- Expedient discovery for novel antifungal leads: 1,3,4-Oxadiazole derivatives bearing a quinazolin-4(3H)-one fragment
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Developing novel fungicide candidates are intensively promoted by the rapid emergences of resistant fungi that outbreak on agricultural production. Aiming to discovery novel antifungal leads, a series of 1,3,4-oxadiazole derivatives bearing a quinazolin-4(3H)-one fragment were constructed for evaluating their inhibition effects against phytopathogenic fungi in vitro and in vivo. Systematically structural optimizations generated the bioactive molecule I32 that was identified as a promising inhibitor against Rhizoctonia solani with the in vivo preventative effect of 58.63% at 200 μg/mL. The observations that were captured by scanning electron microscopy and transmission electron microscopy demonstrated that the bioactive molecule I32 could induce the sprawling growth of hyphae, the local shrinkage and rupture on hyphal surfaces, the extreme swelling of vacuoles, the striking distortions on cell walls, and the reduction of mitochondria numbers. The above results provided an indispensable complement for the discovery of antifungal lead bearing a quinazolin-4(3H)-one and 1,3,4-oxadiazole fragment.
- Chai, Jianqi,Chen, Min,Jin, Fei,Kong, Xiangyi,Wang, Xiaobin,Xue, Wei,Yang, Chunlong
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- PDIA4 INHIBITORS AND USE THEREOF FOR INHIBITING ?-CELL PATHOGENESIS AND TREATING DIABETES
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Disulfide-Isomerase A4 (PDIA4) inhibitors and use thereof for inhibiting pancreatic β-cell pathogenesis and treating diabetes are disclosed. Drug candidates that inhibit PDIA4 with IC50 values ranging from 4 μM to 300 nM are identified. The compounds are highly active in augmenting insulin secretion from pancreatic β-cells. The representative compound No. 8 (4,5-dimethoxy-2-propiolamidobenzoic acid), alone or in combination with metformin, is effective in preserving pancreatic β-cell function, treating and/or reversing, returning blood glucose concentration to a normal level in a diabetic.
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Page/Page column 10
(2021/06/11)
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- Synthesis, biological evaluation and molecular docking studies of novel 1,2,3-triazole-quinazolines as antiproliferative agents displaying ERK inhibitory activity
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ERK1/2 inhibitors have attracted special attention concerning the ability of circumventing cases of innate or log-term acquired resistance to RAF and MEK kinase inhibitors. Based on the 4-aminoquinazoline pharmacophore of kinases, herein we describe the synthesis of 4-aminoquinazoline derivatives bearing a 1,2,3-triazole stable core to bridge different aromatic and heterocyclic rings using copper-catalysed azide-alkyne cycloaddition reaction (CuAAC) as a Click Chemistry strategy. The initial screening of twelve derivatives in tumoral cells (CAL-27, HN13, HGC-27, and BT-20) revealed that the most active in BT-20 cells (25a, IC50 24.6 μM and a SI of 3.25) contains a more polar side chain (sulfone). Furthermore, compound 25a promoted a significant release of lactate dehydrogenase (LDH), suggesting the induction of cell death by necrosis. In addition, this compound induced G0/G1 stalling in BT-20 cells, which was accompanied by a decrease in the S phase. Western blot analysis of the levels of p-STAT3, p-ERK, PARP, p53 and cleaved caspase-3 revealed p-ERK1/2 and p-STA3 were drastically decreased in BT-20 cells under 25a incubation, suggesting the involvement of these two kinases in the mechanisms underlying 25a-induced cell cycle arrest, besides loss of proliferation and viability of the breast cancer cell. Molecular docking simulations using the ERK-ulixertinib crystallographic complex showed compound 25a could potentially compete with ATP for binding to ERK in a slightly higher affinity than the reference ERK1/2 inhibitor. Further in silico analyses showed comparable toxicity and pharmacokinetic profiles for compound 25a in relation to ulixertinib.
- Nunes, Paulo Sérgio Gon?alves,da Silva, Gabriel,Nascimento, Sofia,Mantoani, Susimaire Pedersoli,de Andrade, Peterson,Bernardes, Emerson Soares,Kawano, Daniel Fábio,Leopoldino, Andreia Machado,Carvalho, Ivone
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- Design, synthesis and biological evaluation of novel N-sulfonylamidine-based derivatives as c-Met inhibitors via Cu-catalyzed three-component reaction
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In our continuing efforts to develop novel c-Met inhibitors as potential anticancer candidates, a series of new N-sulfonylamidine derivatives were designed, synthesized via Cu-catalyzed multicomponent reaction (MCR) as the key step, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, HT-29, MKN-45 and MDA-MB-231). Most of the target compounds showed moderate to significant potency at both the enzyme-based and cell-based assay and possessed selectivity for A549 and HT-29 cancer cell lines. The preliminary SAR studies demonstrated that compound 26af (c-Met IC50 = 2.89 nM) was the most promising compound compared with the positive foretinib, which exhibited the remarkable antiproliferative activities, with IC50 values ranging from 0.28 to 0.72 μM. Mechanistic studies of 26af showed the anticancer activity was closely related to the blocking phosphorylation of c-Met, leading to cell cycle arresting at G2/M phase and apoptosis of A549 cells by a concentration-dependent manner. The promising compound 26af was further identified as a relatively selective inhibitor of c-Met kinase, which also possessed an acceptable safety profile and favorable pharmacokinetic properties in BALB/c mouse. The favorable drug-likeness of 26af suggested that N-sulfonylamidines may be used as a promising scaffold for antitumor drug development. Additionally, the docking study and molecular dynamics simulations of 26af revealed a common mode of interaction with the binding site of c-Met. These positive results indicated that compound 26af is a potential anti-cancer candidate for clinical trials, and deserves further development as a selective c-Met inhibitor.
- Fang, Sen-Biao,Li, Hui-Jing,Nan, Xiang,Wu, Rui,Wu, Yan-Chao,Zhang, Jing,Zhang, Zhi-Zhou
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- Synthesis and biological evaluation of quinoline/cinnamic acid hybrids as amyloid-beta aggregation inhibitors
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Abstract: The objective of the current study is to evaluate the potency of quinoline/cinnamic acid hybrids against amyloid-beta (Aβ) aggregation. In total, six new target quinoline/cinnamic acid hybrids were synthesized and screened for their in vitro anti-Aβ42 aggregation activity. Some hybrids, including (E)-N-(2-cinnamamidoethyl)-6,7-dimethoxyquinoline-2-carboxamide, (E)-6,7-dimethoxy-N-[2-[3-(4-methoxyphenyl)acrylamido]ethyl]quinoline-2-carboxamide, and (E)-6,7-dimethoxy-N-[2-[3-(2-methoxyphenyl)acrylamido]ethyl]quinoline-2-carboxamide, showed significant anti-Aβ42 aggregation activity. Molecular docking method was used to predict the binding modes of these compounds with Aβ42. In addition, their cytotoxicity towards neuroblastoma SH-SY5Y and human normal hepatocyte LO2 cells were tested. Neuroprotective evaluation demonstrated that these compounds could attenuate Aβ42-induced neurotoxicity towards SH-SY5Y cells in a dose-dependent manner. Overall, the present study provides quinoline/cinnamic acid hybrids as a new template for developing Aβ aggregation inhibitors against Alzheimer’s disease. Graphic abstract: [Figure not available: see fulltext.].
- Cheng, Zhi-Qiang,Ge, Yong-Xi,Jiang, Cheng-Shi,Jiao, Yang,Liu, Guangpu,Wang, Yin-Yin,Xie, Hong-Xu,Zhou, Lei,Zhu, Kongkai
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- Synthesis and pharmacological evaluation of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as sigma-2 receptor ligands
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Increasing evidences have implicated that sigma-2 receptor is a biomarker and significantly over-expressed in many proliferative cancer cells with no or low expression in normal cells. Sigma-2 receptor selective ligands have been successfully used as valuable tools to study its pharmacological functions, tumor imaging, and cancer therapeutics or adjuvants. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolinylalkyl benzamides are among a few categories of structures that have demonstrated high affinities and selectivities for sigma-2 receptor and been used extensively as study tools in various tumor imaging and therapy. As a continuous effort, we have synthesized a new series of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives and evaluated their affinities for both sigma-1 and sigma-2 receptors. Most of these newly developed analogs showed good to excellent binding affinities for sigma-2 receptor with no or low affinities for sigma-1 receptor. In particular, compounds 3b, 3e, 4b, and 4e demonstrated Ki values of 5–6 nM affinities and excellent selectivities for sigma-2 receptor. In addition, these analogs also demonstrated moderate anticancer activities against human liver Huh-7 tumor cells and human esophagus KYSE-140 cancer cells. But their cytotoxicities seem not to be correlated with their sigma-2 receptor affinities.
- Sun, Yu-Tong,Wang, Gui-Fei,Yang, Yi-Qiu,Jin, Fujun,Wang, Yifei,Xie, Xiao-Yang,Mach, Robert H.,Huang, Yun-Sheng
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p. 227 - 237
(2018/02/14)
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- Studies on the interactions of 5-R-3-(2-pyridyl)-1,2,4-triazines with arynes: inverse demand aza-Diels-Alder reaction versus aryne-mediated domino process
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The interactions between substituted 5-R-3-(pyridyl-2)-1,2,4-triazines with in situ generated substituted aryne intermediates have been studied. The reaction afforded either inverse demand (ID) aza-Diels-Alder products or 1,2,4-triazine ring rearrangement (domino) products as major ones depending on the nature of both the substituents at the C5 position of the 1,2,4-triazine core or in the aryne moiety. The structures of the key products were confirmed based on X-ray data. Based on the density functional theoretical (DFT) studies of the Diels-Alder transition state geometries, the influence of the nature of arynes on the direction of the 1,2,4-triazine transformation has been proposed.
- Kopchuk, Dmitry S.,Nikonov, Igor L.,Khasanov, Albert F.,Giri, Kousik,Santra, Sougata,Kovalev, Igor S.,Nosova, Emiliya V.,Gundala, Sravya,Venkatapuram, Padmavathi,Zyryanov, Grigory V.,Majee, Adinath,Chupakhin, Oleg N.
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p. 5119 - 5135
(2018/07/29)
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- Tetrahydroisoquinoline derivatives preparation and application of (by machine translation)
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The invention mainly relates to a series of containing tetrahydroisoquinoline structure the synthesis of the compounds and in the medical field of application. Specifically, the invention relates to a series of tetrahydroisoquinoline structure compound, it can inhibit the polymerization of A β, antagonizing A β O in combination and in nerve cells caused by the cytotoxic, therapeutic or improve AD has application prospect. (by machine translation)
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- Design and discovery of quinazoline- and thiourea-containing sorafenib analogs as EGFR and VEGFR-2 dual TK inhibitors
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Both EGFR and VEGFR-2 play a critical role in tumor growth, angiogenesis and metastasis, and targeting EGFR and VEGFR-2 simultaneously represents a promising approach to cancer treatment. In this work, a series of novel quinazoline- and thiourea-containing sorafenib analogs (10a–v) were designed and synthesized as EGFR and VEGFR-2 dual TK inhibitors. Their in vitro enzymatic inhibitory activities against EGFR and VEGFR-2, and antiproliferative activities against HCT-116, MCF-7 and B16 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and TK kinases. Compounds 10b and 10q which exhibited the most potent inhibitory activities against EGFR (IC50 = 0.02 μM and 0.01 μM, respectively), VEGFR-2 (IC50 = 0.05 μM and 0.08 μM, respectively), and good antiproliferative activities, also displayed competitive anti-tumor activities than sorafenib in vivo by B16 melanoma xenograft model test.
- Sun, Shaofeng,Zhang, Jingwen,Wang, Ningning,Kong, Xiangkai,Fu, Fenghua,Wang, Hongbo,Yao, Jianwen
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- Erlotinib derivative with antitumor activity, and preparation method and application thereof
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The invention discloses an erlotinib derivative with antitumor activity, and a preparation method and application thereof, and belongs to the technical field of synthesis of antitumor active medicine. The method has the main technical scheme that the erlotinib derivative with antitumor activity has a structure formula shown as the accompanying drawing, wherein R is phenyl, p-methylphenyl, m-nitrophenyl, o-chlorphenyl or o-hydroxy benzon phenyl. The invention also discloses a concrete synthesis process of the erlotinib derivative with antitumor activity and application of the erlotinib derivative with antitumor activity to preparation of liver cancer treatment medicine. The erlotinib molecules are modified and are structurally connected with a series of different 1,2,3-triazole groups; the synthesized erlotinib derivative is subjected to anti-tumor activity test; the test result shows that the compound has high inhibition activity on liver cancer HepG2 cells.
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- Chemoselective Hydrazine-mediated Transfer Hydrogenation of Nitroarenes by Co3O4 Nanoparticles Immobilized on an Al/Si-mixed Oxide Support
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Cobalt oxide nanoparticles (size 2 to 3.5 nm) were successfully impregnated on an alumina–silica (mixed oxide) support through an experimentally viable and easily reproducible protocol. The prepared material was well characterized by XRD, HR-TEM, BET surface area, EDX and XPS analyses. Porous alumina–silica having a high surface area served as a protective heterogeneous support on which the well-dispersed Co3O4 nanoparticles served as an active catalytic species for the hydrazine-mediated transfer hydrogenation of nitroarenes. About 2 mol % of the active catalyst in ethanol at 60 °C was adequate for a successful conversion. Moreover, transfer hydrogenation of nitroarenes by the catalyst was found to take place chemoselectively in the presence of other labile functional groups such as halide, alkene, nitrile, carbonyl, and ester. This inexpensive catalyst was also able to catalyze the reaction on a gram scale reaction and found to be robust and recyclable up to eight runs.
- Reddy, P. Linga,Tripathi, Mohit,Arundhathi,Rawat, Diwan S.
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p. 785 - 791
(2017/04/13)
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- 6,7-Dimethoxy-quinazolin-4-yl-amino-thiophene-2-carboxamides as Potent Inhibitors of VEGF Receptors 1 and 2
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The identification of agents with antiproliferative activity against endothelial cells has significant value for the treatment of many angiogenesis-dependent pathologies. The vascular endothelial growth factor (VEGF) and its receptors have been implicated as key factors in tumor angiogenesis and are major targets in cancer therapy. A series of novel 6,7-dimethoxy-quinazolin-4-yl-amino-thiophene-2-carboxamides were synthesized and evaluated as antagonists of VEGFR-1 and VEGFR-2. More specifically, several analogues exhibited low micromolar to nanomolar potency in the inhibition of VEGFR-1 and VEGFR-2. The most potent compound in this series, compound 7b, was found to be a potent inhibitor of VEGFR-2 in a homogeneous time-resolved fluorescence enzymatic assay with an IC50 as low as 87 nm.
- Ashok, Abhishek,Thanukrishnan, Kannan,Bhojya Naik, Halehatty S.,Shaik, Abdul Gaffar
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p. 1065 - 1070
(2017/03/27)
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- 6,7-Dimethoxy-Quinazolin-4-yl-Amino-Nicotinamide Derivatives as Potent Inhibitors of VEGF Receptor II
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The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough to cause life-threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor-induced angiogenesis. Inhibition of the VEGF signaling pathway has emerged as one of the most promising new approaches for cancer therapy. A series of 6,7-dimethoxy-quinazolin-4-yl-amino-nicotinamides were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). Many compounds display VEGFR-2 inhibitory activity, and compound 7a was found to be a potent inhibitor of VEGFR-2 in an homogeneous time-resolved fluorescence enzymatic assay with an IC50 as low as 48 nM (comparable activity to ZD-6474).
- Ashok, Abhishek,Thanukrishnan, Kannan,Bhojya Naik, Halehatty S.,Ghosh, Soma
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p. 1723 - 1728
(2017/05/29)
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- Dual inhibitors of epidermal growth factor receptor and topoisomerase IIα derived from a quinoline scaffold
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Based on the quinazoline bearing EGFR inhibitors, a series of thirty four compounds having a quinoline scaffold were synthesised and evaluated in vitro for EGFR kinase inhibitory activity. A structure-activity relationship study revealed that 2,4-bis(arylamino) substituted quinolines possessed better anti-EGFR kinase activity. Compounds 3f and 3m emerged as potent EGFR kinase inhibitors (200 and 210 nM, respectively) and showed excellent anticancer activity at the micromolar level against a panel of cancer cell lines comparable to erlotinib. Furthermore, representative compounds inhibited the human topoisomerase IIα selectively and catalytically, did not intercalate with DNA, increased intracellular ROS concentration (except 3m) and altered the mitochondrial membrane potential of the cancer cells. Cell cycle analysis and annexin-V staining in a lung cancer cell line showed that the compounds delayed cell cycle progression by inducing cell cycle arrest and subsequent apoptosis at the G1 phase. The facts were further corroborated through molecular modeling studies.
- Chauhan, Monika,Joshi, Gaurav,Kler, Harveen,Kashyap, Archana,Amrutkar, Suyog M.,Sharma, Praveen,Bhilare, Kiran D.,Chand Banerjee, Uttam,Singh, Sandeep,Kumar, Raj
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p. 77717 - 77734
(2018/06/22)
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- Novel 4-[5-(substituted-1,2,4-oxadiazol-3-yl)phenylamine] derivatives of 6,7-dimethoxy-quinazolines as potent inhibitors of VEGF receptors I and II
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A series of novel 4-[5-(substituted-1,2,4-oxadiazol-3-yl)phenylamine] derivatives at C-4 position of 6,7-dimethoxy-quinazolines were synthesized through multistep synthesis. The new compounds were tested for inhibition of vascular endothelial growth factor receptor II (VEGFR-2). Many compounds display VEGFR-2 inhibitory activity with an IC50 as low as 0.017 μM in an HTRF enzymatic assay. Compound 8j exhibited good antibacterial activity by inhibiting the growth of methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA) and ATCC 35218 Escherichia coli (MIC: 0.25-16.00 μg/mL).
- Ashok, Abhishek,Thanukrishnan, Kannan,Naik, Halehatty S. Bhojya,Ghosh, Soma
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p. 2122 - 2130
(2016/07/20)
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- Reductive ring closure methodology toward heteroacenes bearing a dihydropyrrolo[3,2- B ]pyrrole core: Scope and limitation
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A newly developed reductive ring closure methodology to heteroacenes bearing a dihydropyrrolo[3,2-b]pyrrole core was systematically studied for its scope and limitation. The methodology involves (i) the cyclization of an o-aminobenzoic acid ester derivative to give an eight-membered cyclic dilactam, and (ii) the conversion of the dilactams into the corresponding diimidoyl chloride, which undergoes (iii) reductive ring closure to install the dihydropyrrolo[3,2-b]pyrrole core. The first step of the methodology plays the key role due to its substrate limitation, which suffers from the competition of oligomerization and hydrolysis. All the dilactams could successfully convert to the corresponding diimidoyl chlorides, most of which succeeded to give the dihydropyrrolo[3,2-b]pyrrole core. The influence of the substituents and the elongation of conjugated length on the photophysical properties of the obtained heteroacenes were then investigated systematically using UV-vis spectroscopy and cyclic voltammetry. It was found that chlorination and fluorination had quite a different effect on the photophysical properties of the heteroacene, and the ring fusing pattern also had a drastic influence on the band gap of the heteroacene. The successful preparation of a series of heteroacenes bearing a dihydropyrrolo[3,2-b]pyrrole core would provide a wide variety of candidates for further fabrication of organic field-effect transistor devices.
- Qiu, Li,Wang, Xiao,Zhao, Na,Xu, Shiliang,An, Zengjian,Zhuang, Xuhui,Lan, Zhenggang,Wen, Lirong,Wan, Xiaobo
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p. 11339 - 11348
(2015/01/09)
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- Design and synthesis of 6,7-dimethoxyquinazoline analogs as multi-targeted ligands for α1- and AII-receptors antagonism
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Multiple-targeted ligands can have certain advantages for the management of hypertension which has multiple controls. Molecules with dual bioactivities are available in literature for treating metabolic disorders like diabetes, hypertension and hypercholesterolemia. After scrutinizing the SAR of prazosin-type α1-blockers and AII-antagonists it was planned to develop dual α1- and AII-antagonists. Five series of quinazoline derivatives were synthesized and evaluated as dual α1- and AII-antagonists on rat aortic strips for the blockade of known α1- and AII-agonist mediated contractions. Many compounds showed balanced activity on both the receptors but compound (22) was found to be the most active derivative having higher antagonistic activity on both the receptors. In the in vivo experiments the chosen compound (22) was slightly less active than prazosin but was found to be equipotent to losartan. These findings shed a new light on the structural requirements for both α1- as well as AII-receptor antagonists.
- Yadav,Naik,Gandhi,Chauhan,Giridhar
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p. 3959 - 3966
(2013/07/27)
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- Process for Preparing Quinazolinone Derivatives
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The invention relates to a method for producing quinazolinone derivatives of general formula (I), wherein the radicals R1 to R3 have the meanings indicated in the claims and the description.
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Page/Page column 5; 6
(2009/01/24)
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- Ferrous sulfide/aqueous ammonia: Simple, efficient, and chemoselective reagent for the conversion of aromatic azide to amine
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A practical, environmentally benign, rapid, and efficient method for the reduction of aromatic azide to amine is described using FeS/aqueous ammonia in the presence of other reducible functionalities. Application of a novel reducing reagent results in aromatic amines with excellent yield and high chemoselectivity, without need of any purification techniques. Copyright Taylor & Francis Group, LLC.
- Gadakh, Amol V.,Karale, Bhausaheb K.
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p. 186 - 191
(2008/03/17)
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- Simple and facile reduction of azides to amines: Synthesis of DNA interactive pyrrolo[2,1-c][1,4]benzodiazepines
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The reduction of aromatic azido compounds to the corresponding amines with hydriodic acid has been investigated and found to result in high yields. This reductive methodology which proceeds under non refluxing condition has been extended for the synthesis of DNA-interactive pyrrolo[2,1-c][1,4] benzodiazepine antibiotics.
- Kamal, Ahmed,Reddy,Reddy, D.Rajasekhar
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p. 6629 - 6631
(2007/10/03)
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- A modified synthesis of iodoazidoaryl prazosin.
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The antihypertension agent iodoazidoaryl prazosin (IAAP) has been made using a convergent route involving addition of an acylated piperazine 7 to 2-chloroquinazoline 5. IAAP has been shown to function as a multidrug resistance (MDR) reversal agent and bind to P-glycoprotein, a transmembrane transport protein. A study is also reported involving palladium-catalyzed substitution with amine heterocycles. With N,N-bis(2,6-diisopropyl)dihydroimidazolium chloride (10) as the ligand (2 mol %) for palladium(II) acetate (2 mol %) in THF at room temperature, morpholine added to 5 in 81% yield.
- Andrus, Merritt B,Mettath, Sashikumar N,Song, Chun
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p. 8284 - 8286
(2007/10/03)
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- Search for potential amoebicides. Part V. N-substituted 2-nitro-4,5-dimethoxybenzamides and anils of 2-amino-3-methoxy and 2-amino-4,5-dimethoxybenzoic acids.
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The authors in all have synthesised 28 new N-substituted 2-nitro, 4,5-dimethoxy-benzamides, and anils of 2-amino-3-methoxy and 2-amino-4,5-dimethoxybenzoic acids with a view to obtain potent amoebicides. Their work is based on the observation that a large number of dimethoxyphenyl substituted derivatives occupy an important place as antiamobic agents. Fourteen belonging to different series subjected to in vitro screening for amoebicidal activity against E. histolytica failed to show any significant activity.
- Misra,Saxena
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p. 301 - 304,302,303
(2007/10/05)
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