- Fluorescent Probe for Selective Imaging of α-Synuclein Fibrils in Living Cells
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Plaques of amyloid fibrils composed of neuronal protein α-synuclein are one of the hallmarks of Parkinson's disease, and their selective imaging is crucial to study the mechanism of its pathogenesis. However, the existing fluorescent probes for amyloids are efficient only in solution and tissue systems, and they are not selective enough for the visualization of amyloid fibrils in living cells. In this study, we present two molecular rotor-based probes RB1 and RB2. These thiazolium probes show affinity to α-synuclein fibrils and turn-on fluorescence response upon interactions. Because of its extended π-conjugation and high rotational degree of freedom, RB1 exhibits a 76 nm red-shift of absorption maxima and 112-fold fluorescence enhancement upon binding to amyloid fibrils. Owing to its strong binding affinity to α-synuclein fibrils, RB1 can selectively stain them in the cytoplasm of living HeLa and SH-SY5Y cells with high optical contrast. RB1 is a cell-permeable and noncytotoxic probe. Taken together, we have demonstrated that RB1 is an amyloid probe with an outstanding absorption red-shift that can be used for intracellular imaging of α-synuclein fibrils.
- Gaur, Pankaj,Galkin, Maksym,Kurochka, Andrii,Ghosh, Subrata,Yushchenko, Dmytro A.,Shvadchak, Volodymyr V.
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- Novel 6-phenylnicotinohydrazide derivatives: Design, synthesis and biological evaluation as a novel class of antitubercular and antimicrobial agents
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In our ongoing efforts to develop potent antitubercular agents based on the 6-phenylnicotinohydrazide, herein we report the design, synthesis and biological evaluation of three sets of 6-phenylnicotinohydrazide derivatives 8a-g, 12 and 16a, b. The designed compounds were synthesized and in vitro evaluated for their antitubercular activity. In addition, their antifungal and antibacterial activities were evaluated as well. The nicotinohydrazide class displayed different levels of antimicrobial activity and possessed a distinctive pattern of selectivity against the tested microorganisms. However, the 2,6-dichlorobenzylidene counterpart 8b emerged as the most active one in this study, with superior antimycobacterial activity (minimum inhibitory concentration (MIC)=3.90 μg/mL) and potent broad-spectrum antimicrobial activities with MIC range of 0.24-1.95 μg/mL. The structure-activity relationship for such nicotinohydrazides has been established. Further, the cytotoxicity of the most active antitubercular compounds 8b, d and g were tested against the normal breast cells WI-38; none of them displayed significant cytotoxic effect, thereby providing a good therapeutic index.
- Soliman, Dalia Hussein,Eldehna, Wagdy Mohamed,Ghabbour, Hazem Ahmed,Kabil, Maha Mamdouh,Abdel-Aziz, Marwa Mostafa,Abdel-Aziz, Hatem Abdel-Kader
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- Aromatic nucleophilic substitutions under microwave irradiation
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In order to study the effect of microwave irradiation over aromatic nucleophilic substitutions at atmospheric pressure and in a homogeneous medium, experiments with disubstituted-benzenes and the nucleophiles piperidine and potassium t-butoxide, in refluxing DMSO or DMF, were carried out. The aromatic nucleophilic substitutions under microwave irradiation were 2.7 to 12 times faster than under conventional reflux.
- Salmoria, Gean V.,Dall'Oglio, Evandro,Zucco, Cesar
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- The Role of N-Substituents in Radiationless Deactivation of Aminated Derivatives of a Locked GFP Chromophore
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We report the creation of a novel group of the ABDI-BF2 fluorescent dyes based on the conformationally locked GFP chromophore. We studied the intramolecular mechanism of radiationless deactivation of the ABDI-BF2 fluorophore by introducing the various substituents at the nitrogen atom. The results of this study and our previous work allowed us to claim that in case of ABDI-BF2 this deactivation is determined by the formation of the nonfluorescent internal charge transfer exited state with a planar quinoidal structure. The electronic effects have a greater impact on the radiationless deactivation than the conformation. Thus, the introduction of an electron-donating group is more effective than the creation of rigid derivatives. The presented dyes are characterized by high fluorescence quantum yields and pH-independence in the physiological pH range, making them promising candidates for a wide spectrum of fluorescence labeling applications.
- Baleeva, Nadezhda S.,Zaitseva, Snezhana O.,Gorbachev, Dmitriy A.,Smirnov, Alexander Yu.,Zagudaylova, Marina B.,Baranov, Mikhail S.
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- Cu(II)-catalyzed C-N coupling of (hetero)aryl halides and N-Nucleophiles promoted by α-benzoin oxime
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We first reported the new application of a translate metal chelating ligand α-benzoin oxime for improving Cu-catalyzed C-N coupling reactions. The system could catalyse coupling reactions of (hetero)aryl halides with a wide of nucleophiles (e.g., azoles, piperidine, pyrrolidine and amino acids) in moderate to excellent yields. The protocol allows rapid access to the most common scaαolds found in FDA-approved pharmaceuticals.
- Yuan, Chunling,Zhang, Lei,Zhao, Yingdai
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- Multifunctional quinoxaline-hydrazone derivatives with acetylcholinesterase and monoamine oxidases inhibitory activities as potential agents against Alzheimer’s disease
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Multitarget molecules are considered as an effective way for the treatment of AD, instead of the classic one-drug-one-target strategy because of the multifactorial nature of AD. A variety of studies indicate that several enzymes inhibitors can be useful in the treatment of AD, including acetylcholinesterase (AchE), butyrylcholinesterase (BuChE) and monoamine oxidase (MAO). Various substituted quinoxaline-hydrazone derivatives were synthesized, and their activity in vitro were investigated, including AChE/BuChE inhibitory activity and MAOA/B inhibitory activity. Based on the experimental results, compound 5l exhibited good inhibitory potency on both AchE (IC50 = 0.028 ± 0.001 μM) and monoamine oxidase B (IC50 = 0.046 ± 0.002 μM). Molecular modeling studies showed that 5l could bind to the active site of AChE and MAO-B. Taken together, these results suggested that compound 5l might be a potential multifunctional agent for the treatment of AD.
- Ilgin, Sinem,Karaduman, Abdullah Burak,Levent, Serkan,Osmaniye, Derya,?avu?o?lu, Betül Kaya,?evik, Ulviye Acar,?zkay, Yusuf,Kaplancikli, Zafer As?m,Karaburun, Ahmet ?a?r?,Sa?lik, Begüm Nurpelin,Turan, Gülhan
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- Synthesis of new benzothiazole acylhydrazones as anticancer agents
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During the last five decades, a large number of BT (Benzothiazole) derivatives formed one of the eligible structures in medicinal chemistry as anticancer agents. Most of the studies reveal that various substitutions at specific positions on BT scaffold modulate the antitumor property. The potential of BTs encouraged us to synthesize a number of new 2-((5-substitutedbenzothiazol-2-yl)thio)-N’-(2-(4-(substitutedphenyl)ethylidene)acetohydrazide derivatives and investigate their probable anticancer activity. 4-Substitued benzaldehyde derivatives (1a–1e) were afforded by the reaction of appropriate secondary amine and 4-fluorobenzaldehyde in DMF. Equimolar quantitates of 5-substitutedbenzothiazole-2-thiol, ethyl chloroacetate and K2CO3 were refluxed in acetone to obtain 2-((5-substitutedbenzothiazol-2-yl)thio)acetate derivatives (2a,2b), which reacted with excess of hydrazine hydrate to get 2-((5-substitutebenzothiazol-2-yl)thio)acetohydrazides (3a,3b). In the last step, 2-((5-substitutedbenzothiazol-2-yl)thio)-N’-(4-substitutedbenzylidene)acetohydrazide derivatives (4a–4j) were synthesized by the reaction of 1a–1e and 3a–3b in EtOH. The anticancer activity of target compounds was evaluated in three steps. First, an MTT test (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was performed to observe cytotoxic activity of the compounds against carcinogenic C6 (Rat brain glioma cell line), A549 (Human lung adenocarcinoma epithelial cell line), MCF-7 (Human breast adenocarcinoma cell line), and HT-29 (Human colorectal adenocarcinoma cell line) cancer cell lines. Healthy NIH3T3 (Mouse embryo fibroblast cell line) cells were also subjected to MTT assay to determine selectivity of the compounds towards carcinogenic cell lines. Secondly, inhibitory effects of selected compounds 4d, 4e, and 4h on DNA synthesis of C6 cells were investigated. Finally, flow cytometric analysis were performed to identify the death pathway of the carcinogenic cells.
- Osmaniye, Derya,Levent, Serkan,Karaduman, Abdullah Burak,Ilg?n, Sinem,Zkay, Yusuf,Kaplancikli, Zafer Asim
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- Discovery of new schiff bases tethered pyrazole moiety: Design, synthesis, biological evaluation, and molecular docking study as dual targeting DHFR/DNA gyrase inhibitors with immunomodulatory activity
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A series of Bis-pyrazole Schiff bases (6a-d and 7a-d) and mono-pyrazole Schiff bases (8a-d and 9a-d) were designed and synthesized through the reaction of 5-aminopyrazoles 1a-d with aldehydes 2-5 using mild reaction condition with a good yield percentage.
- Hassan, Ashraf S.,Askar, Ahmed A.,Naglah, Ahmed M.,Naglah, Ahmed M.,Almehizia, Abdulrahman A.,Ragab, Ahmed
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- Design and Synthesis of some new 2,4,6-trisubstituted quinazoline EGFR inhibitors as targeted anticancer agents
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The present study describes the synthesis of 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines starting from 4-chloro derivative VI via the reaction with either phenolic compounds to obtain VIIa-f, IXa-d, 2-amino-6-(un)substituted benzothiazole to produce VIIIa-c or hydrazine hydrate to give X. Reaction of the hydrazino functionality of X with appropriate acid anhydride, acid chloride or aldehyde affords XIa-c, XIIa-c and XIVa-i, respectively. The target compounds were screened for their efficacy as EGFR inhibitors compared to gefitinib. Compounds eliciting superior EGFR inhibitory activity were further screened for their in vitro cytotoxicity against two human cancer cell lines namely: MCF7 (breast) and A549 (lung), in addition to normal fibroblast cell WI38 relative to gefitinib as a reference. Furthermore, compounds that showed potent inhibitory activity on wild-type EGFR were screened against mutant EGFR and assayed for their cytotoxicity against mutant EGFR-expressing cell lines PC9 and HCC827. The unsubstituted benzothiazol-2-amine VIIa showing superior EGFR inhibition (IC50 = 0.096 μM) and anticancer activity against MCF-7 cell line (IC50 = 2.49 μM) was subjected to cell cycle analysis and apoptotic assay. Moreover, a molecular docking study was performed to investigate the interaction of some representive compounds with the active site of EGFR- TK.
- Abbass, Safinaz E. S.,Allam, Heba Abdelrasheed,Aly, Enayat E.,El Kerdawy, Ahmed M.,Farouk, Ahmed K. B. A. W.,Rashwan, Essam
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- Design and synthesis of methoxyphenyl- and coumarin-based chalcone derivatives as anti-inflammatory agents by inhibition of NO production and down-regulation of NF-κB in LPS-induced RAW264.7 macrophage cells
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Exaggerated inflammatory responses may cause serious and debilitating diseases such as acute lung injury and rheumatoid arthritis. Two series of chalcone derivatives were prepared as anti-inflammatory agents. Methoxylated phenyl-based chalcones 2a-l and c
- Emam, Soha H.,Sonousi, Amr,Osman, Eman O.,Hwang, Dukhyun,Kim, Gun-Do,Hassan, Rasha A.
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- A facile method for nucleophilic aromatic substitution of cyclic amine
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The expeditious solventless nucleophilic aromatic substitution using microwaves is described. A non-conventional synthetic procedure has been developed where basic alumina has been used as energy transfer medium under Microwave Irradiation (MWI). The results were compared with those obtained by the classical method. This rapid and environmentally benign method avoids the use of excess solvents and toxic bases usually employed in the process make this procedure very attractive for synthesis.
- Kidwai,Sapra,Dave
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- Impact of reaction dynamics on synthesis of novel nitrogen containing aldehydes
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Impact of solvent dynamics, base employed and temperature conditions on the synthesis of novel Nitrogen containing aldehydes was studied. Piperazine, pyrrolidine and piperidine aldehydes were obtained in maximum yield and puritywith the K2CO3 base in presence of DMF solventand at 800 C temperatures.The synthesized compounds were characterized by IR, 1HNMR and MS Spectroscopy.
- Markandewar, Rajashree A.,Zia, Hanfi M.,Baseer
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- An efficient heterogeneous ligand free C-N coupling reaction catalyzed by palladium supported on magnetic nanoparticles
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The catalytic activity of palladium supported on magnetic nanoparticles in the amination coupling reaction of different nitrogen containing substrates with aryl halides was investigated. C-N bond formation was achieved in moderate to excellent yields and the catalyst could be separated by magnetic decantation.
- Rafiee, Ezzat,Ataei, Ali,Joshaghani, Mohammad
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- Quantum yield improvement of red-light-emitting firefly luciferin analogues for in vivo bioluminescence imaging
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The dimethylamino group of AkaLumine ((4S)-2-[(1E,3E)-4-[4-(dimethylamino)phenyl]-1,3-butadien-1-yl]-4,5-dihydro-4-thiazolecarboxylic acid), a red-light-emitting firefly luciferin analogue, was replaced by cyclic amino groups (1-pyrrolidinyl, 1-piperidino, 1-azepanyl, and 4-morpholino) to give AkaLumine analogues exhibiting desirable bioluminescence with emission maxima in the red region (656–667 nm). In particular, a bioluminescence reaction of 1-pyrrolidinyl analogue with a recombinant Photinus pyralis luciferase showed a higher quantum yield than that with AkaLumine, giving an improved bioluminescence intensity. The 1-pyrrolidinyl analogue also showed the strongest luminescence in whole-body luciferase-expressing mice among the analogues, indicating that a quantum yield improvement of a luciferin analogue is effective to increase bioluminescence imaging intensity.
- Kiyama, Masahiro,Iwano, Satoshi,Otsuka, Satoshi,Lu, Shijia W.,Obata, Rika,Miyawaki, Atsushi,Hirano, Takashi,Maki, Shojiro A.
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- Novel 1,4-dihydropyrano[2,3-c]pyrazole derivatives: Synthesis, characterization, biological evaluation and in silico study
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In the present study, a series of novel and biologically potent 6-amino-1-(2,4-dinitrophenyl)-4-phenyl-1,4-dihydropyrano [2,3-c]pyrazole-5-carbonitrile derivatives (5a-5u) have been synthesized through multicomponent reaction between various substituted a
- Vasava, Mahesh S.,Bhoi, Manoj N.,Rathwa, Sanjay K.,Shetty, Shilpa S.,Patel, Rikin D.,Rajani, Dhanji P.,Rajani, Smita D.,Patel, Alpesh,Pandya, Himanshu A.,Patel, Hitesh D.
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- Photoconductive properties of PVK-based photorefractive polymer composites doped with fluorinated styrene chromophores
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We have synthesized nine anisotropic chromophores, with different degrees of fluorination, and studied the effect of the chromophore's ionization potential on charge-transfer complexation, photoconductivity, and response time in photorefractive polymer mi
- Hendrickx, Eric,Zhang, Yadong,Ferrio, Kyle B.,Herlocker, Jon A.,Anderson, Jeff,Armstrong, Neal R.,Mash, Eugene A.,Persoons, Andre P.,Peyghambarian, Nasser,Kippelen, Bernard
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- Synthesis, structure and chemical transformations of 4-aminobenzaldehyde
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A possibility of nucleophilic substitution of the fluorine atom in 4-fluorobenzaldehyde with amines (morpholine, piperidine or cytisine) under convection heating and microwave irradiation was shown. Reactions of 4-morpholinyl- and 4-piperidinylbenzaldehyd
- Nurkenov,Fazylov,Arinova,Turdybekov,Turdybekov,Talipov,Ibragimov
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- 3-(5-METHOXY-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE DERIVATIVES AND USES THEREOF
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The present disclosure relates to compounds of formula (I') and pharmaceutical compositions and their use in reducing Widely Interspaced Zinc Finger Motifs (WIZ) expression levels, or inducing fetal hemoglobin (HbF) expression, and in the treatment of inherited blood disorders (e.g., hemoglobinopathies, e.g., beta-hemoglobinopathies), such as sickle cell disease and beta-thalassemia.
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- Pyridoxine-resveratrol hybrids as novel inhibitors of MAO-B with antioxidant and neuroprotective activities for the treatment of Parkinson's disease
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A series of pyridoxine-resveratrol hybrids were designed and synthesized as monoamine oxidase B inhibitors for the treatment of Parkinson's disease. Most of them exhibited potent inhibitory activities on MAO-B with high selectivity. Specifically, compounds 12a, 12g and 12l showed the most excellent inhibition to hMAO-B with the IC50 values of 0.01 μM, 0.01 μM and 0.02 μM, respectively. Further reversibility study demonstrated that 12a and 12l were reversible and 12g was irreversible MAO-B inhibitors. Molecular docking studies of MAO revealed the binding mode and high selectivity of these compounds with MAO-B. In addition, these three representative compounds also exhibited low cytotoxicity and excellent neuroprotective effect in the test on H2O2-induced PC-12 cell injury. Moreover, 12a, 12g and 12l showed good antioxidant activities and high blood-brain barrier permeability. Overall, all of these results highlighted 12a, 12g and 12l were potential and excellent MAO-B inhibitors for PD treatment.
- Cao, Zhongcheng,Deng, Yong,Li, Wei,Shi, Yichun,Song, Qing,Yang, Xia,Zhang, Li
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- Design, synthesis, characterization and fluorescence property evaluation of dehydroacetic acid-based chalcones
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Abstract: In this study, we decided to synthesize some new chalcone-type dyes derived from dehydroacetic acid (DHA) by the condensation of 4-amino-substituted benzaldehyde with DHA under the base-catalyzed condition and investigate their ability for rearrangement in acidic condition. For this purpose, initially we prepared the 4-aminobenzaldehyde derivatives via nucleophilic aromatic substitution reaction of 4-fluorobenzaldehyde with variety of amines in the presence of K2CO3 as base in DMF. The Knoevenagel condensation of DHA with 4-aminobenzaldehyde derivatives results in the desired compounds. In continuation, Fries rearrangement applied on DHA-chalcone compounds results in characterization of new pyranilidene-type derivatives. The optical responses of new dyes containing UV–Vis absorption and fluorescence spectroscopy were measured in dichloromethane (ET = 40?kcal/mol). Pyranilidene derivatives show low λmax values in comparison with chalcones, and molecule with strong dipole, in polar solvents, shows the bathochromic shift due to more stabilization of excited state in compared with ground state of molecule. Large stocks shifts were obtained for synthesized compounds. Graphic abstract: [Figure not available: see fulltext.].
- Teimuri-Mofrad, Reza,Rahimpour, Keshvar,Gholizadeh, Mohammad
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p. 1103 - 1109
(2019/12/30)
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- Methyl-α-d-glucopyranoside as Green Ligand for Selective Copper-Catalyzed N-Arylation
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In the selective N-arylation of amines or azoles with aryl halidesa-, methyl-α-d-glucopyranoside (MG) was found to function as a green ligand of copper powder. In addition, nitrogen heterocyclic amine compounds can also undergo the N-arylation coupling with heterocyclic aryl chlorides. This process allows access to a variety of aromatic amines and aryl azoles under mild reaction conditions, has good tolerance, and proceeds in moderate to high yield.
- Chen, Fengyang,Chen, Guoliang,Chen, Yuanguang,Du, Fangyu,Zhou, Qifan
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p. 4590 - 4600
(2019/12/11)
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- Application of hydrazino and hydrazido linkers to connect benzenesulfonamides with hydrophilic/phobic tails for targeting the middle region of human carbonic anhydrases active site: Selective inhibitors of hCA IX
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Herein we report the design and synthesis of three different sets of novel benzenesulfonamides (5a-e, 7a-e and 10a-d) incorporating hydrophilic/hydrophobic tails by hydrazido or hydrazino linkers. The newly synthesized benzenesulfonamides were examined in vitro for their inhibitory activity towards four human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII using a stopped-flow CO2 hydrase assay. All these isoforms were inhibited by the sulfonamides (5a-e, 7a-e and 10a-d) with variable degrees in the following KI ranges: 76.8–357.4 nM for hCA I, 8.2–94.6 nM for hCA II, 2.0–46.3 nM for hCA XI, and 8.3–88.3 nM for hCA XII. The sulfonamide 7d exhibited potent anti-proliferative activity against breast MCF-7 cancer cell line under both normoxic and hypoxic conditions with IC50 values equal 3.32 ± 0.06 and 8.53 ± 0.32 μM, respectively, which are comparable to the reference drug doxorubicin (IC50 = 2.36 ± 0.04 and 8.39 ± 0.25 μM, respectively). Furthermore, 7d was screened for cell cycle disturbance and apoptosis induction in MCF-7 cells. It was found to persuade cell cycle arrest at G2-M stage as well as to alter the Sub-G1 phase, also, 7d resulted in a significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.03 to 18.54%. Molecular docking study was carried out for 7d within the hCA IX and hCA XII active sites to rationalize the obtained inhibition results.
- Allam, Heba Abdelrasheed,Fahim, Samar H.,F.Abo-Ashour, Mahmoud,Nocentini, Alessio,Elbakry, Mohamed E.,Abdelrahman, Mohamed A.,Eldehna, Wagdy M.,Ibrahim, Hany S.,Supuran, Claudiu T.
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p. 547 - 556
(2019/07/04)
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- Nickel-Catalyzed Decarboxylation of Aryl Carbamates for Converting Phenols into Aromatic Amines
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Herein, we describe a new catalytic approach to accessing aromatic amines from an abundant feedstock, namely phenols. The most reliable catalytic method for converting phenols to aromatic amines uses an activating group, such as a trifluoromethane sulfonyl group. However, this activating group is eliminated as a leaving group during the amination process, resulting in significant waste. Our nickel-catalyzed decarboxylation reaction of aryl carbamates forms aromatic amines with carbon dioxide as the only byproduct. As this amination proceeds in the absence of free amines, a range of functionalities, including a formyl group, are compatible. A bisphosphine ligand immobilized on a polystyrene support (PS-DPPBz) is key to the success of this reaction, generating a catalytic species that is significantly more active than simple nonsupported variants.
- Nishizawa, Akihiro,Takahira, Tsuyoshi,Yasui, Kosuke,Fujimoto, Hayato,Iwai, Tomohiro,Sawamura, Masaya,Chatani, Naoto,Tobisu, Mamoru
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supporting information
p. 7261 - 7265
(2019/05/16)
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- A group of diphosphine-thiosemicarbazone complexes of palladium: Efficient precursors for catalytic C–C and C–N coupling reactions
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Reaction of 4-R-benzaldehyde thiosemicarbazone (denoted in general as HL-R; where H stands for the dissociable acidic proton and R (R = OCH3, CH3, H, Cl and NO2) for the substituent) with [Pd(dppe)(EtOH)2]2+, generated in situ via interaction of [Pd(dppe)Cl2] (dppe = 1,2-bis(diphenylphosphino)ethane) with AgNO3 in hot ethanol, in the presence of triethylamine affords a group of orange complexes of the type [Pd(dppe)(L-R)]NO3. Structures of [Pd(dppe)Cl2] and [Pd(dppe)(L-OCH3)]NO3 have been determined by X-ray crystallography. In the [Pd(dppe)(L-R)]NO3 complexes, the thiosemicarbazone ligands are coordinated to the metal center as monoanionic bidentate N,S-donors forming five-membered chelate rings. The [Pd(dppe)(L-R)]NO3 complexes show intense absorptions in the visible and ultraviolet regions, which have been analyzed by TDDFT calculations. All the [Pd(dppe)(L-R)]NO3 complexes are found to efficiently catalyze Suzuki-type C–C and Buchwald-type C–N coupling reactions.
- Thapa, Kiran,Paul, Piyali,Bhattacharya, Samaresh
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p. 232 - 239
(2018/11/06)
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- Synthesis and biological evaluation of new thiosemicarbazone derivative schiff bases as monoamine oxidase inhibitory agents
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Twenty-six novel thiosemicarbazone derivative B1–B26 were synthesized via condensation reactions between the corresponding thiosemicarbazides and aldehydes. The chemical characterization of the compounds was carried out by infrared (IR), mass (MS), proton and carbon nuclear magnetic resonance (1H- and 13C-NMR) spectroscopic analyses. The compounds were investigated for their monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) inhibitory activity and most of them were more potent against MAO-A enzyme when compared with MAO-B enzyme. N-Cyclohexyl-2-[4-[(4-chlorophenyl)thio]benzylidene]hydrazine-1-carbothioamide (B24) was the most active compound against MAO-A. The enzyme kinetics study revealed that compound B24 has a reversible and competitive mode of binding. Interaction modes between compound B24 and MAO-A were clarified by docking studies. In addition, the favourable absorption, distribution, metabolism, and excretion (ADME) properties and non-toxic nature of compound B24 make this compound a promising MAO-A inhibitor.
- ?avu?o?lu, Betül Kaya,Sa?l?k, Beg m Nurpelin,Sa?l?k, Begüm Nurpelin,Osmaniye, Derya,Levent, Serkan,Evik, Ulviye Acar,Karaduman, Abdullah Burak,Zkay, Yusuf,Kaplanc?kl?, Zafer As?m
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- Biological evaluation and in silico molecular docking study of a new series of thiazol-2-yl-hydrazone conglomerates
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A new series of hybridized thiazol-2-yl-hydrazone derivatives having diverse substituents were designed, synthesized, and screened for their anti-inflammatory property by a carrageenan-induced paw edema method. The compounds 11a, 11b, 11c, 11d, 11e, 11g, 11m and 11p revealed significant inhibition when compared to Diclofenac sodium. Subsequently, two highly potent compounds (11d and 11e) were evaluated for their cytotoxic effect on the tumor cell line. The binding interactions of thiazol-2-yl-hydrazones with the cyclooxygenase-2 (COX-2) protein (PDB: 3LN1) displayed effective interactions with Arg-120, Tyr-385 and Tyr-355 amino acids, the main criteria of the COX-2 inhibitor. In addition, all the compounds showed moderate to good in vitro antibacterial activity. Most active benzyloxy derivatives were also tested to understand the radical scavenging efficacy by the 2,2-diphenyl-1-picrylhydrazyl method. Graphical Abstract: [Figure not available: see fulltext.].
- Bhat, Mahima,Gurubasavaraja Swamy,Poojary, Boja,Revanasiddappa,Vijay Kumar,Kumar, Vasantha
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p. 2779 - 2805
(2018/02/19)
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- Synthesis and anticandidal activity of new imidazole-chalcones
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In the present work, 15 new 1-(4-(1H-imidazol-1-yl)phenyl)-3-(4-substituedphenyl)prop-2-en-1-one derivatives (3a–3o) were synthesized to evaluate their antifungal activity. Structures of newly synthesized imidazole derivatives (3a–3o) were characterized by IR,1H-NMR,13C-NMR, and LCMSMS spectroscopic methods. The anticandidal activity of compounds (3a–3o) against C. albicans (ATCC 24433), C. krusei (ATCC 6258), C. parapsilosis (ATCC 22019), and C. glabrata (ATCC 90030) was elucidated according to the EUCAST definitive (EDef 7.1) method. Consistent with the activity studies, 3a–3d were found to be more potent derivatives with their MIC50 values (0.78 μg/mL–3.125 μg/mL) against Candida strains. Compound 3c indicated similar antifungal activity to ketoconazole against all Candida species and was evaluated as the most active derivative in the series. Effects of the most potent derivatives 3a–3d on ergosterol biosynthesis were observed by LC-MS-MS method, which is based on quantification of the ergosterol level in C. krusei. Moreover, these compounds were subjected to a cytotoxicity test for the preliminary toxicological profiles and were found as non-cytotoxic. Furthermore, docking studies for the most active derivative 3c were performed to evaluate its binding modes on lanosterol 14-α-demethylase. In addition to in vitro tests, docking studies also revealed that Compound 3c is a potential ergosterol biosynthesis inhibitor.
- Osmaniye, Derya,Avu?o Glu, Bet l Kaya,Sa gl?k, Beg m Nurpelin,Levent, Serkan,Acar evik, Ulviye,Atl?, Zlem,Zkay, Yusuf,Kaplanc?kl?, Zafer As?m
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- Cholinesterases inhibition and molecular modeling studies of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones
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Super-activation of cholinesterases (acetylcholinesterase and butyrylcholinesterase) are linked to various neurological problems most precisely Alzheimer's disease (AD), which leads to senile dementia. Therefore, cholinesterases (AChE & BChE) inhibition are considered as a promising strategy for the treatment of Alzheimer's disease. FDA approved drugs for the treatment of AD, belong to a group of cholinesterase inhibitors. However, none of them is able to combat or completely abrogate the disease progression. Herein, we report a series of newly synthesized chalcone derivatives with anti-AD potential. For this purpose, a series of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones were tested for their cholinesterases (AChE & BChE) inhibitory activity. All compounds were found as selective inhibitor of AChE. In piperidyl chalcones derivatives compound 1e having IC50 of 0.16?±?0.008?μM and 2m in 2-pyrazoline chalcones with IC50 of 0.13?±?0.006?μM, were found to be the most potent inhibitors of AChE, exhibiting ≈142 and?≈?173-fold greater inhibitory potential compared to the reference inhibitor i.e., Neostigmine (IC50?±?SEM?=?22.2?±?3.2?μM). Molecular docking studies of most potent inhibitors were carried out to investigate the binding interactions inside the active site. Molecular docking study revealed that potent compounds and co-crystalized ligand had same binding orientation within the active site of target enzyme. Most of these compounds are selective inhibitors of AChE with a potential use against progressive neurodegenerative disorder and age related problems.
- Shah, Muhammad Shakil,Khan, Shafi Ullah,Ejaz, Syeda Abida,Afridi, Saifullah,Rizvi, Syed Umar Farooq,Najam-ul-Haq, Muhammad,Iqbal, Jamshed
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p. 615 - 624
(2017/01/16)
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- Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s)
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Undesirable side effects associated with orthosteric agonists/antagonists of cannabinoid 1 receptor (CB1R), a tractable target for treating several pathologies affecting humans, have greatly limited their translational potential. Recent discovery of CB1R negative allosteric modulators (NAMs) has renewed interest in CB1R by offering a potentially safer therapeutic avenue. To elucidate the CB1R allosteric binding motif and thereby facilitate rational drug discovery, we report the synthesis and biochemical characterization of first covalent ligands designed to bind irreversibly to the CB1R allosteric site. Either an electrophilic or a photoactivatable group was introduced at key positions of two classical CB1R NAMs: Org27569 (1) and PSNCBAM-1 (2). Among these, 20 (GAT100) emerged as the most potent NAM in functional assays, did not exhibit inverse agonism, and behaved as a robust positive allosteric modulator of binding of orthosteric agonist CP55,940. This novel covalent probe can serve as a useful tool for characterizing CB1R allosteric ligand-binding motifs.
- Kulkarni, Pushkar M.,Kulkarni, Abhijit R.,Korde, Anisha,Tichkule, Ritesh B.,Laprairie, Robert B.,Denovan-Wright, Eileen M.,Zhou, Han,Janero, David R.,Zvonok, Nikolai,Makriyannis, Alexandros,Cascio, Maria G.,Pertwee, Roger G.,Thakur, Ganesh A.
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- Synthesis and antitumor evaluation of new heterocycles derived from 3-Methyl-2-benzothiazolinone Hydrazone
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3-Methyl-2-benzothiazolinone hydrazone condensed with some selected aldehydes to give the corresponding Schiff bases. Cyclizing the obtained Schiff base derivatives with thioglycolic acid afforded the respective thiazolylideneaminothiazolidenones. Condens
- Ibrahim, Nabila M.,Yosef, Hisham A.A.,Ewies, Ewies F.,Mahran, Mohamed R.H.,Ali, Mamdouh M.,Mahmoud, Abeer E.
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p. 1086 - 1097
(2015/06/16)
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- Monocarboxylate transporter 1 inhibitors as potential anticancer agents
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Potent monocarboxylate transporter 1 inhibitors (MCT1) have been developed based on α-cyano-4-hydroxycinnamic acid template. Structure-activity relationship studies demonstrate that the introduction of p-N, N-dialkyl/diaryl, and o-methoxy groups into cyanocinnamic acid has maximal MCT1 inhibitory activity. Systemic toxicity studies in healthy ICR mice with few potent MCT1 inhibitors indicate normal body weight gains in treated animals. In vivo tumor growth inhibition studies in colorectal adenocarcinoma (WiDr cell line) in nude mice xenograft models establish that compound 27 exhibits single agent activity in inhibiting the tumor growth.
- Gurrapu, Shirisha,Jonnalagadda, Sravan K.,Alam, Mohammad A.,Nelson, Grady L.,Sneve, Mary G.,Drewes, Lester R.,Mereddy, Venkatram R.
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p. 558 - 561
(2015/05/27)
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- Design, synthesis, 3D pharmacophore, QSAR, and docking studies of carboxylic acid derivatives as Histone Deacetylase inhibitors and cytotoxic agents
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In this study, five series of (E)-6-(4-substituted phenyl)-4-oxohex-5-enoic acids IIb-f (E), (E)-3-(4-(substituted)-phenyl)acrylic acids IIIa-g (E), 4-(4-(substituted)phenylamino)-4-oxobutanoic acids VIa,b,e, 5-(4-(substituted)phenylamino)-5-oxopentanoic acids VIIa,f and 2-[(4-(substituted)phenyl) carbamoyl]benzoic acids VIIIa,e were designed and synthesized. Selected compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumor cell lines. Compound IIf (E) displayed significant inhibitory activity against NCI Non-Small Cell Lung A549/ATCC Cancer cell line (68% inhibition) and NCI-H460 Cancer cell line (66% inhibition). Moreover, the final compounds were evaluated in vitro for their cytotoxic activity on HepG2 Cancer cell line in which histone deacetylase (HDAC) is overexpressed. Compounds IIc (E), IIf (E), IIIb (E), and IIIg (E) exhibited the highest cytotoxic activity against HepG2 human cancer cell lines with IC50ranging from 2.27 to 10.71 μM. In addition, selected compounds were tested on histone deacetylase isoforms (HDAC1-11). Molecular docking simulation was also carried out for HDLP enzyme to investigate their HDAC binding affinity. In addition, generation of 3D-pharmacophore model and quantitative structure activity relationship (QSAR) models were combined to explore the structural requirements controlling the observed cytotoxic properties.
- Abdel-Atty, Mona M.,Farag, Nahla A.,Kassab, Shaymaa E.,Serya, Rabah A.T.,Abouzid, Khaled A.M.
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- Synthesis of 2-aryl-1,1-bis(silyl)alkenes containing alkyl(aryl)amine groups
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4-Alkyl-(aryl)aminobenzaldehydes have been generated via the nucleophilic aromatic substitution reaction of 4-fluorobenzaldehyde with appropriated amines and N-heterocycles using hexadecyltrimethylammonium bromide as catalyst and converted to 1,1-bis(silyl)-1-alkene derivatives via the Peterson olefination reaction. The reaction of (HMe2Si)3CLi with these aromatic aldehydes led to new 2-aryl-1,1-bis(silyl)alkenes.
- Safa, Kazem Dindar,Nadimi, Sanaz,Alyari, Maryam
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p. 498 - 501
(2014/11/08)
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- Antimycobacterial activity evaluation, time-kill kinetic and 3D-QSAR study of C-(3-aminomethyl-cyclohexyl)-methylamine derivatives
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A series of C-(3-aminomethyl-cyclohexyl)-methylamine derivatives were synthesized and evaluated for their antitubercular activity. Some of the compounds exhibited potent activity against Mycobacterium tuberculosis H37Rv. One of the compound having t-butyl at para position of the benzene ring showed excellent activity even better than the standard drug ethambutol with MIC value 1.1 ± 0.2 μM. The time-kill kinetics study of two most active compounds showed rapid killing of the M. tuberculosis within 4 days. Additionally atom-based quantitative structure-activity relationship (QSAR) model was developed that gave a statistically satisfying result (R2) = 0.92, Q2 = 0.75, Pearson-R = 0.96 and effectively predicts the anti-tuberculosis activity of training and test set compounds.
- Kumar, Deepak,Raj, K. Kranthi,Bailey, Maiann,Alling, Torey,Parish, Tanya,Rawat, Diwan S.
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supporting information
p. 1365 - 1369
(2013/03/14)
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- New two-photon absorption organic chromophores containing imino and hydroxyl groups: Synthesis, ESIPT and chemosensors
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In this work, a variety of new conjugated chromophores containing imino and hydroxyl groups are presented. Excited state intramolecular proton transfer (ESIPT) of these chromophores under one- and two-photon irradiation was surveyed. One-photon absorption
- Gao, Fang,Wang, Xinchao,Li, Hongru,Ye, Xiaojuan
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p. 5355 - 5366
(2013/07/05)
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- Synthesis and evaluation of p-N,N-dialkyl substituted chalcones as anti-cancer agents
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Several new N,N-dialkyl substituted chalcones (chalconoids or benzylideneacetophenones) have been synthesized via the condensation of corresponding N,N-dialkylbenzaldehyde with various aryl methyl ketones. All the chalcones have been synthesized from readily available and cheap starting materials under environmentally benign conditions in very high yields without work up and column chromatographic purification. Synthesized compounds have been tested for their biological activity against pathogenic microorganisms such as Escherichia coli, Bacillus subtilis, and Mycobacterium smegmatis. Anti-cancer activity of these compounds has also been tested against multiple myeloma (RPMI-8226) and human mammary adenocarcinoma (MCF-7) cell lines. The most hydrophilic molecules 23 and 24 showed very good anti-cancer activity against MCF-7 cell lines at low micro-molar concentrations. All the compounds have also been evaluated for their activity against Beta-secretase 1 enzyme. One of the synthesized compounds showed Beta-secretase 1 enzyme inhibition activity at micro-molar concentration.
- Nelson, Grady,Alam, Mohammad A.,Atkinson, Tyler,Gurrapu, Shirisha,Sravan Kumar,Bicknese, Chris,Johnson, Joseph L.,Williams, Michael
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p. 4610 - 4614
(2013/09/23)
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- Anti-HIV-1 and cytotoxicity studies of piperidyl-thienyl chalcones and their 2-pyrazoline derivatives
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A series of 12 new pyrazoline derivatives was prepared from piperidyl chalcones, which in turn were synthesized by condensing 4-piperidin-1- ylbenzaldehyde with diverse acetylthiophenes. The target compounds were characterized by spectroscopic techniques
- Rizvi, Syed Umar Farooq,Siddiqui, Hamid Latif,Johns, Melissa,Detorio, Mervi,Schinazi, Raymond F.
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p. 3741 - 3749
(2013/02/25)
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- Ultrasonic promoted synthesis and antibacterial screening of some novel piperidine incorporated α-aminophosphonates
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A simple and high-yielding method was developed for the synthesis of novel -aminophosphonates from imines, obtained from 4-(piperidine-1-yl)benzaldehyde, by using triethylphosphite in the presence of dilute HCl under ultrasound irradiation. This method, w
- Mandhane, Priyanka G.,Joshi, Ratnadeep S.,Nagargoje, Deepak R.,Chate, Asha V.,Gill, Charansingh H.
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experimental part
p. 149 - 158
(2011/04/22)
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- Synthesis and anti-arrhythmic activity of some piperidine-based 1,3-thiazole, 1,3,4-thiadiazole, and 1,3-thiazolo[2,3-c]-1,2,4-triazole derivatives
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The reaction of 1-[4-(piperidin-1-yl)benzylidene]thiosemicarbazide with hydrazonoyl chlorides afforded 1,3-thiazole derivatives. Cyclization of two compounds of the latter 1,3-thiazole by means of bromine in the presence of sodium acetate at room temperature gave 1,3-thiazolo[2,3-c]-1,2,4-triazole derivatives. The reaction of 2-cyano-3-(4-piperidin-1-ylphenyl)prop-2- enethioamide with hydrazonoyl chlorides under reflux in ethanol in the presence of triethylamine yielded 1,3-thiazoles. Treatment of 3-oxo-3-(piperidin-1-yl) propanenitrile with phenyl isothiocyanate in DMF, in the presence of KOH, at ambient temperature, resulted in the formation of 3-anilino-3-mercapto-2- (piperidin-1-ylcarbonyl)acrylonitrile which was reacted with hydrazonoyl chlorides to yield the corresponding 1,3,4-thiadiazole derivatives. Some of the newly synthesized compounds had significant anti-arrhythmic activity.
- Abdel-Aziz, Hatem A.,Abdel-Wahab, Bakr F.,El-Sharief, Marwa A. M. Sh.,Abdulla, Mohamed M.
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body text
p. 431 - 437
(2010/06/16)
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- Study of ultrasound promoted aromatic nucleophilic substitution of halobenzenes with amines
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The sonochemical nucleophilic aromatic substitution of substituted haloarenes with different amines were studied. The reaction course was found to be strongly depended on basicity, bulkiness, and boiling point of amines as well as on the electron-withdrawing property of the substituents.
- Meciarova, Maria,Toma, Stefan,Podlesna, Jana,Kiripolsky, Michal,Cisarova, Ivana
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- Novel non-steroidal/non-anilide type androgen antagonists with an isoxazolone moiety
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3-Substituted (Z)-4-(4-N,N-dialkylaminophenylmethylene)-5(4H)-isoxazolones and related compounds were designed and prepared as candidates for structurally novel androgen antagonists. Several compounds showed potent anti-androgenic activity as assessed by nuclear androgen receptor binding assay and growth inhibition assay using androgen-dependent Shionogi carcinoma cells SC-3. They were approximately 10-220 times more potent than flutamide in these assay systems. They also showed anti-androgenic activity toward prostate tumor cell line LNCaP, which has an aberrant nuclear androgen receptor.
- Ishioka, Toshiyasu,Kubo, Asako,Koiso, Yukiko,Nagasawa, Kazuo,Itai, Akiko,Hashimoto, Yuichi
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p. 1555 - 1566
(2007/10/03)
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- Ultrasound effect on the synthesis of 4-alkyl-(aryl)aminobenzaldehydes
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The sonochemical nucleophilic aromatic substitutions on 4-fluorobenzaldehyde with different azacycloalkanes and azoles have been studied. A beneficial ultrasound effect was observed, reactions were clean and high yields of the products were isolated after 15 min sonication.
- Magdolen, Peter,Me?iarová, Mária,Toma, ?tefan
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p. 4781 - 4785
(2007/10/03)
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- Coordination control of intramolecular electron transfer in boronate-bridged zinc porphyrin - Diimide molecules
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Three sets of dyads, in which a zinc-porphyrin (ZP) electron donor is connected to an aromatic diimide electron accepter, either pyromellitimide (PI) or naphthalene-1,8:4,5-tetracarboxylic acid diimide (NI), via a boronate-ester bridge, a piperidine bridge, and a 1,3-dioxolane bridge, respectively, were prepared for the purpose of control of intramolecular electron transfer (ET) by acid-base reactions at the connecting bridge. Boronate - ester bridge is a Lewis acidic site and confers a chance to regulate intramolecular ET reaction upon base coordination. This has been demonstrated by suppression of photoinduced ET from ZP to PI or NI in highly electron-pair donating solvents or upon addition of a fluoride anion. To extend this strategy to control of ET-path selectivity, we prepared triad 18, which consists of a ZP donor bearing NI and PI accepters at similar distances through a boronate - ester bridge and an acetal bridge, respectively. Photoexcitation of 18 in a free form led to intramolecular ET from 1ZP* preferentially to NI, but the ET path was completely switched toward PI in F--coordinated form without a serious drop in the rate, constituting a novel ET-switching molecular system.
- Shiratori,Ohno,Nozaki,Yamazaki,Nishimura,Osuka
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p. 8747 - 8757
(2007/10/03)
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- Synthesis and biological evaluations of 3-substituted indolin-2-ones: A novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases
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3-Substituted indolin-2-ones have been designed and synthesized as a novel class of tyrosine kinase inhibitors which exhibit selectivity toward different receptor tyrosine kinases (RTKs). These compounds have been evaluated for their relative inhibitory properties against a panel of RTKs in intact cells. By modifying the 3-substituted indolin-2-ones, we have identified compounds which showed selective inhibition of the ligand- dependent autophosphorylation of various RTKs at submicromolar levels in cells. Structure-activity analysis for these compounds and their relative potency and selectivity to inhibit particular RTKs has determined that (1) 3- [(five-membered heteroaryl ring)methylidenyl]indolin-2-ones are highly specific against the VEGF (Flk-1) RTK activity, (2) 3-(substituted benzylidenyl)indolin-2-ones containing bulky group(s) in the phenyl ring at the C-3 position of indolin-2-ones showed high selectivity toward the EGF and Her-2 RTKs, and (3) the compound containing an extended side chain at the C- 3 position of the indolin-2-one (16) exhibited high potency and selectivity when tested against the PDGF and VEGF (Flk-1) RTKs. Recent published crystallographic data for two of these 3-substituted indolin-2-ones provides a rationale to suggest that these compounds may bind in the ATP binding pocket of RTKs. The structure-activity analysis supports the use of subsets of these compounds as specific chemical leads for the development of RTK- specific drugs with broad application for the treatment of human diseases.
- Sun, Li,Tran, Ngoc,Tang, Flora,App, Harald,Hirth, Peter,McMahon, Gerald,Tang, Cho
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p. 2588 - 2603
(2007/10/03)
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