- Pericyclic reactions of azafulvenium methides bearing internal dipolarophiles - synthesis of chromene and chromane derivatives
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The reactivity of azafulvenium methides with internal dipolarophiles was explored as an approach to new chromene derivatives. 4,5-Dimethoxycarbonyl- and 5-ethoxycarbonyl- 4-phenylazafulvenium methides with a prop-2-ynyloxyphenyl substituent are converted into 2-[2-(2H-chromen- 8-yl)vinyl]-1H-pyrroles through a sequence of rearrangements. 4,5-Dimethoxycarbonylazafulvenium methide with a more-activated dipolarophile as well as the more-activated 5- (trifluoromethyl)azafulvenium methide with an unactivated alkyne could be trapped by [8π+2π] cycloadditions to afford 8,12a-dihydro-6H-chromeno[4,3-e]indolizines. 5-(Trifluoromethyl) azafulvenium methide with a 2-(3-methoxycarbonylprop- 2-enyloxy)phenyl substituent at C-1 participated in both intramolecular [8π+2π] and [4π+2π] cycloadditions to afford heterocycle-fused chromanes. The microwave-induced rearrangements of 3-[2-(prop-2-ynyloxy)phenyl]-1H,3Hpyrrolo[ 1,2-c]thiazoles afforded chiral 3-(2H-chromen-8-yl)- 1H,3H-pyrrolo[1,2-c]thiazoles.
- Ribeiro Laia, Fernanda M.,Soares, Maria I. L.,Gomes, Clara S. B.,Pinho E Melo, Teresa M. V. D.
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- An expedient strategy for the diversity-oriented synthesis of macrocyclic compounds with natural product-like characteristics
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Naturally-derived macrocyclic compounds are associated with a diverse range of biological activities, including antibacterial effects, and there are over 100 marketed macrocycle drugs derived from natural products. However, synthetic macrocycles are widely considered to be poorly explored in antibiotic development (indeed, within drug discovery in general). This has been attributed to challenges associated with the generation of such compounds. Whilst there are synthetic methods that can produce large collections of structurally similar macrocycles (i.e., compounds with varying appendages based around similar core macrocyclic ring architectures) there is a relative dearth of strategies for the efficient generation of more structurally diverse macrocycle collections in which there is greater variation in the nature of macrocyclic scaffolds present. Such macrocycle collections should contain compounds with a broad range of biological activities (including antibacterial activities) and the requisite robust synthetic methodology useful for analogue synthesis and lead optimization once an active compound has been identified in a biological screen. Herein, we describe a new and expedient diversity-oriented synthesis (DOS) strategy for the generation of a library of novel structurally diverse macrocyclic compounds with a high level of scaffold diversity. The strategy is concise, proceeds from readily-available starting materials, is modular in nature and features a variety of macrocyclisation techniques. In this proof-of-concept study, the synthesis of several previously unreported macrocyclic compounds was achieved. Each of these macrocycles was based around a distinct molecular scaffold and contained natural product-like structural features (e.g., three-dimensionality and multiple hydrogen bond donors and acceptors) as well as synthetic handles for potential further elaboration. The successful generation of these macrocycles demonstrates the feasibility of the new DOS strategy as a synthetic platform for library generation.
- Ciardiello, Joe J.,Galloway, Warren R.J.D.,O'Connor, Cornelius J.,Sore, Hannah F.,Stokes, Jamie E.,Wu, Yuteng,Spring, David R.
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- 4? Participation of 1-Aza-1,3-butadienes in Cycloaddition Reactions: Intramolecular Diels-Alder Reactions of α,β-Unsaturated N-Sulfonylimines
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The 4? participation of α,β-unsaturated N-sulfonylimines in intramolecular Diels-Alder reactions with unactivated dienophiles is detailed in studies which further extend the scope of the cycloaddition reactions of this new class of 1-aza-1,3-butadienes.Similar to observations made in the intermolecular cycloaddition reactions, a strong endo diastereoselectivity (>20:1) was observed to dominate in the cycloaddition reaction of 5b versus 5a and 5c.This endo specific reaction may be attributed to the combination of a pronounced, stabilizing secondary orbital interaction and preferred cycloaddition through an anti-endo transition state in which the lone pair on nitrogen and the C-aryl bond of the dienophile lie trans periplanar to one another benefiting from stabilization analogous to the ground-state anomeric effect.
- Boger, Dale L.,Corbett, Wendy L.
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- Intramolecular allyl transfer reaction from allyl ether to aldehyde groups: Experimental and theoretical studies
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The intramolecular transfer of the allyl group of functionalized allyl aryl ethers to an aldehyde group in the presence of Ni0 complexes was studied from chemical, electrochemical and theoretical points of view. The chemical reaction involves the addition of Ni0 to the allyl ether followed by stoichiometric allylation. The electrochemical process is catalytic in nickel and involves the reduction of intermediate η3-allylnickel(II) complexes.
- Franco, Delphine,Wenger, Karine,Antonczak, Serge,Cabrol-Bass, Daniel,Dunach, Elisabet,Rocamora, Merce,Gomez, Montserrat,Muller, Guillermo
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- MACROCYCLIC COMPOUNDS USEFUL AS CHITINASE INHIBITORS
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The present invention relates to macrocyclic compounds of formula (I) and their use as chitinase inhibitors as well as to pharmaceutical compositions and methods of preparation thereof. The compounds can in particular be used in the treatment, prevention and/or amelioration of asthma.
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Paragraph 0127; 0180-0181; 0193
(2021/07/29)
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- Discovery of seneciobipyrrolidine derivatives for the amelioration of glucose homeostasis disorders through 4E-BP1/Akt/AMPK signaling activation
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Modulating the glucose transport in skeletal muscle is a promising strategy for ameliorating glucose homeostasis disorders. However, the complicated mechanisms of glucose transport make it difficult to find compounds therapeutically relevant molecular mechanisms of action, while phenotypic screening is thought to be an alternative approach to mimic the cell state of interest. Here, we report (±)-seneciobipyrrolidine (1a) is first found to enhance glucose uptake in L6 myotubes through phenotype-based screening. Further SAR investigation led to the identfication of compound A27 (EC50 = 2.7 μM). Proteomiic analysis discloses the unique function mechanism of A27 through upregulating the level of the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), subsequently enhancing the Akt and AMPK phosphorylation, thereby promoting the glucose uptake. Chronic oral administration of A27 significantly lowers blood glucose and improves glucose tolerance in db/db mice. This work is new research on seneciobipyrrolidine derivatives, providing a promising avenue for ameliorating glucose homeostasis.
- Che, Jinxin,Chen, Binhui,Dong, Xiaowu,Gan, Lishe,Hu, Yongzhou,Jin, Xinxin,Li, Jingya,Lu, Jialiang,Ma, Canliang,Shi, Qiuqiu,Song, Rui,Xu, Fan
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- SUBSTITUTED CHROMANES, ANALOGS THEREOF, AND METHODS OF USE AND SYNTHESIS
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Disclosed are chromane compounds, analogs thereof, and methods of their synthesis and use. The compounds may be synthesized by methods involving reductive annulations of arylidene malonates with unsaturated electrophiles using photoredox/Lewis acid cooperative catalysis. The compounds may be formulated in a pharmaceutical composition for treating one of the aforementioned diseases or disorders.
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Paragraph 0162; 0185-0186
(2021/01/25)
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- tert-Butyl Hydroperoxide-Initiated Radical Cyclization of 1-(Allyloxy)-2-(1-Arylvinyl)Benzenes with Sulfinic Acids to Access Sulfonated Benzoxepines
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A tert-butyl hydroperoxide-initiated radical cyclization of 1-(allyloxy)-2-(1-arylvinyl)benzenes with sulfinic acids for the construction of sulfonated benzoxepines is developed. This reaction involves a radical pathway and offers a straightforward route to the formation of seven-membered ring via sulfonylation/cyclization process. This methodology features mild reaction conditions, a broad substrate scope and good functional group tolerance. (Figure presented.).
- Kuang, Kaimo,Wu, Meixia,Wu, Sixin,Xia, Ziqin,Xu, Qiankun,Zhang, Man,Zhou, Nengneng
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supporting information
p. 3491 - 3495
(2021/06/28)
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- CHEMOSENSOR AND A METHOD OF DETECTING PALLADIUM IONS
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A palladium selective chemosensor based on a fluorescein-allyloxy benzene scaffold and a method of detecting palladium ions in a fluid sample with the chemosensor, whereby the fluid sample is contacted with a solution that includes water and the chemosensor to form a mixture. An ultraviolet visible absorption profile and/or a fluorescence emission profile of the mixture is measured to determine a presence or absence of palladium ions in the fluid sample, wherein the chemosensor has an ultraviolet visible absorption peak at 315 to 325 nm and a fluorescence emissions peak at 380 to 400 nm in the solution, and wherein a bathochromic shift in the ultraviolet visible absorption peak to 338 to 342 nm in the mixture and/or a bathochromic shift in the fluorescence emissions peak to 530 to 550 nm in the mixture indicates the presence of palladium ions in the fluid sample.
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Paragraph 0046; 0149
(2020/12/25)
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- Highly regioselective O-allylation of phenol derivatives using MMZCu(I)Y catalyst
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A clean and effective method has been developed for the regioselective of O-allylation of phenol derivatives using a recyclable Cu(I)-exchanged multi-size porous material. Ease of preparation of catalyst through simple solid-state exchange and its compatibility in producing excellent amount of O-allylated products and a plausible mechanistic pathway for the regioselectivity are highlighted. This reported procedure is not requiring any external stabilizing ligand for Cu(I) species and further purification of products.
- Thangapriya, Cheirmakani,Ilaamirthamani, Simsonrubarathinam,Kumarraja, Mayilvasagam
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p. 361 - 367
(2019/12/11)
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- Cascade Claisen and Meinwald Rearrangement for One-Pot Divergent Synthesis of Benzofurans and 2 H-Chromenes
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A new cascade approach has been developed for the one-pot four-step divergent synthesis of polysubstituted benzofurans and 2H-chromenes, featuring a novel cascade aromatic Claisen rearrangement/Meinwald rearrangement/dehydrative or oxidative cyclization. This new method was demonstrated with 39 examples tolerating different substitutions at an epoxide, allylic ether, and aromatic ring, and we showcased its utility with the first total synthesis of natural product liparacid A in seven steps.
- Song, Liyan,Su, Qian,Lin, Xi,Du, Zhihui,Xu, Huiyou,Ouyang, Ming-An,Yao, Hongliang,Tong, Rongbiao
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supporting information
p. 3004 - 3009
(2020/04/20)
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- Synthetic method of flavonoid compound containing CMe2CF3 group
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The invention belongs to the field of chemical synthesis, and particularly relates to a synthetic method of a flavonoid compound containing a CMe2CF3 group; the synthetic method has the characteristics of simple operation, good functional group compatibility and the like, and the flavonoid compound containing the CMe2CF3 group and obtained by reaction has a wide application prospect.
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Paragraph 0024-0025
(2020/06/17)
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- Metal-free synthesis of phosphinoylchroman-4-ones via a radical phosphinoylation–cyclization cascade mediated by K2S2O8
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A variety of chroman-4-ones bearing phosphine oxide motifs were conveniently synthesized from readily available diphenylphosphine oxides and alkenyl aldehydes via a metal-free tandem phosphinoylation/cyclization protocol. The reaction utilizes K2S2O8 as oxidant and proceeds in DMSO/H2O at environmentally benign conditions with a broad substrate scope and afforded the title compounds in moderate yields.
- Liu, Qiang,Lu, Weibang,Wang, Xiaoxia,Xie, Guanqun
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supporting information
p. 1974 - 1982
(2020/10/02)
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- Catalytic Generation of Rhodium Silylenoid for Alkene-Alkyne-Silylene [2 + 2 + 1] Cycloaddition
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An alkene-alkyne-silylene [2 + 2 + 1] cycloaddition takes place in the rhodium-catalyzed reaction of 1,6-enynes with borylsilanes bearing an alkoxy group on the silicon atoms, which react as synthetic equivalents of silylene. The reaction proceeds efficiently in 1,2-dichloroethane at 80-110 °C in the presence of a rhodium catalyst bearing bis(diphenylphosphino)methane (DPPM) as a ligand to afford 1-silacyclopent-2-enes in good to high yields.
- Ohmura, Toshimichi,Sasaki, Ikuo,Suginome, Michinori
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supporting information
p. 1649 - 1653
(2019/03/20)
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- The winding road of the uvaretin class of natural products: From total synthesis to bioactive agent discovery
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Herein, we disclose the development of a synthetic route to gain access to the uvaretin class of chalcone natural products. In this, the construction of a small library was achieved, and the collection was evaluated for cytotoxicity and other biological properties. Uvaretin (1) was accessed via a seven-step route in an overall yield of 15.1%. Within this route, the unsaturated enone variant of uvaretin (2), also a natural product, was accessed in a 16.7% yield over six steps. This route provides a nearly three-fold increase in yields of 1 and 2 in comparison to the previous synthetic route accessing them in 5.8% and 3.0% overall yields, respectively. Evaluation of 1 and 2 revealed IC50 values between 2.0 and 5.1 μM in the cancerous cell lines HeLa, U937, A549, and MIA PaCa-2. Screening of the whole chalcone library set led to the discovery of over 30 compounds, within six cancerous cell lines, possessing single digit μM IC50 activity as sole agents. Furthermore, multiple library members were found to possess promising potentiating properties with known chemotherapeutic agents.
- Dallman, Johnathan,Lansakara, Ashabha,Nguyen, Thi,Weeramange, Chamitha,Hulangamuwa, Wasundara,Rafferty, Ryan J.
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p. 1420 - 1431
(2019/08/21)
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- Synthesis of Chromenoisoxazolidines from Substituted Salicylic Nitrones via Visible-Light Photocatalysis
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This effort reports the first redox-neutral visible-light photocatalytic intramolecular dipolar cycloaddition for the diastereoselective synthesis of chromenoisoxazolidines. The authors have found that alkenylphenyl nitrones with a diverse substitution pattern on the aromatic ring and the alkenyl substituent undergo visible-light-promoted cycloadditions in the presence of catalytic amounts of Ru(bpy)3Cl2 in high yields and selectivities. Evidence indicates that the proposed redox-neutral pathway is the predominant photoredox mechanism for this transformation.
- Haun, Graham,Paneque, Alyson N.,Almond, David W.,Austin, Brooke E.,Moura-Letts, Gustavo
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supporting information
p. 1388 - 1392
(2019/03/08)
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- Visible-Light-Promoted Cascade Radical Cyclization: Synthesis of 1,4-Diketones Containing Chroman-4-One Skeletons
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A visible-light-induced cascade radical cyclization of aroyl chlorides with 2-(allyloxy)-benzaldehyde derivatives has been developed. The method takes advantages of unactivated C=C bonds as the acyl radical acceptors and offers a mild and green approach for the synthesis of 1,4-diketones bearing biologically important chroman-4-one skeletons with moderate to good yields.
- He, Xiang-Kui,Cai, Bao-Gui,Yang, Qing-Qing,Wang, Long,Xuan, Jun
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supporting information
p. 3269 - 3273
(2019/09/17)
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- Synthesis of chroman-4-one and indanone derivatives via silver catalyzed radical ring opening/coupling/cyclization cascade
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A variety of chroman-4-one and indanone derivatives were conveniently synthesized from readily available cyclopropanols and alkenyl aldehydes via a silver catalyzed radical ring-opening/coupling/cyclization cascade. The reaction proceeded under mild and neutral conditions with broad substrate scope and afforded the desired products in moderate to good yields. A probable mechanism for the cascade reaction was also proposed.
- Liu, Qiang,Xie, Guanqun,Wang, Qiang,Mo, Zhendong,Li, Chen,Ding, Shujiang,Wang, Xiaoxia
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- Tetrahydrobenzochromene Synthesis Enabled by a Deconjugative Alkylation/Tsuji-Saegusa-Ito Oxidation on Knoevenagel Adducts
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A modular and practical route to versatile cyano-1,3-dienes by a sequence involving deconjugative alkylation and "Tsuji-Saegusa-Ito oxidation" is reported. In this letter, the versatility of the products is also explored, including a route to benzochromene scaffolds common to many natural products.
- Navaratne, Primali V.,Grenning, Alexander J.
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supporting information
p. 4566 - 4570
(2018/08/09)
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- Silver-Catalyzed Radical Cascade Cyclization toward 1,5-/1,3-Dicarbonyl Heterocycles: An Atom-/Step-Economical Strategy Leading to Chromenopyridines and Isoxazole-/Pyrazole-Containing Chroman-4-Ones
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A novel and convenient silver-catalyzed radical cascade cyclization toward a large variety of 1,5-/1,3-dicarbonyl heterocycles containing a chroman-4-one, indanone, or 2,3-dihydroquinolin-4(1H)-one moiety was developed, by reacting various 2-functionalized benzaldehydes, including 2-allyloxy benzaldehydes, 2-allyl benzaldehyde, and 2-N(Ts)CH2-CH CH2 substituted benzaldehyde, with 1,3-dicarbonyl compounds in the presence of AgNO3/K2S2O8 in one pot under mild reaction conditions. The newly obtained 1,5-/1,3-dicarbonyl-containing heterocycles were further used directly to synthesize more structurally diverse polyheterocycles, mainly including chromenopyridines as well as isoxazole- or pyrazole-containing chroman-4-ones.
- Hu, Hao,Chen, Xiaolan,Sun, Kai,Wang, Junchao,Liu, Yan,Liu, Hui,Fan, Lulu,Yu, Bing,Sun, Yuanqiang,Qu, Lingbo,Zhao, Yufen
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supporting information
p. 6157 - 6160
(2018/10/05)
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- Bicyclic Heterocycles from Levulinic Acid through a Fast and Operationally Simple Diversity-Oriented Multicomponent Approach
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Levulinic acid, which is one of the most important renewable building blocks derived from lignocellulosic biomass, has been converted in a diversity-oriented manner into two families of drug-like bicyclic nitrogen heterocycles. The methodology, endowed with high step economy and operational simplicity, is based on an Ugi multicomponent reaction, which employs amino alcohols as components, followed by a SN2 cyclization. Noteworthy is the successful synthesis of hexahydro pyrrolodiazepinediones, since the cyclization of the isocyanide-derived secondary amide onto an alcohol to give a seven-membered ring was unprecedented. Also enantiopure products have been prepared by using chiral amino alcohols.
- Lambruschini, Chiara,Basso, Andrea,Moni, Lisa,Pinna, Alessandro,Riva, Renata,Banfi, Luca
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supporting information
p. 5445 - 5455
(2018/10/20)
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- Observations concerning the synthesis of heteroatom-containing 9-membered benzo-fused rings by ring-closing metathesis
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A set of benzo-fused dienes with a 1,9-relationship and containing a variety of nitrogen and oxygen heteroatoms was readily synthesized. These dienes were then treated with the Grubbs second generation catalyst with the aim of synthesizing the 9-membered benzannelated heterocycles containing two heteroatoms (either O,O, NR,NR or O,NR where R = Ts or Boc). As previously observed in the literature, many of the dienes did not give the expected ring-closed product. However, a number of the desired products did form, namely with the 1,2-dihydrobenzo[c][1,5]oxazonin-7(5H)-one, 5,7-dihydrobenzo[b][1,5]oxazonine-6(2H)-carboxylate and 2,5,6,7-tetrahydrobenzo[b][1,5]oxazonine cores, albeit in poor yields. Rather surprisingly, the N-allyl-N-(2-(N-allyl-4-methylphenylsulfonamido)benzyl)-4-methylbenzenesulfonamide scaffold gave the desired ring-closed 1,6-ditosyl-2,5,6,7-tetrahydro-1H-benzo[b][1,5]diazonine in a high yield. Furthermore, when treated with the catalyst [RuClH(CO)(PPh3)3] the alkene isomerized into conjugation only with the benzylic NTs group and not with the phenyl NTs group to afford the 1,6-ditosyl-2,3,6,7-tetrahydro-1H-benzo[b][1,5]diazonine structure.
- Aderibigbe, Blessing A.,Green, Ivan R.,Mabank, Tanya,Janse van Rensburg, Mari,Morgans, Garreth L.,Fernandes, Manuel A.,Michael, Joseph P.,van Otterlo, Willem A.L.
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p. 4671 - 4683
(2017/07/10)
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- Hydride transfer reactions of 5-(2-alkohybenzylidene) barbituric acids: Synthesis of 2,4,6-trioxoperhydropyrimidine-5-spiro-3′-chromanes
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The thermal cyclization of 5-(2-phenoxymethylphenyl-methylene)barbituric acid and its derivatives affords 2,4,6-trioxoperhydropyrimidine-5-spiro-3′-chromanes. The reactions require no catalysts and proceed at temperatures from 118 to 240?°C depending on the substrate activity. These cyclization reactions are analogous to T-reactions of tertiary amines involving the hydride transfer.
- Krasnov, Konstantin A.,Dorovatovskii, Pavel V.,Zubavichus, Yan V.,Timofeeva, Tatiana V.,Khrustalev, Victor N.
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p. 542 - 549
(2017/01/12)
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- Semicarbazone derivatives and use thereof
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The invention belongs to the technical field of medicine, and relates to semicarbazone derivatives disclosed as general formula I, and geometrical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the substituent groups M, R1, R2, R and n are defined in the specification. The invention also relates to a method for preparing compounds disclosed as Formula I, a pharmaceutical composition containing the compounds and application of the compounds and pharmaceutical composition in preparing drugs for treating and/or preventing cancers and other hyperplastic diseases.
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Paragraph 0542; 0543; 0544
(2017/08/14)
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- Steric buttressing in the Pauson-Khand reactions of benzyl enynes
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The application of the intramolecular Pauson-Khand reaction of 1,n-enynes provides a convenient method for the construction of polycyclic frameworks but this process has largely been limited to the formation of 5,5- and 5,6-fused ring systems. In this report, we describe the application of the Pauson-Khand cyclization to 1,8-enynes embedded in an aromatic ring system wherein it is determined that the presence of steric buttresses in the form of t-butyl groups facilitates the cycloaddition. These reactions proceed in good yields with either thermal or oxidative activation and in the former case, the diastereoselectivities are high. An investigation of the tolerance of this cycloaddition to substitution around the 1,8-enyne demonstrates that only 2,2-disubstitution does not result in productive cyclization. Cycloadditions with hydroxyl groups at the propargylic position while leading to fused rings are compromised by side reactions leading to reduction and in some cases tautomerization. However, these byproducts are easily minimized through conversion of the hydroxyl group to the corresponding silyl ether.
- Madu, Christian E.,Dias, H.V. Rasika,Lovely, Carl J.
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p. 6118 - 6137
(2017/09/29)
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- Palladium-Catalyzed Fluoroalkylative Cyclization of Olefins
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A palladium-catalyzed fluoroalkylative cyclization of olefins with readily available Rf-I reagents to afford the corresponding fluoroalkylated 2,3-dihydrobenzofuran and indolin derivatives with moderate to excellent yields is reported. This novel procedure provides an efficient method for the construction of Csp3-CF2 and C-O/N bonds in one step. A wide range of functional groups are tolerated. It is proposed that a radical/SET (single electron transfer) pathway proceeding via the fluoroalkyl radical may be involved in the catalytic cycle.
- Liao, Jianhua,Fan, Lianfeng,Guo, Wei,Zhang, Zhenming,Li, Jiawei,Zhu, Chuanle,Ren, Yanwei,Wu, Wanqing,Jiang, Huanfeng
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supporting information
p. 1008 - 1011
(2017/03/15)
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- Cycloisomerization between Aryl Enol Ether and Silylalkynes under Ruthenium Hydride Catalysis: Synthesis of 2,3-Disubstituted Benzofurans
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Metal-catalyzed cycloisomerization reactions of 1,n-enynes have become conceptually and chemically attractive processes in the search for atom economy, which is a key subject of current research. However, metal-catalyzed cycloisomerization between aryl enol ether and silylalkynes has not been developed. The ruthenium hydride complex catalyzed cycloisomerization between aryl enol ether and silylalkynes is reported to give benzofurans having useful functional groups, vinyl and trimethylsilylmethyl, on the 2- and 3-positions, respectively.
- Ohno, Shohei,Takamoto, Kohei,Fujioka, Hiromichi,Arisawa, Mitsuhiro
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supporting information
p. 2422 - 2425
(2017/05/12)
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- A cascade Claisen rearrangement/o-quinone methide formation/electrocyclization approach to 2H-chromenes
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A new approach has been developed for the synthesis of 8-substituted 2H-chromenes, featuring a novel cascade aromatic Claisen rearrangement/o-quinone methide formation/6π-electrocyclization. This new method was demonstrated with 28 examples tolerating different substitutions at alkenes, allylic and aromatic ring and with total syntheses of three 2H-chromene natural products.
- Song, Liyan,Huang, Fang,Guo, Liwen,Ouyang, Ming-An,Tong, Rongbiao
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supporting information
p. 6021 - 6024
(2017/07/10)
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- Aldehydes as Carbon Radical Acceptors: Silver Nitrate Catalyzed Cascade Decarboxylation and Oxidative Cyclization toward Dihydroflavonoid Derivatives
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Silver nitrate-catalyzed cascade decarboxylation and oxidative cyclization of α-oxocarboxylic acids, alkenes, and aldehydes is demonstrated for the first time. With ammonium persulfate as the oxidant, the cascade reactions afford dihydroflavonoid derivatives as products in moderate to good yields, exhibiting a broad substrate tolerance. Control experiments indicated that the mechanism includes a radical pathway with aldehydes as the carbon radical acceptors. (Figure presented.).
- Yang, Wen-Chao,Dai, Peng,Luo, Kai,Ji, Yi-Gang,Wu, Lei
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supporting information
p. 2390 - 2395
(2017/07/22)
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- Catalytic Intramolecular Cycloaddition Reactions by Using a Discrete Molecular Architecture
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A discrete tetragonal tube-shaped complex (MT-1) has been synthesised by coordination-driven self-assembly of a carbazole-based tetraimidazole donor L and a Pd(II) 90° acceptor, that is, [cis-(dppf)Pd(OTf)2] (dppf=diphenylphosphinoferrocene, OTf=CF3SO3?). Complex MT-1 was characterised by multinuclear NMR, ESI-MS and single-crystal X-ray diffraction analysis (SCXRD), which showed its symmetrical tetrafacial tube-shaped architecture possessing a large cavity described by four aromatic walls. This coordination cage was successfully utilised as a molecular vessel to perform intramolecular cycloaddition reactions of O-allylated benzylidinebarbituric acid derivatives inside its confined nanospace. The presence of a catalytic amount of MT-1 promoted [4+2] cycloaddition reactions in a regio- and stereoselective manner, yielding the corresponding penta/tetracyclouracil derivatives in good yields under mild reaction conditions. This protocol is interesting compared with the literature reports for the synthesis of similar chromenopyran pyrimidinedione derivatives under high-temperature reflux conditions or solid-state melt reactions (SSMRs).
- Roy, Bijan,Devaraj, Anthonisamy,Saha, Rupak,Jharimune, Suprita,Chi, Ki-Whan,Mukherjee, Partha Sarathi
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p. 15704 - 15712
(2017/10/23)
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- Synthesis of o-Allyloxy(ethynyl)benzene Derivatives by Cu-Catalyzed Suzuki–Miyaura-Type Reaction and Their Transformations into Heterocyclic Compounds
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We have found that Suzuki–Miyaura-type reactions of o-allyloxy(bromoethynyl)benzenes with arylboronic acids using a hydrazone/Cu catalyst system proceeded smoothly in iPrOH under mild conditions to afford the corresponding o-allyloxy(arylethynyl)benzene derivatives in good yields without decomposition of the allyloxy group. We have further demonstrated that annulation and enyne metathesis of the o-allyloxy(arylethynyl)benzene derivatives using transition-metal catalysts led to various heterocyclic compounds.
- Watanabe, Kohei,Mino, Takashi,Ishikawa, Eri,Okano, Miyu,Ikematsu, Tatsuya,Yoshida, Yasushi,Sakamoto, Masami,Sato, Kazuki,Yoshida, Kazuhiro
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supporting information
p. 2359 - 2368
(2017/05/01)
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- austria takes charge of his Wei derivative and its preparation method and application
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The invention relates to an oseltamivir derivative as well as a preparation method and application thereof. The compound has the structure shown in a formula I. The invention provides an efficient influenza virus neuraminidase inhibitor with high selectivity, which is used for preparing drugs for preventing or curing flu, particularly the diseases caused by N1 influenza virus. The invention also relates to a drug composition comprising the compound shown in the formula I.
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Paragraph 0101; 0102
(2016/10/09)
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- The Synthesis of 5-Amino-dihydrobenzo[b]oxepines and 5-Amino-dihydrobenzo[b]azepines via Ichikawa Rearrangement and Ring-Closing Metathesis
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The combination of Ichikawa's rearrangement and a ring-closing metathesis reaction of allyl carbamates is presented as a method for the preparation of 5-amino-substituted 2,5-dihydro-benzo[b]oxepines, 2,5-dihydro-benzo[b]azepines, and 2,5-dihydro-benzo[b]thiepins. It was demonstrated that the use of nonracemic allyl carbamates enables the synthesis of enantioenriched benzo-fused seven-membered heterocycles. Finally, it was shown that further functionalization of the obtained structures allows access to pharmacologically active 5-amino-substituted 2,3,4,5-tetrahydro-1-benzo[b]oxepine scaffolds.
- Chwastek, Monika,Pieczykolan, Micha?,Stecko, Sebastian
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p. 9046 - 9074
(2016/10/17)
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- Straightforward synthesis of functionalized chroman-4-ones through cascade radical cyclization-coupling of 2-(allyloxy)arylaldehydes
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A novel and direct approach to synthesize a series of phosphonate, azide and hydroxy functionalized chroman-4-ones has been developed. The cascade transformation appears to proceed through an intramolecular addition of an in situ generated acyl radical onto the alkene, followed by a selective nucleophilic radical-electrophilic radical cross coupling.
- Zhao, Jingjing,Li, Pan,Li, Xinjian,Xia, Chungu,Li, Fuwei
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supporting information
p. 3661 - 3664
(2016/03/05)
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- Silaborative Carbocyclizations of 1,7-Enynes. Diastereoselective Preparation of Chromane Derivatives
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Palladium(0)-catalyzed carbocyclization of 1,7-enynes mediated by (chlorodimethylsilyl)pinacolborane proceeds with 1,8-addition of the silicon and boron functions to give functionalized cyclohexane derivatives with boron attached to the exocyclic olefin. A variety of chromane dervatives are accessible by this method. In contrast to the analogous reactions with 1,6-enynes, the configuration of the newly formed stereogenic center is controlled by a stereogenic center present in the substrate.
- Xiao, You-Cai,Moberg, Christina
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supporting information
p. 308 - 311
(2016/02/03)
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- Design, synthesis and biological evaluation of novel 4-phenoxy-6,7-disubstituted quinolines possessing (thio)semicarbazones as c-Met kinase inhibitors
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In continuing our efforts to identify small molecules able to inhibit c-Met kinase, three series of novel 6,7-disubstituted-4-phenoxyquinoline derivatives (23a-w, 26a-d and 30a-d) bearing (thio)semicarbazone scaffold were designed, synthesized and evaluated for their cytotoxicity. The biological data revealed that most compounds exhibited moderate-to-excellent activity against HT-29, MKN-45, A549 cancer cell lines and relative poor potency toward MDA-MB-231 cell as well as hardly any cytotoxicity in normal PBL cell. Eleven compounds were further examined for their inhibitory activity against c-Met kinase and three compounds (23h, 23n and 26a) demonstrated good inhibitory activity. This work resulted in the discovery of a potent c-Met inhibitor 23n, bearing 2-hydroxy-3-allylphenyl group at R2 moiety, as a valuable lead molecule, which possessed remarkable cytotoxicity and high selectivity against A549 and HT-29 cell lines with IC50 values of 11 nM and 27 nM. Besides, it displayed excellent c-Met kinase inhibition on a single-digital nanomolar level (IC50 = 1.54 nM). Meanwhile, the results from preliminarily in vivo study reflected that compound 23n showed promising overall PK profiles, consistent with the efficacy in both MKN-45 and HT-29 tumor xenograft mice model. These results clearly indicated that compound 23n is a potent and highly selective c-Met inhibitor and its favorable in vitro and in vivo profiles warrant further investigation.
- Zhai, Xin,Bao, Guanglong,Wang, Limei,Cheng, Mingke,Zhao, Meng,Zhao, Sijia,Zhou, Hongyang,Gong, Ping
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p. 1331 - 1345
(2016/03/01)
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- Organoselenium and DMAP co-catalysis: Regioselective synthesis of medium-sized halolactones and bromooxepanes from unactivated alkenes
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A catalytic system consisting of bis(4-methoxyphenyl)selenide and 4-(dimethylamino)pyridine (DMAP) has been developed for the regioselective synthesis of medium-sized bromo/iodo lactones and bromooxepanes possessing high transannular strain. 77Se NMR, mass spectrometry and theoretical studies reveal that the reaction proceeds via a quaternary selenium intermediate.
- Verma, Ajay,Jana, Sadhan,Prasad, Ch. Durga,Yadav, Abhimanyu,Kumar, Sangit
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supporting information
p. 4179 - 4182
(2016/03/19)
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- One-pot synthesis, biological evaluation, and docking study of new chromeno-annulated thiopyrano[2,3-c]pyrazoles
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Abstract: A one-pot synthesis of new chromeno-annulated thiopyrano[2,3-c]pyrazoles has been achieved through a domino-Knoevenagel–hetero-Diels–Alder reaction after combining various pyrazol-5-thiones with O-alkenyloxy/alkynyloxy-salicylaldehydes/naphthaldehydes in a Br?nsted acidic ionic liquid, [Hmim]HSO4, methylimidazolium hydrogen sulphate, under microwave irradiation. The method is simple and in many cases the isolated products did not require further purification. The central pyranothiopyranyl cis-fusion was confirmed by 2D NMR NOESY and single-crystal X-ray analysis suggesting that the endo-E-Syn transition state would be the most favored pathway of the reaction. Many heterocycles of this new series were found active against six bacterial and two fungal strains. In addition, all the compounds possess good anti-oxidant activity with the ferric reducing anti-oxidant power value >100mmol/100g. All new structures were docked into active site of angiotensin I converting enzyme (ACE), assuming that the compounds possessed the anti-hypertensive activity potential on the basis of prediction of activity spectra of substances prediction results. Pyranyl ring oxygen in compound 9a forms two hydrogen bonds with HIS353 and HIS513 residues in the active site of the ACE having good G score (- 4.06) of this compound, comparable to that of the reference drug captopril (- 4.93). Graphical Abstract: [Figure not available: see fulltext.]
- Parmar, Bhagyashri D.,Sutariya, Tushar R.,Brahmbhatt, Gaurangkumar C.,Parmar, Narsidas J.,Kant, Rajni,Gupta, Vivek K.,Murumkar, Prashant R.,Sharma, Mayank Kumar,Yadav, Mange Ram
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p. 639 - 657
(2016/07/12)
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- One-pot synthesis of 5-amino-2,5-dihydro-1-benzoxepines: Access to pharmacologically active heterocyclic scaffolds
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A one-pot multibond-forming process involving a thermally mediated Overman rearrangement and a ring closing metathesis reaction of allylic trichloroacetimidates bearing a 2-allyloxyaryl group has been developed for the synthesis of 5-amino-substituted 2,5-dihydro-1-benzoxepines. Chemoselective reduction and functionalization of these compounds allowed access to a range of pharmacologically active 5-amino-2,3,4,5-tetrahydro-1-benzoxepine scaffolds.
- Calder, Ewen D. D.,Sharif, Salaheddin A. I.,McGonagle, Fiona I.,Sutherland, Andrew
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p. 4683 - 4696
(2015/05/13)
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- Silver Tetrafluoroborate-Catalyzed Oxa-Diels-Alder Reaction between Electrically Neutral Dienes and Aldehydes
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Chemoselective oxa-Diels-Alder reactions between electrically neutral 1,3-dienes and various aldehydes were achieved using the commercially available silver tetrafluoroborate (AgBF4) as catalyst. This catalytic process has high functional group tolerance. Heteroatoms at the β-position of the aryl aldehydes can greatly promote the reactivity of the substrates even with heterocyclic aldehydes that were previously believed to be unreactive for the oxa-Diels-Alder reaction. In addition, acroleins with β-heteroatom substitution are also good substrates. High chemoselectivity and regioselectivity were achieved at room temperature for the oxa-Diels-Alder reaction between acroleins and stoichiometric simple 1,3-dienes.
- Zou, Xiaodong,Yang, Lizheng,Liu, Xiangli,Sun, Hao,Lu, Hongjian
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supporting information
p. 3040 - 3046
(2015/11/03)
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- Removal of metabolic liabilities enables development of derivatives of procaspase-activating compound 1 (PAC-1) with improved pharmacokinetics
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Procaspase-activating compound 1 (PAC-1) is an o-hydroxy-N-acylhydrazone that induces apoptosis in cancer cells by chelation of labile inhibitory zinc from procaspase-3. PAC-1 has been assessed in a wide variety of cell culture experiments and in vivo models of cancer, with promising results, and a phase 1 clinical trial in cancer patients has been initiated (NCT02355535). For certain applications, however, the in vivo half-life of PAC-1 could be limiting. Thus, with the goal of developing a compound with enhanced metabolic stability, a series of PAC-1 analogues were designed containing modifications that systematically block sites of metabolic vulnerability. Evaluation of the library of compounds identified four potentially superior candidates with comparable anticancer activity in cell culture, enhanced metabolic stability in liver microsomes, and improved tolerability in mice. In head-to-head experiments with PAC-1, pharmacokinetic evaluation in mice demonstrated extended elimination half-lives and greater area under the curve values for each of the four compounds, suggesting them as promising candidates for further development.
- Roth, Howard S.,Botham, Rachel C.,Schmid, Steven C.,Fan, Timothy M.,Dirikolu, Levent,Hergenrother, Paul J.
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p. 4046 - 4065
(2015/05/27)
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- Synthesis of Chromen[4,3-b]pyrrolidines by Intramolecular 1,3-Dipolar Cycloadditions of Azomethine Ylides: An Experimental and Computational Assessment of the Origin of Stereocontrol
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Azomethine ylides, generated from imine-derived O-cinnamyl or O-crotonyl salicylaldeyde and α-amino acids, undergo intramolecular 1,3-dipolar cycloaddition, leading to chromene[4,3-b]pyrrolidines. Two reaction conditions are used: (a) microwave-assisted heating (200 W, 185 °C) of a neat mixture of reagents, and (b) conventional heating (170 °C) in PEG-400 as solvent. In both cases, a mixture of two epimers at the α-position of the nitrogen atom in the pyrrolidine nucleus was formed through the less energetic endo-approach (B/C ring fusion). In many cases, the formation of the stereoisomer bearing a trans-arrangement into the B/C ring fusion was observed in high proportions. Comprehensive computational and kinetic simulation studies are detailed. An analysis of the stability of transient 1,3-dipoles, followed by an assessment of the intramolecular pathways and kinetics are also reported. The two-component synthesis of chromene[4,3-b]pyrrolidines has been achieved under two different conditions. The strategy was used to obtain N-sulfonylated adducts with interesting biological activity. Calculations show that formation of W and S′ 1,3-dipoles determines the stereochemical outcome of the reaction, which involves asynchronous transition structures.
- Costa, Paulo R. R.,Sansano, José M.,Cossío, Unai,Barcellos, Julio C. F.,Dias, Ayres G.,Nájera, Carmen,Arrieta, Ana,De C?zar, Abel,Cossío, Fernando P.
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p. 4689 - 4698
(2015/08/03)
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- Tandem Claisen Rearrangement/6-endo Cyclization Approach to Allylated and Prenylated Chromones
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Allyl, dimethylallyl and prenyl ethers derived from o-acylphenols reacted upon microwave irradiation to form C-allylated or -prenylated chromone derivatives, depending on the substitution pattern of the arene and the allyl substituent. The reaction proceeds through a tandem Claisen rearrangement and 6-endo-trig or 6-endo-dig cyclization sequence. For prenyl ethers, the tandem sequence can be extended by a Cope rearrangement to furnish 6-prenylchromones. The method is potentially useful for the synthesis of natural products and drugs.
- Schmidt, Bernd,Riemer, Martin,Schilde, Uwe
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supporting information
p. 7602 - 7611
(2016/01/25)
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- Condensation of salicylaldehydes with ethyl 4,4,4-trichloro-3-oxobutanoate: A facile approach for the synthesis of substituted 2H-chromene-3-carboxylates
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A highly efficient and simple protocol has been developed for the preparation of ethyl 2-oxo-2H-chromene-3-carboxylates 3a-v by the condensation of salicylaldehydes 1a-v with ethyl 4,4,4-trichloro-3-oxobutanoate 2 for the first time. The reaction is proceeding via Knoevenagel pathway followed by a selective addition of the phenolic hydroxyl group to the carbonyl group adjacent to the CCl3 group rather than ester carbonyl due to a strong electron withdrawing effect and produced coumarin derivative 3a with the elimination of CHCl3.
- Sairam, Mudulkar,Saidachary, Gannerla,Raju, Bhimapaka China
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supporting information
p. 1338 - 1343
(2015/03/04)
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- Dienamine and friedel-crafts one-pot synthesis, and antitumor evaluation of diheteroarylalkanals
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An asymmetric synthesis of diheteroarylalkanals through one-pot dienamine and Friedel-Crafts reaction is presented. The reaction tolerates a large variety of substituents at different positions of the starting aldehyde and also in the indole nucleophile, and a range of diheterocyclic alkanals can be achieved. Furthermore, we have studied the antiproliferative activity of these new compounds in representative cancer tumor cell lines. All in one: An asymmetric synthesis of diheteroarylalkanals through a one-pot dienamine and Friedel-Crafts reaction is presented (see scheme). The reaction tolerates a large variety of substituents at different positions of the starting aldehyde, and the use of nucleophiles and different diheterocyclic alkanals can also be achieved. The antiproliferative activity of these new compounds in different cancer tumor cell lines has also been investigated and it was found that, with the appropriate substitution, the compounds are as cytotoxic as Cisplatin.
- Frías, María,Padrón, José M.,Alemán, José
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supporting information
p. 8237 - 8241
(2015/05/27)
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- Ring-closing metathesis reaction-based synthesis of new classes of polyether macrocyclic systems
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Ring closing metathesis (RCM) reactions of suitable substrates having terminal olefins, which are assembled from various linkers and hydroxy benzaldehydes and syntheses of a wide range of 16-30 membered, new crown ether-type polyether, aza-polyether, bis aza-polyether macrocycles and dilactone moiety embedded polyether macrocycles (macrolides) are reported. After the ring-closure reaction, installation of different functional groups and functional group modification on the periphery of the synthesized polyether/crown ether macrocycles obtained in the RCM reactions are accomplished using the epoxidation, oxidation and catalytic hydrogenation-based synthetic transformations. Along this line, the syntheses of a variety of polyether macrocycles possessing epoxide or α-hydroxy ketone or 1,2-diol functionalities at the periphery have been shown. Furthermore, the synthesized α-hydroxy ketone functionality installed polyether macrocycles were subjected to the allylation and Reformatsky type reactions to obtain homoallyl alcohol moiety-based and lactone ring-appended polyether macrocycles.
- Naveen,Babu, Srinivasarao Arulananda
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p. 7758 - 7781
(2015/09/08)
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- Mechanism of alcohol oxidation mediated by copper(II) and nitroxyl radicals
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2,2′-Bipyridine-ligated copper complexes, in combination with TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl), are highly effective catalysts for aerobic alcohol oxidation. Considerable uncertainty and debate exist over the mechanism of alcohol oxidation mediated by CuII and TEMPO. Here, we report experimental and density functional theory (DFT) computational studies that distinguish among numerous previously proposed mechanistic pathways. Oxidation of various classes of radical-probe substrates shows that long-lived radicals are not formed in the reaction. DFT computational studies support this conclusion. A bimolecular pathway involving hydrogen-atom-transfer from a CuII-alkoxide to a nitroxyl radical is higher in energy than hydrogen transfer from a CuII-alkoxide to a coordinated nitroxyl species. The data presented here reconcile a collection of diverse and seemingly contradictory experimental and computational data reported previously in the literature. The resulting Oppenauer-like reaction pathway further explains experimental trends in the relative reactivity of different classes of alcohols (benzylic versus aliphatic and primary versus secondary), as well as the different reactivity observed between TEMPO and bicyclic nitroxyls, such as ABNO (ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl).
- Ryland, Bradford L.,McCann, Scott D.,Brunold, Thomas C.,Stahl, Shannon S.
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supporting information
p. 12166 - 12173
(2014/12/09)
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- NEW MACROCYCLIC AMIDINOUREA DERIVATIVES, METHODS OF PREPARATION AND USES THEREOF AS CHITINASE INHIBITORS
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The present invention relates to macrocyclic amidinourea derivatives of formula 8, methods of preparation and uses thereof, pharmaceutical compositions in particular to be used as chitinase inhibitors in the treatment of a fungal infection.
- -
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Page/Page column 18; 19
(2015/01/07)
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- INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION
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The disclosure generally relates to compounds of formula I, including compositions and methods for treating human immunodeficiency virus (HIV) infection. The disclosure provides novel inhibitors of HIV, pharmaceutical compositions containing such compounds, and methods for using these compounds in the treatment of HIV infection. Formule (I)
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Page/Page column 99; 100
(2014/10/18)
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- Synthesis and biological evaluation of benzothiazole derivatives bearing the ortho-hydroxy-N-acylhydrazone moiety as potent antitumor agents
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A novel series of benzothiazole derivatives bearing the ortho-hydroxy-N-acylhydrazone moiety were designed, synthesized, and evaluated for their procaspase-3 kinase activation activities and antiproliferative activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN-45, and MDA-MB-231). Most target compounds showed moderate to excellent cytotoxic activity against all five tested cancer lines. The most promising compound 18e (procaspase-3 EC50- 0.31μM) with IC50 values ranging from 0.24 to 0.92 μM against all tested cell lines was 4.24-12.2 times more active than PAC-1 (procaspase-3 EC50 - 0.41 μM). Structure-activity relationship studies indicated that the phenyl group on the 2-hydroxyphenyl ring (moiety A) was critical for pharmacological activity in vitro. In addition, introduction of a benzyloxyl group on moiety A and a mono-electron-withdrawing group at the 4-position of the benzyloxyl group were more favorable for antitumor activity. Moreover, reduction of the electron density in the phenyl ring of the benzyloxy group led to a dramatic decrease in the procaspase-3 kinase activation activity. -
- Ma, Junjie,Zhang, Guangyan,Han, Xiaoqi,Bao, Guanglong,Wang, Lihui,Zhai, Xin,Gong, Ping
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p. 936 - 949
(2015/02/19)
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- β-(Carbonatoxy)alkyl radicals: A new subset of β-(ester)alkyl radical fragmentation during copper(I)-mediated synthesis of 1,1-dichloro-1-alkenes
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A new subset of β-(ester)alkyl radicals is presented. It is the first study on the chemistry of β-(alkoxycarbonyloxy)alkyl radicals that fill the gap in the spectrum of the migrating groups in β-(ester)alkyl radical reactions. The change from less nucleofugal (acetate) group to the more nucleofugal (carbonate) group in the spectrum of the migrating group changed the reaction path from rearrangement to fragmentation. This approach has been used for the synthesis of 1,1-dichloroalkenes in high yields. The formation of dichloroalkenes was accounted by the involvement of alkene radical cation and carbonate anion pair (a CIP) as a result of heterolysis of the CO bond of the carbonate at the β-position of the β-(alkoxycarbonyloxy)alkyl radical. The alkene radical cation was trapped by nucleophilic reaction with MeOH to form methyl ester.
- Ram, Ram N.,Tittal, Ram K.
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supporting information
p. 4342 - 4345
(2014/07/22)
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- Design, economical synthesis and antiplasmodial evaluation of vanillin derived allylated chalcones and their marked synergism with artemisinin against chloroquine resistant strains of Plasmodium falciparum
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The in vitro blood stage antiplasmodial activity of a series of allylated chalcones based on the licochalcone A as lead molecule was investigated against chloroquine (CQ) sensitive Pf3D7 and CQ resistant PfINDO strains of Plasmodium falciparum using SYBR Green I assay. Of the forty two chalcones tested, eight showed IC50 ≥ 5 μM. Structure-activity relationship (SAR) studies revealed 9 {1-(4-Chlorophenyl)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl] -prop-2-en-1-one} as the most potent (IC∑: 2.5 μM) against Pf3D7 with resistance indices of 1.2 and 6.6 against PfDd2 and PfINDO strains, respectively. Later on, the synergistic effects 9 with standard antimalarials {artemisinin (ART) and chloroquine (CQ)} were studied in order to provide the basis for the selection of the best partner drug. In vitro combinations of 9 with ART showed strong synergy against PfINDO (ΣFIC∑: 0.31-0.72) but additive to slight antagonistic effects (ΣFIC∑: 1.97-2.64) against Pf3D7. ΣFIC∑ 0.31 of ART+9 combination corresponded to a 320 fold and 3 fold reduction in IC∑ of 9 and ART, respectively. Similar combinations of 9 with CQ showed synergy to additivity to mild antagonism against the two strains {ΣFIC∑: 0.668-2.269 (PfINDO); 1.45-2.83 (Pf3D7)}. Drug exposure followed by drug withdrawal indicated that 9 taken alone at IC∑ killed rings, trophozoites and schizonts of P. falciparum. The combination of ART and 9 (1X ΣFIC∑) selectively inhibited the growth of rings while the 2X ΣFIC∑ combination of the same caused killing of rings without affecting trophozoites and schizonts. In contrast, the 1X combination of CQ and 9 (ΣFIC ∑: 0.5) killed rings and trophozoites. DNA fragmentation and loss of mitochondrial membrane potential (ΔΨm) in the 9 treated P. falciparum culture indicated apoptotic death in malaria parasites. Prediction of ADME properties revealed that most of the molecules did not violate Lipinski's parameters and have low TPSA value suggesting good absorption. The results suggest the promising drug-like properties of 9 against CQ resistant Pf and propensity for synergy with classical antimalarial drugs together with easy and economical synthesis.
- Sharma, Nandini,Mohanakrishnan, Dinesh,Sharma, Upendra Kumar,Kumar, Rajesh,Richa,Sinha, Arun Kumar,Sahal, Dinkar
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p. 350 - 368
(2014/05/06)
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