- Computer-Aided Search for 5-Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1-Based Multidrug Resistance
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ABCB1 modulation is an interesting strategy in the search for new anticancer agents that can overcome multidrug resistance (MDR). Hence, 17 new 5-arylideneimidazolones containing an amine moiety, as potential ABCB1 inhibitors, were designed, synthesized, and investigated. The series was tested in both parental (PAR) and multidrug-resistant (MDR) ABCB1-overexpressing T-lymphoma cancer cells using cytotoxicity assays. The ABCB1-modulating activity was examined in rhodamine 123 accumulation tests, followed by Pgp-Glo Assay to determine the influence of the most active compounds on ATPase activity. Lipophilic properties were assessed both, in silico and experimentally (RP-TLC). Pharmacophore-based molecular modelling toward ABCB1 modulation was performed. The studies allowed the identification of anticancer agents (p-fluorobenzylidene derivatives) more potent than doxorubicin, with highly selective action on MDR T-lymphoma cells (selectivity index >40). Most of the investigated compounds showed ABCB1-modulating action; in particular, two 5-benzyloxybenzylidene derivatives displayed activity nearly as strong as that of tariquidar.
- Kaczor, Aneta,Szemerédi, Nikoletta,Kucwaj-Brysz, Katarzyna,D?browska, Monika,Starek, Ma?gorzata,Latacz, Gniewomir,Spengler, Gabriella,Handzlik, Jadwiga
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p. 2386 - 2401
(2021/06/14)
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- Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems
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Polypharmacology approaches may help the discovery of pharmacological tools for the study or the potential treatment of complex and multifactorial diseases as well as for addictions and also smoke cessation. In this frame, following our interest in the de
- Grillo, Alessandro,Chemi, Giulia,Brogi, Simone,Brindisi, Margherita,Relitti, Nicola,Fezza, Filomena,Fazio, Domenico,Castelletti, Laura,Perdona, Elisabetta,Wong, Andrea,Lamponi, Stefania,Pecorelli, Alessandra,Benedusi, Mascia,Fantacci, Manuela,Valoti, Massimo,Valacchi, Giuseppe,Micheli, Fabrizio,Novellino, Ettore,Campiani, Giuseppe,Butini, Stefania,Maccarrone, Mauro,Gemma, Sandra
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- Design, Synthesis, Structure-Activity Relationship Studies, and Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) Modeling of a Series of O-Biphenyl Carbamates as Dual Modulators of Dopamine D3 Receptor and Fatty Acid Amide Hydrolase
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We recently reported molecules designed according to the multitarget-directed ligand paradigm to exert combined activity at human fatty acid amide hydrolase (FAAH) and dopamine receptor subtype D3 (D3R). Both targets are relevant for tackling several types of addiction (most notably nicotine addiction) and other compulsive behaviors. Here, we report an SAR exploration of a series of biphenyl-N-[4-[4-(2,3-substituted-phenyl)piperazine-1-yl]alkyl]carbamates, a novel class of molecules that had shown promising activities at the FAAH-D3R target combination in preliminary studies. We have rationalized the structural features conducive to activities at the main targets and investigated activities at two off-targets: dopamine receptor subtype D2 and endocannabinoid receptor CB1. To understand the unexpected affinity for the CB1 receptor, we devised a 3D-QSAR model, which we then prospectively validated. Compound 33 was selected for PK studies because it displayed balanced affinities for the main targets and clear selectivity over the two off-targets. 33 has good stability and oral bioavailability and can cross the blood-brain barrier.
- De Simone, Alessio,Russo, Debora,Ruda, Gian Filippo,Micoli, Alessandra,Ferraro, Mariarosaria,Di Martino, Rita Maria Concetta,Ottonello, Giuliana,Summa, Maria,Armirotti, Andrea,Bandiera, Tiziano,Cavalli, Andrea,Bottegoni, Giovanni
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p. 2287 - 2304
(2017/04/03)
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- Synthesis and evaluation of antiproliferative activity of novel quinazolin-4(3H)-one derivatives
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Two series of novel quinazolin-4(3H)-one derivatives (10a–g and 11a–g) have been synthesized and evaluated for their in vitro antiproliferative activity against human HeLa, MIAPACA, MDA-MB-231, and IMR-31 cancer cell lines. The synthesized compounds were characterized by spectral (Fourier transform infrared, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, high-resolution mass spectra) methods. Among them, compounds 11e and 11g exhibited potent in vitro antiproliferative activity with GI50 values 0.02, less than 0.01 μM against MIAPACA human cancer cell line. Significantly, compounds 10a, 10b, 10c, 10g, 11b, 11c, 11d, 11e, 11f showed activity with GI50 values ranging from 0.1 to 0.87 μM against human cancer cell lines MIAPACA, MDA-MB-231, and IMR-31. We have explored the probable binding mode and key active site interactions in HDAC8 and EHMT2 proteins. The docking results are complementary to the experimental results.
- Venkatesh, Ramineni,Kasaboina, Suresh,Janardhan, Sridhara,Jain, Nishant,Bantu, Rajashaker,Nagarapu, Lingaiah
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p. 2070 - 2081
(2016/10/03)
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- PHENYL CARBAMATES AND THEIR USE AS INHIBITORS OF THE FATTY ACID AMIDE HYDROLASE (FAAH) ENZYME AND MODULATORS OF THE D3 DOPAMINE RECEPTOR (D3DR)
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The invention provides compounds of Formula (I) or pharmaceutically acceptable salts thereof wherein Ar', R1, R2, R3, R4, X, Y are as defined in the description of invention, as multi-target directed ligands (MT
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Page/Page column 33; 37; 38; 39
(2015/02/02)
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- Binding kinetics of ZM241385 derivatives at the human adenosine A 2A receptor
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Classical drug design and development rely mostly on affinity- or potency-driven structure-activity relationships (SAR). Thus far, a given compound's binding kinetics have been largely ignored, the importance of which is now being increasingly recognized. In the present study, we performed an extensive structure-kinetics relationship (SKR) study in addition to a traditional SAR analysis at the adenosine A2A receptor (A 2AR). The ensemble of 24 A2AR compounds, all triazolotriazine derivatives resembling the prototypic antagonist ZM241385 (4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino) ethyl)phenol), displayed only minor differences in affinity, although they varied substantially in their dissociation rates from the receptor. We believe that such a combination of SKR and SAR analyses, as we have done with the A 2AR, will have general importance for the superfamily of G protein-coupled receptors, as it can serve as a new strategy to tailor the interaction between ligand and receptor. Above and beyond: Insight into the binding kinetics of ZM241385 derivatives at the human adenosine A2A receptor has provided additional information beyond a traditional structure-activity relationship (SAR) analysis. The strategy, combining a structure-kinetics relationship investigation and SAR, can serve as an important tool for more directed medicinal chemistry efforts in the future.
- Guo, Dong,Xia, Lizi,Van Veldhoven, Jacobus P. D.,Hazeu, Marc,Mocking, Tamara,Brussee, Johannes,Ijzerman, Adriaan P.,Heitman, Laura H.
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supporting information
p. 752 - 761
(2014/05/06)
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- An interactive SAR approach to discover novel hybrid thieno probes as ligands for D2-like receptors with affinities in the subnanomolar range
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A series of [(phenylpiperazinyl)alkyl]-isoindole-1,3-dione derivatives was synthesized to serve as probes for dopaminergic receptors. Among this series, compound 6a showed the highest affinity towards D4 and D3 receptors with K i values in the low nanomolar range, and D2/D4- and D2/D3-selectivity indices of 72 and 20, respectively. Optimization rounds were adopted and led to the D4-selective ligand thiophene-2-carboxamide 9a with a Ki(D4) value of 0.62 nM, and to its butyl analog, 10a, with Ki(D4) and Ki(D3) values of 0.03 and 0.26 nM, respectively. Docking experiments revealed the importance of the unique D4 residue Arg186 in manipulating the ligands' D4-subtype-receptor selectivity. Copyright
- Abdel-Fattah, Mohamed A. O.,Lehmann, Jochen,Abadi, Ashraf H.
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p. 2247 - 2266
(2014/01/06)
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- Synthesis and pharmacological evaluation of [(4-Arylpiperazin-1-yl)-alkyl]- carbamic acid ethyl ester derivatives as potential anxiolytic agents
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On the basis of our earlier studies, a series of N-{4-[4-(aryl) piperazin-1-yl]-phenyl}-amine derivatives containing terminal carbamoyl fragment with alkyl spacer of different lengths (15-20) were synthesized as ligands, for 5-hydroxytryptamine-1A (5-HT1A
- Khatri, Manisha,Rai, Santosh K.,Ranbhor, Ranjit,Kishore, Krishna,Tiwari, Manisha
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p. 1143 - 1152
(2012/11/07)
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- Synthesis and anti-inflammatory activity of some novel 3-phenyl-N-[3-(4- phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives
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A new series of 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5- carboxamide derivatives were synthesized and investigated their anti-inflammatory activities using carrageenan-induced rat paw edema model in vivo. All the synthesized compounds were found to be potent anti-inflammatory agents.
- Nagarapu, Lingaiah,Mateti, Jhansi,Gaikwad, Hanmant K.,Bantu, Rajashaker,Sheeba Rani,Prameela Subhashini
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p. 4138 - 4140
(2011/08/06)
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- Synthesis and biological evaluation of (phenylpiperazinyl-propyl)arylsulfonamides as selective 5-HT2A receptor antagonists
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A novel series of 5-HT2A ligands that contain a (phenylpiperazinyl-propyl)arylsulfonamides skeleton was synthesized. Thirty-seven N-(cycloalkylmethyl)-4-methoxy-N-(3-(4-arylpiperazin-1-yl)propyl)-arylsulfonamide and N-(4-(4-arylpiperazin-1-yl)b
- Yoo, Euna,Yoon, Juhee,Pae, Ae Nim,Rhim, Hyewhon,Park, Woo-Kyu,Kong, Jae Yang,Park Choo, Hea-Young
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experimental part
p. 1665 - 1675
(2010/05/02)
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- Synthesis and biological evaluation of oxazole derivatives as T-type calcium channel blockers
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T-type calcium channel is one of therapeutic targets for the treatment of cardiovascular diseases and neuropathic pain. In this study, as a part of our ongoing efforts to develop potent T-type calcium channel blockers, we designed oxazole derivatives subs
- Lee, Jie Eun,Koh, Hun Yeong,Seo, Seon Hee,Baek, Yi Yeon,Rhim, Hyewhon,Cho, Yong Seo,Choo, Hyunah,Pae, Ae Nim
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scheme or table
p. 4219 - 4222
(2010/09/04)
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- Further structure-activity relationships study of hybrid 7-{[2-(4-phenylpiperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2- ol analogues: identification of a high-affinity D3-preferring agonist with potent in vivo activity with long duration
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This paper describes an extended structure-activity relationships study of aminotetralin-piperazine-based hybrid molecules developed earlier for dopamine D2/D3 receptors. Various analogues as positional isomers have been developed where location of the ph
- Biswas, Swati,Zhang, Suhong,Fernandez, Fernando,Ghosh, Balaram,Zhen, Juan,Kuzhikandathil, Eldo,Reith, Maarten E. A.,Dutta, Aloke K.
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p. 101 - 117
(2008/09/20)
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- Design, synthesis and molecular modeling study of iminodiacetyl monohydroxamic acid derivatives as MMP inhibitors
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As the matrix metalloproteinases (MMPs) can be massively up-regulated in degenerative tissues and degrade the extracellular matrix, these key enzymes are promising targets for the therapy of cancer and other degenerative diseases. Here, we are presenting a series of new non-peptidic hydroxamate-based matrix metalloproteinase inhibitors, MMPIs, incorporating the iminodiacetic (IDA) hydroxamic acid scaffold, as mimics of truncated peptidic MMPIs. A series of alkylaryl and sulfonylaryl groups, on the IDA basic scaffold, was investigated with the aim of improving potency and selectivity against MMPs involved in degenerative diseases. The sulfonamide based IDA derivatives studied (compounds B1-B3) showed to be potent (nM range) against deep S1′ pocket MMPs enzymes (i.e., MMP-2).
- Amelia Santos,Marques, Sergio M.,Tuccinardi, Tiziano,Carelli, Paolo,Panelli, Laura,Rossello, Armando
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p. 7539 - 7550
(2008/02/09)
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- Design and synthesis of [(2,3-dichlorophenyl)piperazin-1-yl]alkylfluorenylcarboxamides as novel ligands selective for the dopamine D3 receptor subtype
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The dopamine D3 receptor subtype has been recently targeted as a potential neurochemical modulator of the behavioral actions of psychomotor stimulants, such as cocaine. However, definitive behavioral investigations have been hampered by the lack of highly selective D3 agonists and antagonists. In an attempt to design a novel class of D3 ligands with which to study this receptor system, a series of chemically divergent compounds that possessed various structural features that exist within several classes of reputed D3 agents was screened and compared to the recently reported NGB 2904 (58b). On the basis of these results, a novel series of compounds was designed that included functional moieties that were required for high-affinity and selective binding to D3 receptors. All the compounds in this series included an aryl-substituted piperazine ring, a varying alkyl chain linker (C3-C5), and a terminal aryl amide. The compounds were synthesized and evaluated in vitro for binding in CHO cells transfected with human D2, D3, or D4 receptor cDNAs. D3 binding affinities ranged from Ki=1.4 to 1460 nM. The most potent analogue in this series, 51, demonstrated a D3/D2 selectivity of 64 and a D3/D4 selectivity of 1300. Structure-activity relationships for this class of ligands at D3 receptors will provide new leads toward the development of highly selective and potent molecular probes that will prove useful in the elucidation of the role D3 receptors play in the psychomotor stimulant and reinforcing properties of cocaine.
- Robarge,Husbands,Kieltyka,Brodbeck,Thurkauf,Newman
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p. 3175 - 3186
(2007/10/03)
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- Phenylacetamides as selective α-1A adrenergic receptor antagonists
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A novel class of potent and selective α-1a receptor antagonists has been identified. The structures of these antagonists were derived from truncating the 4-aryl dihydropyridine subunit present in known α-1a antagonists. The design principles which led to the discovery of substituted phenylacetamides, the synthesis and SAR of key analogues, and the results of select in vitro and in vivo studies are described. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Patane, Michael A.,DiPardo, Robert M.,Newton, Randall C.,Price, RoseAnn P.,Broten, Theodore P.,Chang, Raymond S.L.,Ransom, Richard W.,Di Salvo, Jerry,Nagarathnam, Dhanapalan,Forray, Carlos,Gluchowski, Charles,Bock, Mark G.
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p. 1621 - 1624
(2007/10/03)
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- Synthesis of deuterium-labeled antihypertensive 3-(4'-phenyl-1- piperazlnyl)-propyl-2,4-quinazolinedione
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Synthesis of deuterium-labeled 3-(4-phenyl-1-piperazinyl)-propyl- 2,4quinazolinedione (Pelanserine) an anti-hypertensive agent.
- Garcia,Somanathan,Rivero,Aguirre,Hellberg
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p. 2707 - 2711
(2007/10/03)
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- Quantitative structure-activity analyses of novel hydroxyphenylurea derivatives as antioxidants
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A series of substituted hydroxyphenylureas was synthesized, the chemical structure of which was designed based on structures of natural antioxidants, vitamin E (α-tocopherol) and uric acid. They exhibited high inhibitory activity against lipid peroxidation. In order to gain an insight into the mechanism of the inhibition reaction, we analyzed their structure-activity relationships quantitatively. Electronic and steric effects of substituents on the phenolic hydroxyl group were shown to be of importance in governing the inhibitory potency. An increase in the electron donating property of substituents toward the phenolic hydroxyl group enhanced the antioxidative activity by the stabilization of an electron-deficient radical-type transition state. The steric shielding by ortho-substituents stabilized the phenoxy radicals formed following the transition state. Derivatives having the carboxyl group were only weakly active presumably because of an intermolecular ion-dipole interaction of the phenolic hydroxyl group with the carboxylate anion which could retard the formation of the transition state. Copyright (C) 1998 Elsevier Science Ltd.
- Nakao, Kazuya,Shimizu, Ryo,Kubota, Hitoshi,Yasuhara, Mikiko,Hashimura, Yoshimasa,Suzuki, Toshikazu,Fujita, Toshio,Ohmizu, Hiroshi
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p. 849 - 868
(2007/10/03)
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- N-Arylpiperazinyl-N'-propylamino derivatives of heteroaryl amides as functional uroselective α1-adrenoceptor antagonists
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Novel arylpiperazines were identified as α1-adrenoceptor (AR) subtype- selective antagonists by functional in vitro screening. 3-[4-(ortho- Substituted phenyl)piperazin-1:yl]propylamines were derivatized with N,N- dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4- b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a 'negative screen' for the test antagonists. Binding to α1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the α1-AR subtype prevalent in the human lower urinary tract (pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the α(1D)-AR.
- Elworthy, Todd R.,Ford, Anthony P. D. W.,Bantle, Gary W.,Morgans Jr., David J.,Ozer, Rachel S.,Palmer, Wylie S.,Repke, David B.,Romero, Magarita,Sandoval, Leticia,Sjogren, Eric B.,Talamás, Francisco X.,Vazquez, Alfredo,Wu, Helen,Arredondo, Nicolas F.,Blue Jr., David R.,DeSousa, Andrea,Gross, Lisa M.,Kava, M. Shannon,Lesnick, John D.,Vimont, Rachel L.,Williams, Timothy J.,Zhu, Quan-Ming,Pfister, Jürg R.,Clarke, David E.
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p. 2674 - 2687
(2007/10/03)
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- Design, synthesis and biological evaluation of 1,3-diaminopropanes: A new class of polyamine analogs as leishmanicidal agents
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Analogs of 1,3-diaminopropane as inhibitors for the growth of Leishmania donovani have been synthesized and evaluated for their antileishmanial activity. Of the many active compounds, 1-(3-N,N-bis methoxycarbonyl guanidino)propyl-4- methylpiperidine piperazine (4e,f) exhibited significant in vivo inhibitory efficacy against L. donovani by oral and intraperitoneal route of administration.
- Kumar, Versha Vinay,Singh, Sudhir K.,Sharma,Bhaduri,Gupta, Suman,Zaidi, Alima,Tiwari, Suman,Katiyar
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p. 675 - 680
(2007/10/03)
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- A new series of selective dopamine D4 ligands: 3-([4-arylpiperazin-1-yl]alkylamino)-2H-1,4-benzoxazines
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A series of 3-([4-arylpiperaz-1-yl)alkylamino]-2H-1,4-benzoxazines were prepared and their affinities for cloned human D2, D3, and D4 dopamine receptor subtypes were measured. This led to the identification of 1a, 1f, and 1g as high affinity selective antagonists at the D4 receptor.
- He, Xiao Shu,Woodruff, Kristine,Brodbeck, Robbin
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p. 2399 - 2402
(2007/10/03)
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- ISOINDOLINYL-ALKYL-PIPERAZINES
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The invention is generally concerned with isoindolinyl-alkylpiperazine compounds generally characterized by the formula STR1 wherein X is halogen or trifluoromethyl; n is an integer ranging from 2 to 5; Y is STR2 in which R 1 is hydrogen, halogen, lower alkyl, lower alkoxy, trifluoromethyl, cyano; R 2 is hydrogen, halogen, lower alkyl, lower alkoxy; and R 3 is hydrogen, cyano. These compounds are useful as diuretic and/or antihypertensive agents.
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