- Identification of anthranilamide derivatives as potential factor Xa inhibitors: Drug design, synthesis and biological evaluation
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The coagulation enzyme factor Xa (fXa) plays a crucial role in the blood coagulation cascade. In this study, three-dimensional fragment based drug design (FBDD) combined with structure-based pharmacophore (SBP) model and structural consensus docking were employed to identify novel fXa inhibitors. After a multi-stage virtual screening (VS) workflow, two hit compounds 3780 and 319 having persistent high performance were identified. Then, these two hit compounds and several analogs were synthesized and screened for in-vitro inhibition of fXa. The experimental data showed that most of the designed compounds displayed significant in vitro potency against fXa. Among them, compound 9b displayed the greatest in vitro potency against fXa with the IC50 value of 23 nM and excellent selectivity versus thrombin (IC50 Combining double low line 40 μM). Moreover, the prolongation of the prothrombin time (PT) was measured for compound 9b to evaluate its in vitro anticoagulant activity. As a result, compound 9b exhibited pronounced anticoagulant activity with the 2 × PT value of 8.7 μM.
- Xing, Junhao,Yang, Lingyun,Li, Hui,Li, Qing,Zhao, Leilei,Wang, Xinning,Zhang, Yuan,Zhou, Muxing,Zhou, Jinpei,Zhang, Huibin
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Read Online
- Platelet antiaggregant methoxyphenylthienyl ketoxime ethers: Synthesis and structure-activity relationships
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Some new oximinoalkanoic (n = 2,3,4) esters and acids derived from methoxyphenylthienyl ketones have been synthesized and evaluated in vitro for their inhibitory effects on arachidonic acid-induced human platelet aggregation. Of the eighteen oximinoethers
- Varache-Lembege,Nuhrich,Renard,Duboudin,Vercauteren,Devaux
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Read Online
- Remarkably Efficient Iridium Catalysts for Directed C(sp2)-H and C(sp3)-H Borylation of Diverse Classes of Substrates
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Here we describe the discovery of a new class of C-H borylation catalysts and their use for regioselective C-H borylation of aromatic, heteroaromatic, and aliphatic systems. The new catalysts have Ir-C(thienyl) or Ir-C(furyl) anionic ligands instead of the diamine-type neutral chelating ligands used in the standard C-H borylation conditions. It is reported that the employment of these newly discovered catalysts show excellent reactivity and ortho-selectivity for diverse classes of aromatic substrates with high isolated yields. Moreover, the catalysts proved to be efficient for a wide number of aliphatic substrates for selective C(sp3)-H bond borylations. Heterocyclic molecules are selectively borylated using the inherently elevated reactivity of the C-H bonds. A number of late-stage C-H functionalization have been described using the same catalysts. Furthermore, we show that one of the catalysts could be used even in open air for the C(sp2)-H and C(sp3)-H borylations enabling the method more general. Preliminary mechanistic studies suggest that the active catalytic intermediate is the Ir(bis)boryl complex, and the attached ligand acts as bidentate ligand. Collectively, this study underlines the discovery of new class of C-H borylation catalysts that should find wide application in the context of C-H functionalization chemistry.
- Chattopadhyay, Buddhadeb,Hassan, Mirja Md Mahamudul,Hoque, Md Emdadul
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supporting information
p. 5022 - 5037
(2021/05/04)
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- Tumor diagnosis and treatment fluorescent probe for targeting tumor Wolburg effect
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The invention discloses a tumor diagnosis and treatment fluorescent probe for targeting tumor Warburg effect, and the structure of the fluorescent probe is shown as a formula (I). The fluorescent probe can be directly used in a cell line to analyze and detect the expression degree of tumor cell GLUT1 protein, so as to complete the screening of tumor cells. Meanwhile, tumor cell proliferation is inhibited by directly blocking the GLUT1 channel to inhibit intake of sugar nutritional ingredients by tumors. And an effective means and a useful tool are provided for early screening and diagnosis oftumors, development of new anti-tumor drugs and the like.
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- Optimization of a 1,3,4-oxadiazole series for inhibition of Ca2+/calmodulin-stimulated activity of adenylyl cyclases 1 and 8 for the treatment of chronic pain
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Adenylyl cyclases type 1 (AC1) and 8 (AC8) are group 1 transmembrane adenylyl cyclases (AC) that are stimulated by Ca2+/calmodulin. Studies have shown that mice depleted of AC1 have attenuated inflammatory pain response, while AC1/AC8 double-knockout mice display both attenuated pain response and opioid dependence. Thus, AC1 has emerged as a promising new target for treating chronic pain and opioid abuse. We discovered that the 1,3,4-oxadiazole scaffold inhibits Ca2+/calmodulin-stimulated cyclic adenosine 3‘,5‘-monophosphate (cAMP) production in cells stably expressing either AC1 or AC8. We then carried out structure-activity relationship studies, in which we designed and synthesized 65 analogs, to modulate potency and selectivity versus each AC isoform in cells. Furthermore, molecular docking of the analogs into an AC1 homology model suggests the molecules may bind at the ATP binding site. Finally, a prioritized analog was tested in a mouse model of inflammatory pain and exhibited modest analgesic properties. In summary, our data indicate the 1,3,4-oxadiazoles represent a novel scaffold for the cellular inhibition of Ca2+/calmodulin-stimulated AC1- and AC8 cAMP and warrant further exploration as potential lead compounds for the treatment of chronic inflammatory pain.
- Kaur, Jatinder,Soto-Velasquez, Monica,Ding, Zhong,Ghanbarpour, Ahmadreza,Lill, Markus A.,van Rijn, Richard M.,Watts, Val J.,Flaherty, Daniel P.
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p. 568 - 585
(2018/11/26)
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- Probing the effects of the number and positions of –OCH3 and –CN substituents on color tuning of Ir(III) complex derivatives through a joint computational and experimental study
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We performed a joint theoretical and experimental study on sixteen Ir(III) complexes bearing a similar molecular platform of bis(2-phenylbenzothiozolato-N,C2’) iridium(III) (acetylacetonate) by grafting – OCH3 group and/or – CN group on different positions of the C-related arene moiety of the C^N ligand (Cring). Our results reveal that the introduction of – CN renders an overall drop in the FMO energy levels while a reverse increase is observed for – OCH3. The ortho- and para-sites of the C-ring are more effective substitution positions to modulate the HOMO energy level due to the fact that the electronic density of HOMO mainly locates at them while the meta-site would induce a stronger impact on LUMO since the electronic density of LUMO mainly distributes over the position. Utilizing the synergistic effects of the substituents and the substituted positions, a wide color-tuning range from 479 nm to 637 nm was achieved, which covers nearly the whole window of visible spectrum. In particular, the tri-substituted Ir35mo4cn complex (λemmax=637 nm) may be a potential candidate for high efficiency red OLEDs materials due to its greatly enhanced absorption processes, relatively higher3MLCT (%), lower ΔES1–T1, enlarged separation between3MLCT/π–π* and3MC d–d states, and good hole and particle-transporting performances. Finally, six representative complexes were synthesized and their spectra were determined, which confirm the reliability of our computational strategy.
- Qin, Xiao,Li, Ming,Xiang, Minghui,Luo, Yi,Jiao, Yan,Yuan, Rongao,Wang, Ning,Lu, Zhiyun,Pu, Xumei
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p. 470 - 481
(2019/06/03)
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- Preparation method of 3-methoxybenzoyl chloride
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The invention discloses a preparation method of 3-methoxybenzoyl chloride and belongs to the technical field of medicine techniques. The technical problem to be solved by the invention is to relate toa more advanced preparation method of 3-methoxybenzoyl
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Paragraph 0007-0010
(2018/12/03)
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- CoIII-Catalyzed Isonitrile Insertion/Acyl Group Migration Between C?H and N?H bonds of Arylamides
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A general efficient and site-selective cobalt-catalyzed insertion of isonitrile into C?H and N?H bonds of arylamides through C?H bond activation and alcohol assisted intramolecular trans-amidation is demonstrated. This straightforward approach overcomes the limitation by the presence of strongly chelating groups. Isolation of CoIII-isonitrile complex B has been achieved for the first time to understand the reaction mechanism.
- Kalsi, Deepti,Barsu, Nagaraju,Sundararaju, Basker
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supporting information
p. 2360 - 2364
(2018/02/22)
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- A General Cp*CoIII-Catalyzed Intramolecular C?H Activation Approach for the Efficient Total Syntheses of Aromathecin, Protoberberine, and Tylophora Alkaloids
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Herein, we report a Cp*CoIII-catalyzed C?H activation approach as the key step to create highly valuable isoquinolones and pyridones as building blocks that can readily be applied in the total syntheses of a variety of aromathecin, protoberberine, and tylophora alkaloids. This particular C?H activation/annulation reaction was achieved with several terminal as well as internal alkyne coupling partners delivering a broad scope with excellent functional group tolerance. The synthetic applicability of this protocol reported herein was demonstrated in the total syntheses of two Topo-I-Inhibitors and two 8-oxyprotoberberine cores that can be further elaborated into the tetrahydroprotoberberine and the protoberberine alkaloid core. Moreover these building blocks were also transformed to six different tylophora alkaloids in expedient fashion.
- Lerchen, Andreas,Knecht, Tobias,Koy, Maximilian,Daniliuc, Constantin G.,Glorius, Frank
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supporting information
p. 12149 - 12152
(2017/09/13)
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- Selective mono-alkylation of N-methoxybenzamides
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We report our latest discovery of norbornene derivative modulated highly mono-selective ortho-C-H activation alkylation reactions on arenes bearing simple mono-dentate coordinating groups. The reaction features the use of readily available benzamides and alkyl halides. During the study, we prepared 30 mono-alkylated aryl amides in good yields with good mono-selectivity. We have also demonstrated that structurally rigid alkenes such as norbornene and its derivatives are a good class of ligand and could be used for future direct C-H functionalizations. The utilization of norbornene type ligands for assistance in C-H activation processes has opened a new window for future molecular design using direct C-H functionalization strategies.
- Chen, Zenghua,Hu, Le'an,Zeng, Fanyun,Zhu, Ranran,Zheng, Shasha,Yu, Qingzhen,Huang, Jianhui
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supporting information
p. 4258 - 4261
(2017/04/21)
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- 2-(3-Methoxyphenyl)quinazoline Derivatives: A New Class of Direct Constitutive Androstane Receptor (CAR) Agonists
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Constitutive androstane receptor (CAR) is a key regulator of xenobiotic and endobiotic metabolism. Together with pregnane X (PXR) and aryl hydrocarbon (AHR) receptors, it is referred to as xenobiotic receptor. The unique properties of human CAR, such as i
- Smutny, Tomas,Nova, Alice,Drechslerová, Marcela,Carazo, Alejandro,Hyrsova, Lucie,Hru?ková, Zuzana Rania,Kune?, Ji?í,Pour, Milan,?pulák, Marcel,Pavek, Petr
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p. 4601 - 4610
(2016/06/13)
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- Chelation-Assisted Nickel-Catalyzed Oxidative Annulation via Double C-H Activation/Alkyne Insertion Reaction
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A nickel/NHC system for regioselective oxidative annulation by double C-H bond activation and concomitant alkyne insertion is described. The catalytic reaction requires a bidentate directing group, such as an 8-aminoquinoline, embedded in the substrate. Various 5,6,7,8-tetrasubstituted-N-(quinolin-8-yl)-1-naphthamides can be prepared as well as phenanthrene and benzo[h]quinoline amide derivatives. Diarylalkynes, dialkylalkynes, and arylalkylalkynes can be used in the system. A Ni0/NiII catalytic cycle is proposed as the main catalytic cycle. The alkyne plays a double role as a two-component coupling partner and as a hydrogen acceptor. In two shakes: Oxidative annulation by a double C-H activation/alkyne insertion reaction was achieved by a nickel/NHC system. A Ni0/NiII catalytic cycle is proposed as the main catalytic cycle. The alkyne plays a double role as a two-component coupling partner and as a hydrogen acceptor.
- Misal Castro, Luis C.,Obata, Atsushi,Aihara, Yoshinori,Chatani, Naoto
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supporting information
p. 1362 - 1367
(2016/01/25)
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- Diastereoselective [3+2] Annulation of Aromatic/Vinylic Amides with Bicyclic Alkenes through Cobalt-Catalyzed C-H Activation and Intramolecular Nucleophilic Addition
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A highly diastereoselective method for the synthesis of dihydroepoxybenzofluorenone derivatives from aromatic/vinylic amides and bicyclic alkenes is described. This new transformation proceeds through cobalt-catalyzed C-H activation and intramolecular nucleophilic addition to the amide functional group. Transition-metal-catalyzed C-H activation reactions of secondary amides with alkenes usually lead to [4+2] or [4+1] annulation; to the best of our knowledge, this is the first time that a [3+2] cycloaddition is described in this context. The reaction proceeds under mild conditions and tolerates a wide range of functional groups. Mechanistic studies imply that the C-H bond cleavage may be the rate-limiting step. [3+2] instead of [4+2] or [4+1]: The diastereoselective [3+2] annulation of secondary amides with alkenes proceeds by cobalt-catalyzed C-H activation and intramolecular nucleophilic addition to the amide functional group under mild conditions. Mechanistic studies suggest that the C-H bond cleavage is the rate-limiting step.
- Gandeepan, Parthasarathy,Rajamalli, Pachaiyappan,Cheng, Chien-Hong
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supporting information
p. 4308 - 4311
(2016/04/01)
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- Transition-Metal-Free Synthesis of N-Aryl Hydroxamic Acids via Insertion of Arynes
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An efficient and transition-metal-free N-arylation of amides via the insertion of arynes into the N-H bonds in the N-alkoxy amides is described. A variety of the reactive functional groups including the reactive aldehyde carbonyl group, furan ring, carbon-carbon double bonds, and free N-H bond of indole are found to be compatible with this process. In particular, the protocol is applicable in the synthesis of structurally diverse N-aryl hydroxamates and hydroxamic acids derived from N-protecting amino acids and peptides. In the presence of multiple amide N-H bonds, the N-arylation reaction can proceed selectively in the N-H bonds of terminal N-OBn amides giving rise to the desired N-aryl hydroxamates.
- Zhang, Lanlan,Geng, Yu,Jin, Zhong
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p. 3542 - 3552
(2016/05/24)
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- A facile color-tuning strategy for constructing a library of Ir(III) complexes with fine-tuned phosphorescence from bluish green to red using a synergetic substituent effect of -OCH3 and -CN at only the C-ring of C∧N ligand
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By simply grafting a -CN group and/or a -OCH3 group onto the meta- and/or para-site of the C-ring, a series of Ir(iii) complexes bearing a similar molecular platform of bis(1,2-diphenyl-1H-benzimidazolato-N,C2′)iridium(iii)(acetylacetonate), but showing fine-tuned phosphorescence covering nearly the whole window of the visible spectrum with a wide color-tuning range of 109 nm was acquired. With the help of DFT calculations, it was revealed that if the C-related arene moiety of the C∧N ligand (C-ring) contributes substantially to both the HOMO and LUMO of an Ir(iii) complex, the concurrent introduction of an electron-donating -OCH3 and an electron-withdrawing -CN groups on the C-ring at the meta- and para-sites relative to the Ir atom may lead to a favorable synergetic substituent effect on the color-tuning direction. This may represent a facile yet effective molecular design strategy for Ir(iii) complexes with a desirous emission color. A bluish green organic light-emitting diode (OLED) based on one of the objective complexes displayed a maximum current efficiency of 62.1 cd A-1, an external quantum efficiency of 19.8%, and a brightness of 48-040 cd m-2, implying that high-performance red and blue OLED phosphors as well as libraries of Ir(iii) complexes bearing similar molecular platforms may be developed through this -OCH3 and -CN synergetic substitution strategy.
- Jiao, Yan,Li, Ming,Wang, Ning,Lu, Tao,Zhou, Liang,Huang, Yan,Lu, Zhiyun,Luo, Daibing,Pu, Xuemei
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supporting information
p. 4269 - 4277
(2016/06/01)
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- Palladium-catalyzed directing group-assisted C8-triflation of naphthalenes
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The transition-metal-catalyzed direct triflation of naphthyl amides and naphthyl ketones has been accomplished for the first time. Benzophenone (BP) was found to be a suitable ligand for the cross-coupling reactions. Density functional theory (DFT) calculations revealed that excessive amounts of HOTf inhibit the reductive elimination of the C-F bond to realize the unusual reductive elimination of the C-OTf bond.
- Yang, Zhi-Wei,Zhang, Qi,Jiang, Yuan-Ye,Li, Lei,Xiao, Bin,Fu, Yao
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supporting information
p. 6709 - 6711
(2016/06/01)
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- Ligand-Promoted Rh(III)-Catalyzed Coupling of Aryl C-H Bonds with Arylboron Reagents
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Rhodium(III)-catalyzed C-H arylation of arenes with phenylboronic acid pinacol esters has been achieved using a readily removable N-pentafluorophenylbenzamide directing group for the first time. The use of a bidentate phosphine ligand (Binap) significantly increased the yield of the cross-coupling of C-H bonds with organoboron reagents.
- Wang, Huai-Wei,Cui, Pei-Pei,Lu, Yi,Sun, Wei-Yin,Yu, Jin-Quan
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p. 3416 - 3422
(2016/05/19)
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- DERIVATIVES OF 2-PHENYL-7,7a-DIHYDRO-3aH-PYRANO[3,4-d]OXAZOLE-6(4H)-ONE
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Derivatives of 2-phenyl-7,7a-dihydro-3aH-pyrano[3,4-d]oxazole-6(4H)- one of formula (I), where the meanings for the substituents are those listed in the description. These compounds are useful as inhibitors of HIF-2α and SOX-2.
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Page/Page column 34; 35
(2016/07/05)
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- Design and synthesis of cyclic acylguanidines as BACE1 inhibitors
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Based on the lead compound 1 reported in literature, a series of novel BACE1 inhibitors were designed and synthesized, among which compound 11 exhibited a 14-fold improvement in potency over the lead compound 1. This represents a good lead for the discovery of more promising BACE1 inhibitors for the potential treatment of AD.
- Liu, Jia-Kuo,Gu, Wei,Cheng, Xiao-Rui,Cheng, Jun-Ping,Zhou, Wen-Xia,Nie, Ai-Hua
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p. 1327 - 1330
(2015/12/31)
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- Synthesis and biological screening of 1,2,4-triazole derivatives
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A series of 2-((arylamino)methyl)-5-(3-methoxyphenyl)-1-phenyl-1H-1,2,4-triazole-3-thione derivatives have been synthesized and characterized by FT-IR, NMR, mass spectral and elemental analysis. Compounds (MM4a-m) have been evaluated for their
- Godhani, Dinesh R.,Jogel, Anand A.,Sanghani, Anil M.,Mehta, Jignasu P.
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p. 556 - 564
(2015/04/27)
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- Cu(II)-catalyzed coupling of aromatic C-H bonds with malonates
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A new Cu(II)-catalyzed oxidative coupling of arenes with malonates has been developed using an amide-oxazoline directing group. The reaction proceeds via C(sp2)-H activation and malonate coupling, followed by intramolecular oxidative N-C bond formation. A variety of arenes bearing different substituents are shown to be compatible with this reaction.
- Wang, Hong-Li,Shang, Ming,Sun, Shang-Zheng,Zhou, Zeng-Le,Laforteza, Brian N.,Dai, Hui-Xiong,Yu, Jin-Quan
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supporting information
p. 1228 - 1231
(2015/03/14)
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- 6,7-dimethoxyquinazolines as potential cytotoxic agents: Synthesis and in vitro activity
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It has been reported that 6,7-dimethoxyquinazoline derivatives have cytotoxic potential independent of their a1-adrenoceptor blocking potential. Bioisosteres of 2-arylquinazolines are considered to have anti-tumor properties. In the present study, we have synthesized the 2-aryl and 2-arylmethyl derivatives of quinazolin-4(3H)-one while retaining the 6,7-dimethoxy substituents. Derivatives with n-butyl group attached to position-3 of quinazolinone nucleus were synthesized with the aim of increasing their lipophilicity. The potential of these synthesized compounds was evaluated against NCI (National Cancer Institute) 60 cell panel using the NCI disease oriented antitumor screen protocol. Based on the results of this screening we generalized that compounds having aryl groups directly attached to the quinazoline ring are less active than those which have one atom linker in between the two ring systems. Substitution of a lipophilic group like nbutyl decreases cytotoxic activity among the compounds and 4-aminoquinazolines showed better activity than 4-quinazolinones. Lipophilic groups in the aromatic ring yielded more active compounds as cytotoxic agents. Among the selected compounds, 4h and 13b were found to be potential lead compounds which could be further optimized as potential anti-neoplastic agents.
- Yadav, Mange Ram,Chauhan, Bishram Singh,Naik, Prashant,Gandhi, Hardik,Giridhar, Rajani
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p. 190 - 205
(2015/04/14)
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- Synthesis, biological evaluation, and molecular docking studies of novel 1-benzene acyl-2-(1-methylindol-3-yl)-benzimidazole derivatives as potential tubulin polymerization inhibitors
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A series of 1-benzene acyl-2-(1-methylindol-3-yl)-benzimidazole derivatives were designed, synthesized and evaluated as potential tubulin polymerization inhibitors and for the cytotoxicity against anthropic cancer cell lines. Among the novel compounds, compound 11f was demonstrated the most potent tubulin polymerization inhibitory activity (IC50 = 1.5 μM) and antiproliferative activity against A549, HepG2 and MCF-7 (GI50 = 2.4, 3.8 and 5.1 μM, respectively), which was compared with the positive control colchicine and CA-4. We also evaluated that compound 11f could effectively induce apoptosis of A549 associated with G2/M phase cell cycle arrest. Docking simulation and 3D-QSAR model in these studies provided more information that could be applied to design new molecules with more potent tubulin inhibitory activity.
- Wang, Yan-Ting,Qin, Ya-Juan,Yang, Na,Zhang, Ya-Liang,Liu, Chang-Hong,Zhu, Hai-Liang
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p. 125 - 137
(2015/06/22)
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- BENZHYDRYL DERIVATIVES FOR THE TREATMENT OF RESPIRATORY DISEASES
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The invention relates to novel compounds of formula (I) having a benzhydryl structure which are both phosphodiesterase 4 (PDE4) enzyme inhibitors and muscarinic M3 receptor antagonists, methods of preparing such compounds, compositions containing them and therapeutic use thereof.
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Page/Page column 44; 45
(2015/06/18)
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- Carboxylate Assisted Ni-Catalyzed C-H Bond Allylation of Benzamides
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A one-step synthetic method was developed for allylation of benzamides using Ni(COD)2/RCO2H and [Ni(μ-H2O)(OOCCMe3)2(HOOCCMe3)2]2 (A′) catalytic system. Efficient, well-defined, air and moisture-stable Ni-pivalate complex was isolated and employed in catalytic allylation. The influence of solvent on product selectivity was also investigated. Nickel-back: A one-step synthetic method was developed for the allylation of benzamides using in situ formed nickel carboxylate Ni(COD)2/RCO2H catalyst (see scheme). The air and moisture stable Ni-pivalate complex was isolated and employed in catalytic allylation. The influence of solvent on product selectivity is discussed.
- Barsu, Nagaraju,Kalsi, Deepti,Sundararaju, Basker
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supporting information
p. 9364 - 9368
(2015/06/30)
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- Bifunctional organocatalysts for the enantioselective synthesis of axially chiral isoquinoline n -oxides
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Bifunctional catalysts bearing amino and urea functional groups have been applied for a novel, highly enantioselective synthesis of axially chiral isoquinoline N-oxides, which are promising chiral ligands or organocatalysts in organic synthesis. This is t
- Miyaji, Ryota,Asano, Keisuke,Matsubara, Seijiro
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supporting information
p. 6766 - 6769
(2015/06/16)
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- Synthesis and biological evaluation of acetylenic chalcones as novel anti-inflammatory agents
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37 acetylenic chalcones were designed, synthesized by the Pd/Cu catalyzed Sonogashira coupling reaction, and evaluated for anti-inflammatory activities. A majority of these compounds showed remarkable inhibitions of the expression of inflammatory cytokine
- Zhao, Chengguang,Feng, Jianpeng,Zuo, Mingming,Zhang, Ying,Zhao, Jianfeng,Xu, Shanmei,Zheng, Suqing,Zhang, Yali,Tang, Qinqin,Lu, Zhongqiu,Liang, Guang,Zhou, Jianmin
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p. 567 - 572
(2015/08/18)
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- Cu(II)-mediated C-H amidation and amination of arenes: Exceptional compatibility with heterocycles
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A Cu(OAc)2-mediated C-H amidation and amination of arenes and heteroarenes has been developed using a readily removable directing group. A wide range of sulfonamides, amides, and anilines function as amine donors in this reaction. Heterocycles present in both reactants are tolerated, making this a broadly applicable method for the synthesis of a family of inhibitors including 2-benzamidobenzoic acids and N-phenylaminobenzoates.
- Shang, Ming,Sun, Shang-Zheng,Dai, Hui-Xiong,Yu, Jin-Quan
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supporting information
p. 3354 - 3357
(2014/03/21)
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- Design, synthesis, molecular docking studies and in vitro screening of ethyl 4-(3-benzoylthioureido) benzoates as urease inhibitors
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Thioureas are exceptionally versatile building blocks towards the synthesis of wide variety of heterocyclic systems, which also possess extensive range of pharmacological activities. The substituted benzoic acids were converted into corresponding acid chlorides, these acid chlorides were then treated with potassium thiocyanate in acetone and then the reaction mixture was refluxed for 1-2 h afford ethyl 4-(3-benzoylthioureido)benzoates thioureas in good yields. All the newly synthesized compounds were evaluated for their urease inhibitory activities and were found to be potent inhibitors of urease enzyme. Compounds 1f and 1g were identified as the most potent urease inhibitors (IC50 0.21 and 0.13 μM, respectively), and was 100-fold more potent than the standard inhibitors. Further molecular docking studies were carried out using the crystal structure of urease to find out the binding mode of the inhibitors with the enzyme.
- Saeed, Aamer,Khan, Muhammad Siraj,Rafique, Hummera,Shahid, Mohammad,Iqbal, Jamshed
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- Synthesis and evaluation of novel azoles as potent antifungal agents
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Using a rational approach to the design of antifungal agents, a series of azole agents with 1,3,4-oxadiazole side chains were designed and synthesized. The results of preliminary in vitro antifungal tests with eight human pathogenic compounds showed that all of the title compounds exhibited excellent activities against all of the tested fungi except Aspergillus fumigatus. Compounds 11e and 11f were found to be the most effective, with a minimum inhibitory concentration of 0.0039 μg/mL, followed by voriconazole, which has a MIC of 0.0625 μg/mL. The 1,3,4-oxadiazole side chain is not the major contributor but plays a role in eliciting the observed antifungal activity.
- Li, Liangjing,Ding, Hao,Wang, Baogang,Yu, Shichong,Zou, Yan,Chai, Xiaoyun,Wu, Qiuye
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supporting information
p. 192 - 194
(2014/01/17)
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- Rhodium-catalyzed C-H alkynylation of arenes at room temperature
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The rhodium(III)-catalyzed ortho C-H alkynylation of non-electronically activated arenes is disclosed. This process features a straightforward and highly effective protocol for the synthesis of functionalized alkynes and represents the first example of merging a hypervalent iodine reagent with rhodium(III) catalysis. Notably, this reaction proceeds at room temperature, tolerates a variety of functional groups, and more importantly, exhibits high selectivity for monoalkynylation. Hot rhod: A rhodium-catalyzed, electronically reversed Sonogashira reaction between unbiased arenes and the hypervalent iodine reagent 1 proceeds through C-H activation. This reaction displays excellent functional-group tolerance and high efficiency, and thus opens a new synthetic pathway to access functionalized alkynes. Cp=C5Me5, DCE=1,2-dichloroethane, Piv=pivaloyl, TIPS=triisopropylsilyl.
- Feng, Chao,Loh, Teck-Peng
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supporting information
p. 2722 - 2726
(2014/03/21)
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- Palladium(II)-catalyzed ortho-C-H arylation/alkylation of N-benzoyl α-amino ester derivatives
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The palladium-catalyzed arylation/alkylation of ortho-C-H bonds in N-benzoyl α-amino ester derivatives is described. In such a system both the NH-amido and the CO2R groups in the α-amino ester moieties play a role in successful C-H activation/C-C bond formation using iodoaryl coupling partners. A wide variety of functional groups and electron-rich/ deficient iodoarenes are tolerated. The yields obtained range from 20 to 95 %. C-H activation: The transformation of N-benzoyl amino acid ester derivatives (Gly, Asp) has been studied, in which the ortho-C-H activation/C-C bond formation was achieved by using the synergistic system Pd(OAc)2/AgOAc and halide compounds as coupling partners in t-Amyl-OH under air (see scheme).
- Misal Castro, Luis C.,Chatani, Naoto
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supporting information
p. 4548 - 4553
(2014/05/06)
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- COMPOUNDS HAVING MUSCARINIC RECEPTOR ANTAGONIST AND BETA2 ADRENERGIC RECEPTOR AGONIST ACTIVITY
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Compounds of formula (I) defined herein act both as muscarinic receptor antagonists and beta2 adrenergic receptor agonists and are useful for the prevention and/or treatment of broncho-obstructive or inflammatory diseases.
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Paragraph 0466-0468
(2014/06/24)
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- Copper-mediated ortho-nitration of (hetero)arenecarboxylates
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Various (hetero)arenecarboxylic acids were converted to the corresponding Daugulis amides and nitrated selectively in the ortho-position in the presence of [CuNO3(PPh3)2] and AgNO2 at 50 °C. A microwave-assisted saponification allows regenerating the carboxylate group within minutes, which may then be removed tracelessly by protodecarboxylation, or substituted by aryl- or alkoxy-groups via decarboxylative cross-coupling.
- Katayev, Dmitry,Pfister, Kai F.,Wendling, Timo,Goossen, Lukas J.
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supporting information
p. 9902 - 9905
(2014/08/18)
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- Total synthesis of isoquinocyclinone
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The total synthesis of the heptacyclic natural product isoquinocyclinone has been achieved. A Hauser annulation was used to assemble the anthraquinone core structure. The unique 2,4,5,6-tetrahydropyrrolo[2,3-b]pyrrole substructure was prepared by alkyne addition to a lactone intermediate and subsequent Ni 0-mediated cyanide addition, the conversion of an O,O- into an N,O-acetal, and final intramolecular N-alkylation. Hauser annulation: An efficient total synthesis of isoquinocyclinone was achieved using a pentacyclic lactone as the key intermediate (see scheme). The pyrrolo-pyrrole substructure was elaborated by acetylide acylation, conversion of an O,O-acetal into an N,O-acetal, and intramolecular amidine alkylation.
- Dischmann, Mike,Frassetto, Timo,Breuning, M. André,Koert, Ulrich
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supporting information
p. 11300 - 11302
(2014/10/15)
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- Ni(II)-catalyzed oxidative coupling between C(sp2)-H in benzamides and C(sp3)-H in toluene derivatives
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Oxidative coupling between C(sp2)-H bonds and C(sp3)-H bonds is achieved by the Ni(II)-catalyzed reaction of benzamides containing an 8-aminoquinoline moiety as the directing group with toluene derivatives in the presence of heptafluoroisopropyl iodide as the oxidant. The method has a broad scope and shows high functional group compatibility. Toluene derivatives can be used as the coupling partner in an unreactive solvent.
- Aihara, Yoshinori,Tobisu, Mamoru,Fukumoto, Yoshiya,Chatani, Naoto
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supporting information
p. 15509 - 15512
(2014/12/11)
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- Rhodium(III)-catalyzed C-H activation/annulation with vinyl esters as an acetylene equivalent
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The behavior of electron-rich alkenes in rhodium-catalyzed C-H activation/annulation reactions is investigated. Vinyl acetate emerges as a convenient acetylene equivalent, facilitating the synthesis of sixteen 3,4-unsubstituted isoquinolones, as well as select heteroaryl-fused pyridones. The complementary regiochemical preferences of enol ethers versus enol esters/enamides is discussed.
- Webb, Nicola J.,Marsden, Stephen P.,Raw, Steven A.
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supporting information
p. 4718 - 4721
(2015/04/27)
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- Copper-catalyzed phosphorylation of sp2 C-H bonds
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The phosphorylation of the ortho C-H bonds in benzamides containing an 8-aminoquinoline moiety as a bidentate directing group with H-phosphonates using copper as a catalyst under mild temperature conditions is described. This method shows high functional group compatibility and selectively gives mono-substituted products. This journal is
- Wang, Shan,Guo, Rui,Wang, Gao,Chen, Shan-Yong,Yu, Xiao-Qi
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supporting information
p. 12718 - 12721
(2015/05/20)
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- 3H-1,2,4-Dithiazol-3-one compounds as novel potential affordable antitubercular agents
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Small molecules with oxathiazol-2-one moiety were recently reported as potent inhibitors of Mycobacterium bovis var. bacilli Calmette-Guérin (BCG), among which HT1171 was the most potent and selective proteasome inhibitor. Herein we synthesized a series of novel compounds by bioisosteric replacement of the oxathiazol-2-one ring with 3H-1,2,4-dithiazol-3-one, and also fifteen 1,3,4-oxathiazol-2-one molecules in order for potency comparison and structure-activity relationship elucidation since their antibacterial effects on the virulent strains were not evaluated before. All the compounds were assessed for antitubercular activities on the virulent H37Rv strain by a serial dilution method. Among the tested compounds, 3H-1,2,4-dithiazol-3-one compound 4n was found to be the most active with a lowest MIC90 value of 1 μg/mL. Furthermore, the cytotoxicities of all the compounds against normal human liver cell line L02 were determined by an MTT method. Compound 4n displayed a lower inhibitory ratio than HT1171 at the concentration of 100 μM, indicating its better safety profile.
- Yang, Jianzhong,Pi, Weiyi,Xiong, Li,Ang, Wei,Yang, Tao,He, Jun,Liu, Yuanyuan,Chang, Ying,Ye, Weiwei,Wang, Zhenling,Luo, Youfu,Wei, Yuquan
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supporting information
p. 1424 - 1427
(2013/03/14)
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- Synthesis, antimycobacterial, antiviral, antimicrobial activity and QSAR studies of N2-acyl isonicotinic acid hydrazide derivatives
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A series of N2-acyl isonicotinic acid hydrazides (1-17) was synthesized and tested for its in vitro antimycobacterial activity against Mycobacterium tuberculosis and the results indicated that the compound, isonicotinic acid N′- tetradecanoyl-hydrazide (12) was more active than the reference compound isoniazid. The results of antimicrobial activity of the synthesized compounds against S. aureus, B. subtilis, E. coli, C. albicans and A. niger indicated that compounds with dichloro, hydroxyl, tri-iodo and N 2 -tetradecanoyl substituent were the most active ones. The antiviral activity studies depicted that none of the tested compounds were active against DNA or RNA viruses. The multi-target QSAR model was found to be effective in describing the antimicrobial activity of N2-acyl isonicotinic acid hydrazides.
- Judge, Vikramjeet,Narasimhan, Balasubramanian,Ahuja, Munish,Sriram, Dharmarajan,Yogeeswari, Perumal,De Clercq, Erik,Pannecouque, Christophe,Balzarini, Jan
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- Nickel-catalyzed direct alkylation of C-H bonds in benzamides and acrylamides with functionalized alkyl halides via bidentate-chelation assistance
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The alkylation of the ortho C-H bonds in benzamides and acrylamides containing an 8-aminoquinoline moiety as a bidentate directing group with unactivated alkyl halides using nickel complexes as catalysts is described. The reaction shows high functional group compatibility. In reactions of meta-substituted aromatic amides, the reaction proceeds in a highly selective manner at the less hindered C-H bond.
- Aihara, Yoshinori,Chatani, Naoto
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supporting information
p. 5308 - 5311
(2013/05/21)
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- Synthesis and antibacterial evaluation of novel pleuromutilin derivatives
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A series of novel pleuromutilin derivatives possessing thioether moiety has been synthesized via acylation reaction under mild conditions. Their in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli, and Streptococcus agalactiae were tested by agar dilution method and Oxford cup assay. Among the 17 compounds screened, 14-O-[(4-methoxybenzamide-2- methylpropane-2-yl) thioacetate] mutilin 4i, 14-O-[(2-aminobenzamide-2- methylpropane-2-yl) thioacetate] mutilin 5a and 14-O-[(4-aminobenzamide-2- methylpropane-2-yl) thioacetate] mutilin 5c were resulted as most active antibacterial agents.
- Shang, Ruofeng,Liu, Yu,Xin, Zhijun,Guo, Wenzhu,Guo, Zhiting,Hao, Baocheng,Jianping, Liang
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p. 231 - 238
(2013/07/27)
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- Discovery of N-(4-sulfamoylphenyl)thioureas as Trypanosoma brucei leucyl-tRNA synthetase inhibitors
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Human African trypanosomiasis (HAT) is one of the most neglected diseases in the tropic regions, which is fatal if not treated in time. There is an urgent need for new therapeutics, especially those in new chemical classes. Leucyl-tRNA synthetase (LeuRS) has been paid much attention as a recently clinically validated antimicrobial target. Our group has previously reported T. brucei LeuRS (TbLeuRS) inhibitors, including benzoxaboroles targeting the editing site and pyrrolinones targeting the synthetic site. Here we report the discovery of N-(4-sulfamoylphenyl)thioureas as a new class of TbLeuRS inhibitors. The R1 and R2 groups, reminiscent of the leucyl and adenyl regions of aa-AMP and aa-AMS, were optimized to result in a significant 13-fold increase of inhibitory activity (compound 19, IC 50 = 13.7 μM). Aided by ligand-protein docking, the 1,3-substitution at the central phenyl ring was predicted and proved to give significantly improved activity (59, IC50 = 1.1 μM). This work provided a new scaffold for the exploration of novel inhibitors against TbLeuRS, which may become potential therapeutics for the treatment of HAT.
- Zhang, Fenglong,Du, Jin,Wang, Qing,Hu, Qinghua,Zhang, Jiong,Ding, Dazhong,Zhao, Yaxue,Yang, Fei,Wang, Enduo,Zhou, Huchen
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p. 5310 - 5324
(2013/08/23)
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- Efficient synthesis of hydroxyl isoindolones by a Pd-mediated C-H activation/annulation reaction
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Radical reaction: A convenient synthesis of hydroxyl isoindolones by a Pd-catalyzed C-H activation/annulation reaction with near "click chemistry" efficiency is presented (see scheme; TBHP=tert-butyl hydrogen peroxide). This methodology features short reaction times (10-30 min), high atom economy, wide substrate scope (22 examples), and good reaction yields (up to 93 %). Copyright
- Yu, Qingzhen,Zhang, Nana,Huang, Jianhui,Lu, Shaonan,Zhu, Yi,Yu, Xiaoxiao,Zhao, Kang
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supporting information
p. 11184 - 11188
(2013/09/02)
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- Gram-scale ketone synthesis by direct reductive coupling of alkyl iodides with acid chlorides
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Alkyl aryl ketones were prepared on a gram scale by the nickel-catalyzed reductive coupling of alkyl iodides with aroyl chlorides. When scaled up 30-fold, this reaction shows a comparable coupling efficiency to the previously reported reaction performed under small-scale conditions. The mild and convenient reaction conditions show excellent tolerance to a range of functional groups and provide the ketones in good to excellent yields. Georg Thieme Verlag Stuttgart. New York.
- Lu, Wenbin,Liang, Zhuye,Zhang, Yuwei,Wu, Fan,Qian, Qun,Gong, Hegui
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p. 2234 - 2240
(2013/09/02)
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- Optimization of N-benzoylindazole derivatives as inhibitors of human neutrophil elastase
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Human neutrophil elastase (HNE) is an important therapeutic target for treatment of pulmonary diseases. Previously, we identified novel N-benzoylindazole derivatives as potent, competitive, and pseudoirreversible HNE inhibitors. Here, we report further development of these inhibitors with improved potency, protease selectivity, and stability compared to our previous leads. Introduction of a variety of substituents at position 5 of the indazole resulted in the potent inhibitor 20f (IC50 ～10 nM) and modifications at position 3 resulted the most potent compound in this series, the 3-CN derivative 5b (IC50 = 7 nM); both derivatives demonstrated good stability and specificity for HNE versus other serine proteases. Molecular docking of selected N-benzoylindazoles into the HNE binding domain suggested that inhibitory activity depended on geometry of the ligand-enzyme complexes. Indeed, the ability of a ligand to form a Michaelis complex and favorable conditions for proton transfer between Hys57, Asp102, and Ser195 both affected activity.
- Crocetti, Letizia,Schepetkin, Igor A.,Cilibrizzi, Agostino,Graziano, Alessia,Vergelli, Claudia,Giomi, Donatella,Khlebnikov, Andrei I.,Quinn, Mark T.,Giovannoni, Maria Paola
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p. 6259 - 6272
(2013/09/02)
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- Synthesis of biaryl imino/keto carboxylic acids via aryl amide directed C-H activation reaction
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A novel Pd-catalysed C-H activation reaction for the synthesis of biaryl imino/keto carboxylic acids is developed. This reaction underwent aryl amide directed C-H activation ortho-acylation followed by ring closing and ring opening processes to give a range of biaryl imino/keto carboxylic acids. Our methodology features the utilization of a cheap and green oxidant (TBHP) as well as readily available aldehydes.
- Zhang, Nana,Yu, Qingzhen,Chen, Ruixue,Huang, Jianhui,Xia, Yeqing,Zhao, Kang
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supporting information
p. 9464 - 9466
(2013/10/01)
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- Analogues of fenarimol are potent inhibitors of trypanosoma cruzi and are efficacious in a murine model of chagas disease
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We report the discovery of nontoxic fungicide fenarimol (1) as an inhibitor of Trypanosoma cruzi (T. cruzi), the causative agent of Chagas disease, and the results of structure-activity investigations leading to potent analogues with low nM IC50s in a T. cruzi whole cell in vitro assay. Lead compounds suppressed blood parasitemia to virtually undetectable levels after once daily oral dosing in mouse models of T. cruzi infection. Compounds are chemically tractable, allowing rapid optimization of target biological activity and drug characteristics. Chemical and biological studies undertaken in the development of the fenarimol series toward the goal of delivering a new drug candidate for Chagas disease are reported.
- Keenan, Martine,Abbott, Michael J.,Alexander, Paul W.,Armstrong, Tanya,Best, Wayne M.,Berven, Bradley,Botero, Adriana,Chaplin, Jason H.,Charman, Susan A.,Chatelain, Eric,Von Geldern, Thomas W.,Kerfoot, Maria,Khong, Andrea,Nguyen, Tien,McManus, Joshua D.,Morizzi, Julia,Ryan, Eileen,Scandale, Ivan,Thompson, R. Andrew,Wang, Sen Z.,White, Karen L.
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supporting information; experimental part
p. 4189 - 4204
(2012/07/27)
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- Palladium-catalyzed direct ortho -alkynylation of aromatic carboxylic acid derivatives
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The palladium-catalyzed direct alkynylation of C-H bonds in aromatic carboxylic acid derivatives is described. The use of 8-aminoquinoline as a directing group facilitates the alkynylation of an electronically diverse range of C(sp2)-H bonds.
- Ano, Yusuke,Tobisu, Mamoru,Chatani, Naoto
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supporting information; experimental part
p. 354 - 357
(2012/03/09)
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- Cytotoxic potential of novel 6,7-dimethoxyquinazolines
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Herein, we report the synthesis and cytotoxicity of a series of substituted 6,7-dimethoxyquinazoline derivatives. The cytotoxic activity of all synthesized compounds has been evaluated against HCT116p53+/+ and HCT116p53 -/- colon cancer cells and a HEY ovarian cancer cell line naturally resistant to cisplatin. Nine of the tested compounds showed significant cytotoxicity in all cell lines at 10 μM. The most promising derivative (7c) showed IC50values of 0.7 and 1.7 μM in the two colon cancer cell lines.
- Yadav, Mange R.,Grande, Fedora,Chouhan, Bishram S.,Naik, Prashant P.,Giridhar, Rajani,Garofalo, Antonio,Neamati, Nouri
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experimental part
p. 231 - 243
(2012/03/26)
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- Pd-catalysed synthesis of isoquinolinones and analogues via C-H and N-H bonds double activation
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An atom economical synthesis of isoquinolinones and analogues via ligand-free Pd-catalysed C-H and N-H double activation has been developed. A series of isoquinolinones were obtained in good to excellent yields. Good regioselectivities were also observed during the activation reactions with unsymmetrical alkynes. A practical one-pot procedure for the preparation of N-H isoquinolinones is also described. The Royal Society of Chemistry 2012.
- Zhong, Hongban,Yang, Dan,Wang, Songqing,Huang, Jianhui
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supporting information; experimental part
p. 3236 - 3238
(2012/04/11)
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