- Synthesis of diarylidenecyclohexanone derivatives as potential anti-inflammatory leads against COX-2/mPGES1 and 5-LOX
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Inflammation is a pathophysiological condition which progresses through the prostaglandin (PG) and leukotriene (LT) pathways channelized by the enzymes COX/mPGES1 and 5-LOX respectively. Diarylidenecyclohexanone (DAC) derivatives (Ia-j, IIa-c, IIIa and IVa) were synthesized, characterized and screened for their in vitro anti-inflammatory activity via inhibition of 5-LOX and COX-2/mPGES1 enzymes. Compound Ic inhibited PGE2 production exhibiting an IC50 of 6.7 ± 0.19 μM, comparable to the standard inhibitor, licofelone (IC50 of 5.4 ± 0.02 μM). Compounds Ie and Ig showed maximum in vitro inhibitory activity against 5-LOX, exhibiting an IC50 of 1.4 ± 0.1 μM and 1.5 ± 0.13 μM, respectively, and these are comparable to that of the standard drug, zileuton (IC50 = 1.2 ± 0.11 μM). Ie and Ig do not possess radical scavenging properties and may not be disrupting the redox cycle of the enzyme. Hence they may be inhibiting the enzyme by a competitive mode. One of the compounds in the DAC series (IIc) containing a heterocyclic thienyl ring inhibited all the three enzymes. It inhibited 5-LOX and COX-2/mPGES1 with an IC50 of 1.8 ± 0.12 μM and 7.5 ± 0.4 μM respectively. An RT-PCR based mRNA expression study highlighted that Ic predominantly inhibited the expression of COX-2 rather than mPGES1. No toxicity towards the HeLa cell line indicated that the DACs could serve as structural templates towards lead optimization of compounds for discovery of novel, potent, safe and affordable drugs as anti-inflammatory agents.
- Kar, Swayamsiddha,Ramamoorthy, Gayathri,Sinha, Shweta,Ramanan, Meera,Pola, Jeevan Kumar,Golakoti, Nageswara Rao,Nanubolu, Jagadeesh Babu,Sahoo, Suraj Kumar,Dandamudi, Rajesh Babu,Doble, Mukesh
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supporting information
p. 9012 - 9020
(2019/06/18)
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- Syntheses and X-ray crystal structures combined with conformational and Hirshfeld analyses of chalcones based on a cyclohexanone scaffold
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Four chalcone structures based on cyclohexanone cores were presented. The structures of bis-benzylidenecyclohexanone analogs 3a-d were elucidated using spectrophotometric and single-crystal X-ray techniques. Compounds 3a, 3b, and 3d crystalized in the monoclinic crystal system with the space group P21/c. However, 3c crystalized in the orthorhombic system with the space group Pna21. A set of computational studies related to the structures were carried out. Using the B3LYP method and the 6-31G(d,p) basis set, the molecular structures of the studied dienones were optimized, followed by the evaluation of their electronic properties and UV–vis spectra. The bond distances and angles well-correlated with the experimental data. All the dienones were stabilized by C–H?O intramolecular H-bonding interactions. The presence of two Cl atoms at the ortho-position of each phenyl ring in 3c caused steric hinderance with the cyclohexanone ring, leading to the weakest H?O interactions among the studied compounds. The TD-DFT method was used to assign and explain the origin of the electronic spectra of the studied dienones.
- Lotfy,Said, Mohamed M.,El Ashry, El Sayed H.,El Tamany, El Sayed H.,Abdel Aziz, Yasmine M.,Soliman, Saied M.,Al-Majid, Abdullah Mohammed,Ghabbour, Hazem A.,Barakat
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- Ag/P-Stereogenic Phosphine-Catalyzed Enantioselective 1,3-Dipolar Cycloadditions: A Method to Optically Active Pyrrolidines
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A Ag/P-stereogenic phosphine-complex-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with electron-deficient olefins is reported. In this reaction, highly functionalized pyrrolines with a spiro-quaternary stereogenic center were obtained in good yields (up to 99%) with excellent levels of diastereo-(up to >20:1 dr) and enantioselectivities (up to >99% ee). The chirality of adducts was controlled predominantly by the P-stereogenic phosphines.
- Zhi, Mengna,Gan, Zhenjie,Ma, Rong,Cui, Hao,Li, Er-Qing,Duan, Zheng,Mathey, Fran?ois
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supporting information
(2019/05/07)
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- Synthesis, mechanistic and synergy studies of diarylidenecyclohexanone derivatives as new antiplasmodial pharmacophores
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Diarylidenecyclohexanone (DAC) derivatives (Ia-i, IIa-c and IIIa-b) were synthesized, characterized and screened for their invitro antiplasmodial activities against erythrocytic stages of chloroquine (CQ) sensitive and resistant strains of P. falciparum by using SYBR green I fluorescence assay. SAR studies of DAC derivatives showed antiplasmodial activity in the order of 3-NO2 (Ib, IC50 0.95 μM) > 3-chloro (Id, IC50 3 μM) > 4-chloro (Ie, IC50 8.5 μM) > 2-chloro (Ic, IC50 13 μM). Further Ib and Id exhibited nearly equal potencies against CQ-resistant strains P. falciparum Dd2, {IC50 1 μM (Ib) and 2.7 μM (Id)} and PfINDO {IC50 1.1 μM (Ib) and 2.5 μM (Id)}. Drug exposure followed by drug withdrawal-based stage-specific kill kinetic studies showed that Ib is shizonticidal within 3 h while the earliest killing actions against Trophozoites and Rings were seen at >3 h and >6 h, respectively. Combination studies of the most potent leads viz. Ib and Id showed strong to moderate synergistic effects with Artemisinin (?FIC50: 0.34 to 0.63) whereas no interaction (?FIC50: 0.65 to 2.36) was observed with Chloroquine. The DACs showed significant insilico binding affinity with β-haematin and P. falciparum lactate dehydrogenase (PfLDH) suggesting these to be the targets of their antiplasmodial action. High compliance with Lipinski rule of 5 and high selectivity index of Ib (105.3) and Id (8.3) against HeLa cell line indicated that Diarylidenecyclohexanones could serve as structural templates towards lead optimization of compounds for discovery of novel, potent, safe and affordable drugs against malaria.
- Joshi, Bishnu P.,Mohanakrishnan, Dinesh,Mittal, Garima,Kar, Swayamsiddha,Pola, Jeevan Kumar,Golakoti, Nageswara Rao,Nanubolu, Jagadeesh Babu,D, Rajesh Babu,S, Sai Suraj Kumar,Sahal, Dinkar
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p. 2312 - 2324
(2018/09/20)
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- Preparation method for synthesizing photosensitive compound through Claisen-Schmidt reaction
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The invention provides a preparation method for synthesizing a photosensitive compound through a Claisen-Schmidt reaction. An aldehyde free of alpha-H and a ketone containing alpha-H are selected to be synthesized to obtain the product alpha, beta-unsaturated aldehyde ketone. The preparation method is simple in condition and mild in reaction. The prepared photosensitive compound serving as a hydrogen abstraction type photoinitiator is long in wave length and small in consumption, and has a good initiation effect on monomer PEFDA without adding initiation auxiliaries. Under an ultraviolet lamp,the absorption wavelength is subjected to red shift from 450 to 500 and finally subjected to blue shift to 400 or below. The photosensitive compound has an AIE effect.
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Paragraph 0060-0064
(2018/10/19)
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- Potent and Selective Inhibitors of Trypanosoma cruzi Triosephosphate Isomerase with Concomitant Inhibition of Cruzipain: Inhibition of Parasite Growth through Multitarget Activity
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Triosephosphate isomerase (TIM) is an essential Trypanosoma cruzi enzyme and one of the few validated drug targets for Chagas disease. The known inhibitors of this enzyme behave poorly or have low activity in the parasite. In this work, we used symmetrical diarylideneketones derived from structures with trypanosomicidal activity. We obtained an enzymatic inhibitor with an IC50value of 86 nm without inhibition effects on the mammalian enzyme. These molecules also affected cruzipain, another essential proteolytic enzyme of the parasite. This dual activity is important to avoid resistance problems. The compounds were studied in vitro against the epimastigote form of the parasite, and nonspecific toxicity to mammalian cells was also evaluated. As a proof of concept, three of the best derivatives were also assayed in vivo. Some of these derivatives showed higher in vitro trypanosomicidal activity than the reference drugs and were effective in protecting infected mice. In addition, these molecules could be obtained by a simple and economic green synthetic route, which is an important feature in the research and development of future drugs for neglected diseases.
- Aguilera, Elena,Varela, Javier,Birriel, Estefanía,Serna, Elva,Torres, Susana,Yaluff, Gloria,de Bilbao, Ninfa Vera,Aguirre-López, Beatriz,Cabrera, Nallely,Díaz Mazariegos, Selma,de Gómez-Puyou, Marieta Tuena,Gómez-Puyou, Armando,Pérez-Montfort, Ruy,Minini, Lucia,Merlino, Alicia,Cerecetto, Hugo,González, Mercedes,Alvarez, Guzmán
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supporting information
p. 1328 - 1338
(2016/07/20)
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- Efficient method for the synthesis of, ′-bis(arylmethylidene) cycloalkanones catalyzed by bromodimethylsulfonium bromide
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Bromodimethylsulfonium bromide (BDMS)-catalyzed crossed aldol condensation between aromatic aldehydes and ketones is reported to access ′-bis(arylmethylidene) cycloalkanones at room temperature in good yields within 3-10 min. The salient features of this method are the simplicity of the procedure, the ready accessibility of the catalyst, and greater yields in relatively short reaction times. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]
- Zhao, Cong-Ying,Liu, Ju-Yan,Wang, Ying,Zhao, Xiao-Jun,Yuan, Bin,Yue, Min-Min
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p. 827 - 835
(2014/03/21)
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- Study of in situ generation of carbocationic system from trityl chloride (Ph3CCl) which efficiently catalyzed cross-aldol condensation reaction
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Organocatalyst trityl chloride (Ph3CCl), by in situ formation of trityl carbocation with inherent instability, efficiently promotes the cross-aldol condensation reaction between cycloalkanones and arylaldehydes in solvent-free and homogeneous media to afford α,α′- bis(arylidene)cycloalkanones in high yields. Moreover, an attractive and plausible mechanism based on observations and the literature is proposed for the reaction.
- Zare, Abdolkarim,Merajoddin, Maria,Hasaninejad, Alireza,Moosavi-Zare, Ahmad Reza,Khakyzadeh, Vahid
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p. 380 - 384
(2013/08/25)
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- Sulfuric acid-modified PEG-6000 (PEG-SO3H): An efficient, bio-degradable and reusable catalyst for synthesis of α, α′ bis(arylidene) cycloalkanones under solvent-free conditions
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A green and efficient method for synthesis of α, α′ -bis (arylidene) cycloalkanones, starting from aromatic aldehydes in reaction with ketones using sulfonated polyethylene glycol 6000 (PEG-SO3H) as a stable, reusable and biodegradable catalyst under solvent-free conditions at 80 °C is described. The use of a nontoxic, inexpensive, easily available and recyclable catalyst makes this protocol practical, environmentally friendly and economically attractive.
- Nasseri, Mohammad A.,Salimi, Mehri
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p. 164 - 170
(2013/07/26)
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- Substituted thiazoles V. Synthesis and antitumor activity of novel thiazolo[2,3-b]quinazoline and pyrido[4,3-d]thiazolo[3,2-a]pyrimidine analogues
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A novel series of thiazolo[2,3-b]quinazoline (14-23, 26 and 27), and pyrido[4,3-d]thiazolo[3,2-a]pyrimidine (34-43, 45 and 46) analogues were designed and synthesized. The obtained compounds were evaluated for their in-vitro antitumor activity at the National Cancer Institute (NCI) 60 cell lines panel assay. Compounds 22, 38, 40 and 41 showed remarkable broad-spectrum antitumor activity. Compounds 22 and 38 are almost nine fold more active than 5-FU, with GI50, TGI, and LC50 values of 2.5, >100, >100; and 2.4, 9.1, 36.2 μM, respectively; while 40 and 41 are almost seven fold more active than 5-FU, with GI50, TGI, and LC50 values of 2.9, 12.4, 46.6 and 3.0, 16.3, 54.0 μM, respectively.
- Al-Omary, Fatmah A.M.,Hassan, Ghada S.,El-Messery, Shahenda M.,El-Subbagh, Hussein I.
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experimental part
p. 65 - 72
(2012/02/15)
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- Exploration and synthesis of curcumin analogues with improved structural stability both in vitro and in vivo as cytotoxic agents
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Curcumin has a surprisingly wide range of chemo-preventive and chemo-therapeutic activities and is under investigation for the treatment of various human cancers. However, the clinical application of curcumin has been significantly limited by its instability and poor metabolic property. Although a number of synthetic modifications of curcumin have been studied intensively in order to develop a molecule with enhanced bioactivities, few synthetic studies were done for the improvement of pharmacokinetic profiles. In the present study, a series of mono-carbonyl analogues of curcumin were designed and synthesized by deleting the reactive β-diketone moiety, which was considered to be responsible for the pharmacokinetic limitation of curcumin. The results of the in vitro stability studies and in vivo pharmacokinetic studies indicated that the stability of these mono-carbonyl analogues was greatly enhanced in vitro and their pharmacokinetic profiles were also significantly improved in vivo. Furthermore, the cytotoxic activities of mono-carbonyl analogues were evaluated in seven different tumor cell lines by MTT assay and the structure-activity relation (SAR) was discussed and concluded. The results suggest that the five-carbon linker-containing analogues of curcumin may be favorable for the curcumin-based drug development both pharmacokinetically and pharmacologically.
- Liang, Guang,Shao, Lili,Wang, Yi,Zhao, Chengguang,Chu, Yanhui,Xiao, Jian,Zhao, Yu,Li, Xiaokun,Yang, Shulin
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experimental part
p. 2623 - 2631
(2009/09/06)
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- Synthesis and anti-inflammatory activities of mono-carbonyl analogues of curcumin
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Curcumin has been extensively studied for its anti-inflammatory activities. However, its potential beneficial effects on various disease preventions and treatments are limited by its unstable structure. The β-diketone moiety renders curcumin to be rapidly metabolized by aldo-keto reductase in liver. In the present study, a series of curcumin analogues with more stable chemical structures were synthesized and several compounds showed an enhanced ability to inhibit lipopolysaccharide (LPS)-induced TNF-α and IL-6 synthesis in macrophages.
- Liang, Guang,Li, Xiaokun,Chen, Li,Yang, Shulin,Wu, Xudong,Studer, Elaine,Gurley, Emily,Hylemon, Phillip B.,Ye, Faqing,Li, Yueru,Zhou, Huiping
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p. 1525 - 1529
(2008/09/19)
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- Synthesis and spectroscopic and structural studies of cross-conjugated dienones derived from cyclic ketones and aromatic aldehydes
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Cross-conjugated dienones were synthesized by the reactions of cyclic ketones with two equivalents of aromatic aldehydes under basic conditions. An NMR spectroscopic study and X-ray diffraction analysis demonstrated that all reaction products are formed as E,E isomers. Spontaneous photochemical trans-cis isomerization of cross-conjugated dienones under the scattered light in solution was observed for the first time. The degree of isomerization depends mainly on the nature of the central fragment of the dienone molecule. The previously unknown product of photochemical [2+2]-cycloaddition of 2,5-bis[(E)-(3-pyridyl)methylidene]cyclopentanone was synthesized and characterized by spectroscopic methods and X-ray diffraction. Under the conditions used, only one isomer of the cyclobutane adduct was obtained. Springer Science+Business Media, Inc. 2006.
- Vatsadze,Manaenkova,Sviridenkova,Zyk,Krut'ko,Churakov,Antipin,Howard,Lang
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p. 1184 - 1194
(2008/02/02)
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- A convenient synthesis of α,α′-bis(substituted benzylidene)cycloalkanones catalyzed by Yb(OTf)3 under solvent-free conditions
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An array of aromatic aldehydes undergoes crossed aldol condensation with ketones in the presence of a catalytic amount of Yb(OTf)3 under solvent-free conditions to afford the corresponding α,α′- bis(substituted benzylidene)cycloalkanones in excellent yields without occurrence of any side reactions. This method is very general, simple and environmental friendly in contrast with the existing methods, which use many classical Lewis acids. Furthermore, the catalyst can be recovered conveniently and reused efficiently without the loss of activity.
- Wang, Limin,Sheng, Jia,Tian, He,Han, Jianwei,Fan, Zhaoyu,Qian, Changtao
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p. 3060 - 3064
(2007/10/03)
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- The synthesis and chlorosulfonation of some diarylidene and heteroarylidene ketones with varying alicyclic ring size
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A series of diarylidene and heteroarylidene ketones (1-20) was prepared using alicyclic ketones ((CH2)nC=O where n=3 to 7).An improved synthesis of 2,4-dibenzylidenecyclobutanone (1) is described and the ease of preparation of the arylidene derivatives is considered in terms of the size of the alicyclic ring.Treatment of 2,5-dibenzylidenecyclopentanone (2) with chlorosulfonic acid (10 mole equivalents) afforded the 4,4'-bis-sulfonyl chloride (23), reducing the amount of chlorosulfonis acid (6 mole equivalents) produced the corresponding mono-sulfonyl chloride (24).Only the respective 4,4'-bis-sulfonyl chlorides (39, 45, 51) could be isolated from the diarylidene ketones derived from larger alicyclic rings.Attempted chlorosulfonation of 2,4-dibenzylidene cyclobutanone (1) gave a mixture of products which could not be clearly characterised.The sulfonyl chlorides were converted into stable sulfonamides (25-29, 35, 36, 38, 40-44, 46-48, 52, 54) by condensation with amines, and selected samples were screened for biological activity as potential insecticides, herbicides, and fungicides.The orientation of sulfonation is discussed in relation to stereoelectronic factors and the relevant spectral data.Key words: Arylidene and heteroarylidene ketones, chlorosulfonation, sulfonamides
- Cremlyn, Richard J.,Frearson, Martin J.,Graham, Stephen
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p. 205 - 218
(2007/10/03)
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