- Non-alkylator anti-glioblastoma agents induced cell cycle G2/M arrest and apoptosis: Design, in silico physicochemical and SAR studies of 2-aminoquinoline-3-carboxamides
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Malignant gliomas are the most common brain tumors, with generally dismal prognosis, early clinical deterioration and high mortality. Recently, 2-aminoquinoline scaffold derivatives have shown pronounced activity in central nervous system disorders. We herein reported a series of 2-aminoquinoline-3-carboxamides as novel non-alkylator anti-glioblastoma agents. The synthesized compounds showed comparable activity to cisplatin against glioblastoma cell line U87 MG in vitro. Among them, we found that 6a displayed good inhibitory activity against A172 and U118 MG glioblastoma cell lines and induced cell cycle arrest in the G2/M phase and apoptosis in U87 MG by flow cytometry analysis. Additionally, 6a displayed low cytotoxicity to several normal human cell lines. In silico study showed 6a had promising physicochemical properties and was predicted to cross the blood–brain barrier. Moreover, preliminary structure–activity relationships are also investigated, shedding light on further modifications towards more potent agents on this series of compounds. Our results suggest this compound has a promising potential as an anti-glioblastoma agent with a differential effect between tumor and non-malignant cells.
- Yuan, Pengtao,Gu, Xiangyu,Ni, Xintong,Qi, Yingxue,Shao, Xusheng,Xu, Xiaoyong,Liu, Jianwen,Qian, Xuhong
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supporting information
(2021/09/22)
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- Synthesis and Docking Study of Novel Pyranocoumarin Derivatives
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Abstract: A new series of fused tricyclic coumarin derivatives were designed, synthesized by a simple and convenient method, starting from 4-hydroxycoumarin and virtually screened by molecular docking on the target protein 3FRZ (PDB ID: 3FRZ), a HCV RNA-dependent RNA polymerase, for potency against hepatitis C virus (HCV). Efficient binding to the target protein was found for most of the synthesized compounds.
- Karteek, S. Durga,Reddy, A. Gopi,Tej, M. Bhuvan,Rao, M. V. Basaveswara
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p. 272 - 282
(2021/04/02)
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- Nickel-promoted oxidative domino Csp3-H/N-H bond double-isocyanide insertion reaction to construct pyrrolin-2-ones
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The first nickel-catalyzed oxidative domino Csp3-H/N-H double isocyanide insertion reaction of acetamides with isocyanides has been developed for the synthesis of pyrrolin-2-one derivatives. A wide range of acetamides bearing various functional groups are compatible with this reaction system by utilizing Ni(acac)2as a catalyst. In this transformation, isocyanide could serve as a C1 connector and insert into the inactive Csp3-H bond, representing an effective way to construct heterocycles.
- Wen, Li-Rong,Wang, Ning-Ning,Du, Wu-Bo,Ma, Qiang,Zhang, Lin-Bao,Li, Ming
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supporting information
p. 2895 - 2900
(2021/04/14)
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- Synthesis and biological evaluation of flavone-8-acrylamide derivatives as potential multi-target-directed anti Alzheimer agents and investigation of binding mechanism with acetylcholinesterase
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In a search for novel multifunctional anti-Alzheimer agents, a congeneric set of seventeen flavone-8-acrylamide derivatives (8a─q)were synthesized and evaluated for their cholinesterase inhibitory, antioxidant, neuroprotective and modulation of Aβ aggregation activities. The target compounds showed effective and selective inhibitory activity against the AChE over BuChE. In addition, the target compounds also showed moderate anti-oxidant activity and strong neuroprotective capacities, and accelerated dosage-dependently the Aβ aggregation. Also, we presented here a complete study on the interaction of 8a, 8d, 8e, 8h and 8i with AChE. Through fluorescence emission studies, the binding sites number found to be 1, binding constants were calculated as 2.04 × 104, 2.22 × 104, 1.18 × 104, 9.8 × 103 and 3.2 × 104 M?1 and free energy change as ?5.83, ?5.91, ?5.51, ?5.41 and ?6.12 kcal M?1 at 25 °C which were well agreed with the computational calculations indicating a strong binding affinity of flavones and AChE. Furthermore, the CD studies revealed that the secondary structure of AChE became partly unfolded upon binding with 8a, 8d, 8e, 8h and 8i.
- Shaik, Jeelan Basha,Yeggoni, Daniel Pushparaju,Kandrakonda, Yelamanda Rao,Penumala, Mohan,Zinka, Raveendra Babu,Kotapati, Kasi Viswanath,Darla, Mark Manidhar,Ampasala, Dinakara Rao,Subramanyam, Rajagopal,Amooru, Damu Gangaiah
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- 5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors
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Chronic hepatitis B virus (HBV) infection represents a major health threat. Current FDA-approved drugs do not cure HBV. Targeting HBV core protein (Cp) provides an attractive approach toward HBV inhibition and possibly infection cure. We have previously identified and characterized a 5-amino-3-methylthiophene-2,4-dicarboxamide (ATDC) compound as a structurally novel hit for capsid assembly effectors (CAEs). We report herein hit validation through studies on absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK), and hit optimization via analogue synthesis aiming to probe the structure-activity relationship (SAR) and structure-property relationship (SPR). In the end, these medicinal chemistry efforts led to the identification of multiple analogues strongly binding to Cp, potently inhibiting HBV replication in nanomolar range without cytotoxicity, and exhibiting good oral bioavailability (F). Two of our analogues, 19o (EC50 = 0.11 μM, CC50 > 100 μM, F = 25%) and 19k (EC50 = 0.31 μM, CC50 > 100 μM, F = 46%), displayed overall lead profiles superior to reported CAEs 7–10 used in our studies.
- Tang, Jing,Huber, Andrew D.,Pineda, Dallas L.,Boschert, Kelsey N.,Wolf, Jennifer J.,Kankanala, Jayakanth,Xie, Jiashu,Sarafianos, Stefan G.,Wang, Zhengqiang
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supporting information
p. 179 - 192
(2019/01/04)
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- Synthesis, cytotoxic characterization, and SAR study of imidazo[1,2-b]pyrazole-7-carboxamides
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The synthesis and in vitro cytotoxic characteristics of new imidazo[1,2-b]pyrazole-7-carboxamides were investigated. Following a hit-to-lead optimization exploiting 2D and 3D cultures of MCF-7 human breast, 4T1 mammary gland, and HL-60 human promyelocytic leukemia cancer cell lines, a 67-membered library was constructed and the structure–activity relationship (SAR) was determined. Seven synthesized analogues exhibited sub-micromolar activities, from which compound 63 exerted the most significant potency with a remarkable HL-60 sensitivity (IC50 = 0.183 μM).
- Demjén, András,Alf?ldi, Róbert,Angyal, Anikó,Gyuris, Márió,Hackler, László,Szebeni, Gábor J.,W?lfling, János,Puskás, László G.,Kanizsai, Iván
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- New Flavone-Cyanoacetamide Hybrids with a Combination of Cholinergic, Antioxidant, Modulation of β-Amyloid Aggregation, and Neuroprotection Properties as Innovative Multifunctional Therapeutic Candidates for Alzheimer's Disease and Unraveling Their Mechanism of Action with Acetylcholinesterase
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In line with the modern multi-target-directed ligand paradigm of Alzheimer's disease (AD), a series of 19 compounds composed of flavone and cyanoacetamide groups have been synthesized and evaluated as multifunctional agents against AD. Biological evaluation demonstrated that compounds 7j, 7n, 7o, 7r, and 7s exhibited excellent inhibitory potency (AChE, IC50 of 0.271 ± 0.012 to 1.006 ± 0.075 μM) and good selectivity toward acetylcholinesterase, significant antioxidant activity, good modulation effects on self-induced Aβ aggregation, low cytotoxicity, and neuroprotection in human neuroblastoma SK-N-SH cells. Further, an inclusive study on the interaction of 7j, 7n, 7o, 7r, and 7s with AChE at physiological pH 7.2 using fluorescence, circular dichroism, and molecular docking methods suggested that these derivatives bind strongly to the peripheral anionic site of AChE mostly through hydrophobic interactions. Overall, the multifunctional profiles and strong AChE binding affinity highlight these compounds as promising prototypes for further pursuit of innovative multifunctional drugs for AD.
- Basha, Shaik Jeelan,Mohan, Penumala,Yeggoni, Daniel Pushparaju,Babu, Zinka Raveendra,Kumar, Palaka Bhagath,Rao, Ampasala Dinakara,Subramanyam, Rajagopal,Damu, Amooru Gangaiah
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p. 2206 - 2223
(2018/05/23)
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- Synthesis, pharmacological assessment, molecular modeling and in silico studies of fused tricyclic coumarin derivatives as a new family of multifunctional anti-Alzheimer agents
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A series of fused tricyclic coumarin derivatives bearing iminopyran ring connected to various amido moieties were developed as potential multifunctional anti-Alzheimer agents for their cholinesterase inhibitory and radical scavenging activities. In vitro studies revealed that most of these compounds exhibited high inhibitory activity on acetylcholinesterase (AChE), with IC50 values ranging from 0.003 to 0.357 μM which is 2-220 folds more potent than the positive control, galantamine. Their inhibition selectivity against AChE over butyrylcholinesterase (BuChE) has increased about 194 fold compared with galantamine. The developed compounds also showed potent ABTS radical scavenging activity (IC50 7.98-15.99 μM). Specifically, the most potent AChE inhibitor 6n (IC50 0.003 ± 0.0007 μM) has an excellent antioxidant profile as determined by the ABTS method (IC50 7.98 ± 0.77 μM). Moreover, cell viability studies in SK N SH cells showed that the compounds 6m-q have significant neuroprotective effects against H2O2-induced cell death, and are not neurotoxic at all concentrations except 6n and 6q. The kinetic analysis of compound 6n proved that it is a mixed-type inhibitor for EeAChE (Ki1 0.0103 μM and Ki2 0.0193 μM). Accordingly, the molecular modeling study demonstrated that 6m-q with substituted benzyl amido moiety possessed an optimal docking pose with interactions at catalytic active site (CAS) and peripheral anionic site (PAS) of AChE simultaneously and thereby they might prevent aggregation of Aβ induced by AChE. Furthermore, in silico ADMET prediction studies indicated that these compounds satisfied all the characteristics of CNS acting drugs. Most active inhibitor 6n is permeable to BBB as determined in the in vivo brain AChE activity. To sum up, the multipotent therapuetic profile of these novel tricyclic coumarins makes them promising leads for developing anti-Alzheimer agents.
- Shaik, Jeelan Basha,Palaka, Bhagath Kumar,Penumala, Mohan,Kotapati, Kasi Viswanath,Devineni, Subba Rao,Eadlapalli, Siddhartha,Darla, M. Manidhar,Ampasala, Dinakara Rao,Vadde, Ramakrishna,Amooru, G. Damu
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p. 219 - 232
(2015/11/24)
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- Synthesis, Biological Evaluation, and Molecular Docking of 8-imino-2-oxo-2H,8H-pyrano[2,3-f]chromene Analogs: New Dual AChE Inhibitors as Potential Drugs for the Treatment of Alzheimer's Disease
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Alzheimer's disease onset and progression are associated with the dysregulation of multiple and complex physiological processes, and a successful therapeutic approach should therefore address more than one target. In line with this modern paradigm, a series of 8-imino-2-oxo-2H,8H-pyrano[2,3-f]chromene analogs (4a–q) were synthesized and evaluated for their multitarget-directed activity on acetylcholinesterase, butyrylcholinesterase (BuChE), 2,2’-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical, and amyloid-β peptide (Aβ) specific targets for Alzheimer's disease therapy. Most of the synthesized compounds showed remarkable acetylcholinesterase inhibitory activities in low nm concentrations and good ABTS radical scavenging activity, however, no evidence of BuChE inhibitory activity. Among them, 3-bromobenzylamide derivative 4m exhibited the best acetylcholinesterase inhibitory activity with IC50 value of 13 ± 1.4 nm which is 51-fold superior to galantamine, a reference drug. Kinetic and molecular docking studies indicated 4m as mixed-type inhibitor, binding simultaneously to catalytic active and peripheral anionic sites of acetylcholinesterase. Five compounds 4e, 4f, 4g, 4j, and 4k have shown 1.4- to 2.5-fold of higher antioxidant activities than trolox. Interestingly, the most active compound 4m demonstrated dosage-dependent acceleration of Aβ1?42 aggregation, which may reduce toxicity of oligomers. Overall, these results lead to discovery of fused tricyclic coumarins as promising dual binding site inhibitors of acetylcholinesterase and afford multifunctional compounds with potential impact for further pharmacological development in Alzheimer's therapy.
- Shaik, Jeelan Basha,Palaka, Bhagath Kumar,Penumala, Mohan,Eadlapalli, Siddhartha,Darla Mark, Manidhar,Ampasala, Dinakara Rao,Vadde, Ramakrishna,Amooru Gangaiah, Damu
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- Synthesis of resveratrol acrylamides derivatives and biological evaluation of their anti-proliferative effect on cancer cell lines
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A new series of resveratrol acrylamides amine derivatives was designed, synthesized, and evaluated for their anti-proliferative activity against three cancer cell lines including human chronic myelocytic leukemia cell K562, human hepatoma HuH-7 and human lung carcinoma A549. Most of the compounds showed superior activity against three cell lines when compared to parent resveratrol. C13 had the best anti-tumor activity against the HuH-7 cell line and its IC 50 was 4.5 μmol/L; C16 had the best anti-tumor activity against the K562 cell line and its IC50 was 2.9 μmol/L; C18 had the best anti-tumor activity against the A549 cell line and its IC50 was 3.8 μmol/L. It could be seen that the activity of the aromatic amine derivatives was better than the fatty amine derivatives by analyzing the experimental data.
- Ruan, Ban-Feng,Wang, Si-Qi,Ge, Xiao-Lin,Yao, Ri-Sheng
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- A simple and general approach for the synthesis of highly functionalized 6-oxo-1,6-dihydropyridines
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A variety of 5-cyano-4-methylthio-6-oxo-1,6-dihydropyridine-3-carboxylates have been efficiently synthesized in a one-pot reaction from N-alkyl and N-aryl derivatives of 2-cyano-3,3-bis(methylthio)acrylamides and selected β-keto esters. The reaction proceeds via potassium hydrogen carbonate mediated conjugate addition of a β-keto ester to 2-cyano-3,3-bis(methylthio) acrylamide followed by loss of methyl mercaptan and subsequent intramolecular condensation of amide group with the acyl carbonyl group. The mechanism of the reaction has been established by isolation of the 2-acetyl-4-cyano-5-amino-3- (methylthio)-5-oxopent-3-enoate intermediate and its independent cyclization to the desired 6-oxo-1,6-dihydropyridine.
- Kumar, Sukeerthi,Thakur, Rajni R.,Margal, Sanjay R.,Thomas, Abraham
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supporting information
p. 5112 - 5118
(2013/06/27)
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- Cyanoacetamides (IV): Versatile one-pot route to 2-quinoline-3-carboxamides
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Cyanoacetic acid derivatives are the starting materials for a plethora of multicomponent reaction (MCR) scaffolds. Herein, we describe scope of a valuable general protocol for the synthesis of arrays of 2-aminoquinoline-3-carboxamides from cyanoacetamides and 2-aminobenzaldehydes or heterocyclic derivatives via a Friedlaender reaction variation. In many cases, the reactions involve a very convenient work up by simple precipitation and filtration. More than 40 new products are described. We foresee our protocol and the resulting derivatives becoming very valuable to greatly expanding the scaffold space of cyanoacetamide derivatives.
- Wang, Kan,Herdtweck, Eberhardt,Doemling, Alexander
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scheme or table
p. 316 - 322
(2012/06/18)
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- Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases
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The 3-aryl-2-cyanoacrylamide scaffold was designed as core pharmacophore for inhibitors of the Dengue and West Nile virus serine proteases (NS2B-NS3). A total of 86 analogs was prepared to study the structure-activity relationships in detail. Thereby, it turned out that the electron density of the aryl moiety and the central double bond have a crucial influence on the activity of the compounds, whereas the influence of substituents of the amide residue is less relevant. The para-hydroxy substituted analog was found to be the most potent inhibitor in this series with a Ki-value of 35.7 μM at the Dengue and 44.6 μM at the West Nile virus protease. The aprotinin competition assay demonstrates a direct interaction of the inhibitor molecule with active centre of the Dengue virus protease. The target selectivity was studied in a counterscreen with thrombin and found to be 2.8:1 in favor of DEN protease and 2.3:1 in favor of WNV protease, respectively.
- Nitsche, Christoph,Steuer, Christian,Klein, Christian D.
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experimental part
p. 7318 - 7337
(2012/01/05)
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- CINNOLINE COMPOUNDS, THEIR PREPARATION, AND THEIR USE
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The present invention relates to cinnoline compounds, particularly 4-amino-N-cyclopropyl- 7-fluoro-8-(3,6-dimethoxypyridazin-4-yl)cinnoline-3-carboxamide and salts thereof. The claimed invention also relates to compositions comprising such a compound, as
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Page/Page column 20-21
(2011/04/13)
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- Development and SAR of functionally selective allosteric modulators of GABAA receptors
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Positive modulators at the benzodiazepine site of α2- and α3-containing GABAA receptors are believed to be anxiolytic. Through oocyte voltage clamp studies, we have discovered two series of compounds that are positive modulators at α2-/α3-containing GABAA receptors and that show no functional activity at α1-containing GABA A receptors. We report studies to improve this functional selectivity and ultimately deliver clinical candidates. The functional SAR of cinnolines and quinolines that are positive allosteric modulators of the α2- and α3-containing GABAA receptors, while simultaneously neutral antagonists at α1-containing GABAA receptors, is described. Such functionally selective modulators of GABAA receptors are expected to be useful in the treatment of anxiety and other psychiatric illnesses.
- Alhambra, Cristobal,Becker, Chris,Blake, Timothy,Chang, Amy,Damewood Jr., James R.,Daniels, Thalia,Dembofsky, Bruce T.,Gurley, David A.,Hall, James E.,Herzog, Keith J.,Horchler, Carey L.,Ohnmacht, Cyrus J.,Schmiesing, Richard Jon,Dudley, Adam,Ribadeneira, Maria D.,Knappenberger, Katherine S.,MacIag, Carla,Stein, Mark M.,Chopra, Maninder,Liu, Xiaodong F.,Christian, Edward P.,Arriza, Jeffrey L.,Chapdelaine, Marc J.
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experimental part
p. 2927 - 2938
(2011/06/21)
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- Methods for the synthesis of substituted amino uracils
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The invention provides novel methods of preparing substituted amino uracil compounds that can be employed as useful intermediates in the synthesis of various xanthines. Highly regioselective unsymmetrical amino uracils can be obtained using these methods
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Page/Page column 5
(2010/11/26)
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- Compounds and Uses Thereof
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This invention relates to novel compounds having the structural formula I below: and their pharmaceutically acceptable salts, tautomers or in vivo-hydrolysable precursors, compositions and methods of use thereof. These novel compounds provide a treatment or prophylaxis of anxiety disorders, cognitive disorders, and/or mood disorders.
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Page/Page column 87
(2008/06/13)
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