- 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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- 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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- Iodotrimethylsilane-Mediated Cross-Aldol Condensation: A Facile Synthesis of α,α′-Bis(substituted benzylidene)cycloalkanones
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A facile and efficient method for the preparation of α, α′-bis(substituted benzylidene)cycloalkanones is described for the first time using iodotrimethylsilane generated in situ from chlorotrimethylsilane and sodium iodide in acetonitrile. The reaction proceeds rapidly at room temperature, giving high yields of products.
- Sabitha, Gowravaram,Reddy, G. S. Kiran Kumar,Reddy, K. Bhaska,Yadav
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p. 263 - 266
(2007/10/03)
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