond
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The most prevalent leucine-rich repeat kinase 2 (LRRK2) mutation G2019S is associated with Parkinson's disease (PD). It enhances kinase activity and has been identified in both familial and sporadic cases. Kinase activity was reported to be required for LRRK2 mutants to exert their toxic effects. Hence LRRK2 kinase inhibition may be a promising therapeutic target for PD. Here we report on the discovery and characterization of indolinone based LRRK2 inhibitors. Indolinone 15b, the most potent and selective inhibitor of the present series, is characterized by an IC50of 15 nM against wild-type LRRK2 and 10 nM against the LRRK2 G2019S mutant, respectively. Compound 15b was further evaluated in a kinase panel including 46 human protein kinases and in a zebrafish embryo phenotype assay, which enabled toxicity determination in whole organisms.
- G?ring, Stefan,Taymans, Jean-Marc,Baekelandt, Veerle,Schmidt, Boris
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p. 4630 - 4637
(2015/02/05)
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- Design, synthesis and glucose uptake activity of some novel glitazones
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Herein, we report a library consisting of some novel glitazones containing thiazolidinedione and its bioisosteres, rhodanine and oxadiazolidine ring structures as their basic scaffold for their antidiabetic activity. Twelve novel glitazones with diverse chemical structures were designed and synthesized by adopting appropriate synthetic schemes and analyzed. Later, subjected to in vitro glucose uptake assay in the absence and presence of insulin to confirm their antidiabetic activity using rat hemi-diaphragm. The titled compounds exhibited glucose uptake activity ranging weak to significant activity. Compounds 4, 5, 9, 11, 15, 16, 19 and 20 showed considerable glucose uptake activity apart from rosiglitazone, a standard drug. Compound 16 happens to be the candidate compound from this study to investigate further. The illustration about their design, synthesis, analysis and glucose uptake activity is reported here along with the in vitro and in silico study based structure-activity relationships.
- Kar, Koyel,Krithika, Uma,Mithuna,Basu, Prabhuddha,Santhosh Kumar,Reji, Anu,Prashantha Kumar
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- Synthesis, antimalarial activity and cytotoxic potential of new monocarbonyl analogues of curcumin
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A series of novel monocarbonyl analogues of curcumin have been designed, synthesized and tested for their activity against Molt4, HeLa, PC3, DU145 and KB cancer cell lines. Six of the analogues showed potent cytotoxicity towards these cell lines with IC50 values below 1 μM, which is better than doxorubicin, a US FDA approved drug. Several analogues were also found to be active against both CQ-resistant (W2 clone) and CQ-sensitive (D6) strains of Plasmodium falciparum in an in-vitro antimalarial screening. This level of activity warrants further investigation of the compounds for development as anticancer and antimalarial agents.
- Manohar, Sunny,Khan, Shabana I.,Kandi, Shamseer Kulangara,Raj, Kranthi,Sun, Guojing,Yang, Xiaochuan,Calderon Molina, Angie D.,Ni, Nanting,Wang, Binghe,Rawat, Diwan S.
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p. 112 - 116
(2013/02/23)
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- Synthesis of some imidazolyl-substituted 2-benzylidene indanone derivatives as potent aromatase inhibitors for breast cancer therapy
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The synthesis and aromatase inhibitory activity of a new series of 2-benzylidene indanones is presented. The imidazolyl-substituted indanones displayed potent aromatase inhibitory activity. The vanilloid-based derivative 2-[4-(3-imidazol-1-ylpropoxy)-3-me
- Bansal, Ranju,Narang, Gaurav,Zimmer, Christina,Hartmann, Rolf W.
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experimental part
p. 661 - 669
(2012/05/20)
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- Synthesis and QSAR studies of 16-(3 -methoxy-4-substituted benzylidene) androstene derivatives as anticancer agents
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In a systematic effort aimed at identifying new steroidal cytotoxic agents with potent antipoliferative activity against cancer cells and developing their QSAR models, a series of 16-(3- methoxy-4-substituted benzylidene)androst-5-ene derivatives have been synthesized. The selected compounds are evaluated for antineoplastic activity against a panel of three human cell lines- breast, CNS and lungs at NCI, Bethesda, USA. The results presented herein indicate that compound 15-18, 21, 22, 25-30 are active anticancer agents. The QSAR investigation with multiple linear regression analysis has been applied to find a correlation between different calculated physicochemical parameters of these compounds and biological activity. Application of datasets by using CODESSA software has led to QSAR equations based on the 3 descriptors. The significant QSAR models have been obtained with R2 values which range from 0.9692-0.8225 and good predictive performance (q2 range: 0.9264-0.7121). These models are expected to be useful for the anticancer screening of androstene derivatives having substitution at position 3, 16 and 17 of steroid nucleus.
- Dubey, Sonal,Kaur, Parmeet,Jindal, Dharam Paul,Satyanarayan, Yalamanchili Darji,Piplani, Poonam
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scheme or table
p. 948 - 955
(2010/10/18)
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- Synthesis and optimization of antitubercular activities in a series of 4-(aryloxy)phenyl cyclopropyl methanols
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A series of [4-(aryloxy)phenyl]cyclopropyl methanones were synthesized by reaction of different benzyl alcohols with 4-chloro-4′-fluorobutyrophenone in DMF in the presence of NaH/TBAB. The methanones were further reduced to respective methanols. The antitubercular activity of these compounds was evaluated in vitro against Mycobacterium tuberculosis H37Rv. Compounds 19, 21, 35, 36 and 37 have shown minimum inhibitory concentration (MIC) of 3.12 μg/mL, while compounds 14, 25 and 18 have shown MIC of 1.56 μg/mL and 0.78 μg/mL respectively. One of the compounds, cyclopropyl-4-[4-(2-piperidin-1- yl-ethoxy)benzyloxy]phenyl}methanol (36) showed 98% killing of intracellular bacilli in mouse bone marrow derived macrophages and was active against MDR, XDR and rifampicin clinical isolates resistant strains with MIC 12.5 μg/mL. Compound 36 was orally active in vivo in mice against M. tuberculosis H37Rv with an increase in MST by 6 days with 1 log reduction in the bacillary density in lungs as compared to control on 30th day after infection.
- Bisht, Surendra S.,Dwivedi, Namrata,Chaturvedi, Vinita,Anand, Namrata,Misra, Mridul,Sharma, Rahul,Kumar, Brijesh,Dwivedi, Richa,Singh, Shyam,Sinha, Sudhir Kumar,Gupta, Versha,Mishra,Dwivedi, Anil K.,Tripathi, Rama P.
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experimental part
p. 5965 - 5978
(2011/01/13)
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- Synthesis and antimicrobial activity of novel analogs of trifenagrel
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Novel analogs of trifenagrel were synthesized by using inexpensive and reusable phosphotungstic acid, H3[PW12O40] (3 mol %) catalyst under classical heating. Two of the newly synthesized triaryl imidazoles exhibited moderate antibacterial activity.
- Nagarapu, Lingaiah,Aneesa,Satyender, Apuri,Chandana,Bantu, Rajaskaker
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experimental part
p. 195 - 200
(2009/07/19)
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- Synthesis of a series of 8-(substituted-phenyl)xanthines and a study on the effects of substitution pattern of phenyl substituents on affinity for adenosine A1 and A2A receptors
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A new series of 8-(substituted-phenyl)xanthines have been synthesized and compounds were evaluated for their affinity for A1 and A2 adenosine receptors (AR) using radioligand binding assays. The effects of varying the positions of 8-phenyl substituents on affinity and selectivity at A1 and A2A adenosine receptors have been studied. Isovanilloid 1,3-dimethyl-8-[4-methoxy-3-(2-morpholin-4-ylethoxy)phenylxanthine (9d) displayed the highest affinity and selectivity towards A2A AR subtypes with Ki = 100 nM over A1 receptors (Ki > 100 mM). It has been observed that substitution pattern on 8-phenyl group greatly affects the affinity and selectivity at adenosine receptors, with A2A tolerating bulkier substituents than did A1 receptors.
- Bansal, Ranju,Kumar, Gulshan,Gandhi, Deepika,Young, Louise C.,Harvey, Alan L.
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experimental part
p. 2122 - 2127
(2009/09/30)
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- Small molecule thienopyrimidine-based protein tyrosine kinase inhibitors
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Various thienopyrimidine-based analog compounds are able to selectively inhibit the Src family of tyrosine kinases. These compounds are useful in the treatment of various diseases including hyperproliferative diseases, hematologic diseases, osteoporosis, neurological diseases, autoimmune diseases, allergic/immunological diseases, or viral infections.
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Page/Page column 41
(2010/02/15)
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- 4- AND 5-ALKYNYLOXINDOLES AND 4- AND 5-ALKENYLOXINDOLES
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4- and 5-alkynyloxindoles as well as 4- and 5-alkenyloxindoles having formula (I) and (II), wherein R, R, R, R, R, X and z have the meaning indicated in the specification, inhibit or modulate protein kinases, in particular JNK protein kinases and are useful as anti-inflammatory agents, particularly in the treatment of rheumatoid arthritis.
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Page/Page column 12; 31
(2010/02/04)
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