13686-51-6Relevant academic research and scientific papers
Structure-Activity Relationships of Benzamides and Isoindolines Designed as SARS-CoV Protease Inhibitors Effective against SARS-CoV-2
Welker, Armin,Kersten, Christian,Müller, Christin,Madhugiri, Ramakanth,Zimmer, Collin,Müller, Patrick,Zimmermann, Robert,Hammerschmidt, Stefan,Maus, Hannah,Ziebuhr, John,Sotriffer, Christoph,Schirmeister, Tanja
supporting information, p. 340 - 354 (2020/10/19)
Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PLpro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the noncovalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS-CoV PLpro. Moreover, we report the discovery of isoindolines as a new class of potent PLpro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS-CoV-2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS-CoV PLpro are valuable starting points for the development of new pan-coronaviral inhibitors.
An umpolung oxa-[2,3] sigmatropic rearrangement employing arynes for the synthesis of functionalized enol ethers
Gaykar, Rahul N.,George, Malini,Guin, Avishek,Bhattacharjee, Subrata,Biju, Akkattu T.
supporting information, p. 3447 - 3452 (2021/05/04)
An oxa-[2,3] sigmatropic rearrangement involving arynes is reported featuring the umpolung of ketones, where the C=O bond polarity is reversed. The in situ-generated sulfur ylides from β-keto thioethers and arynes undergo efficient rearrangement allowing the facile and robust synthesis of functionalized enol ethers in high yields and excellent functional group compatibility. Preliminary mechanistic studies rule out the possibility of Pummerer-type rearrangement operating in this case.
Novel Aryl-Substituted Pyrimidones as Inhibitors of 3-Mercaptopyruvate Sulfurtransferase with Antiproliferative Efficacy in Colon Cancer
Bantzi, Marina,Augsburger, Fiona,Loup, Jérémie,Berset, Yan,Vasilakaki, Sofia,Myrianthopoulos, Vassilios,Mikros, Emmanuel,Szabo, Csaba,Bochet, Christian G.
, p. 6221 - 6240 (2021/05/06)
The enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is one of the more recently identified mammalian sources of H2S. A recent study identified several novel 3-MST inhibitors with micromolar potency. Among those, (2-[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one) or HMPSNE was found to be the most potent and selective. We now took the central core of this compound and modified the pyrimidone and the arylketone sides independently. A 63-compound library was synthesized; compounds were tested for H2S generation from recombinant 3-MST in vitro. Active compounds were subsequently tested to elucidate their potency and selectivity. Computer modeling studies have delineated some of the key structural features necessary for binding to the 3-MST's active site. Six novel 3-MST inhibitors were tested in cell-based assays: they exerted inhibitory effects in murine MC38 and CT26 colon cancer cell proliferation; the antiproliferative effect of the compound with the highest potency and best cell-based activity (1b) was also confirmed on the growth of MC38 tumors in mice.
Identification of the hydantoin alkaloids parazoanthines as novel CXCR4 antagonists by computational and in vitro functional characterization
Vitale, Rosa Maria,Thellung, Stefano,Tinto, Francesco,Solari, Agnese,Gatti, Monica,Nuzzo, Genoveffa,Ioannou, Efstathia,Roussis, Vassilios,Ciavatta, Maria Letizia,Manzo, Emiliano,Florio, Tullio,Amodeo, Pietro
, (2020/10/29)
CXCR4 chemokine receptor represents an attractive pharmacological target due to its key role in cancer metastasis and inflammatory diseases. Starting from our previously-developed pharmacophoric model, we applied a combined computational and experimental approach that led to the identification of the hydantoin alkaloids parazoanthines, isolated from the Mediterranean Sea anemone Parazoanthus axinellae, as novel CXCR4 antagonists. Parazoanthine analogues were then synthesized to evaluate the contribution of functional groups to the overall activity. Within the panel of synthesized natural and non-natural parazoanthines, parazoanthine-B was identified as the most potent CXCR4 antagonist with an IC50 value of 9.3 nM, even though all the investigated compounds were able to antagonize in vitro the down-stream effects of CXC12, albeit with variable potency and efficacy. The results of our study strongly support this class of small molecules as potent CXCR4 antagonists in tumoral pathologies characterized by an overexpression of this receptor. Furthermore, their structure–activity relationships allowed the optimization of our pharmacophoric model, useful for large-scale in silico screening.
A metal-free aerobic oxidative bromination of anilines and aryl ketones with 2-methylpyridinium nitrate as a reusable ionic liquid
Li, Ming-Fang,Wang, Jian,Ke, Yong-Xin,Pan, Song-Cheng,Yin, Hong,Du, Wenting,Li, Jing-Hua
, p. 267 - 270 (2020/01/08)
An aerobic oxidative bromination of anilines and aryl ketones catalyzed by recyclable 2-methylpyridinium nitrate ionic liquid is achieved in water using hydrobromic acid as the bromine source and molecular oxygen as the oxidant. The catalytic system shows good efficiency and atom economy.
Usnic Acid Enaminone-Coupled 1,2,3-Triazoles as Antibacterial and Antitubercular Agents
Bangalore, Pavan K.,Vagolu, Siva K.,Bollikanda, Rakesh K.,Veeragoni, Dileep K.,Choudante, Pallavi C.,Misra, Sunil,Sriram, Dharmarajan,Sridhar, Balasubramanian,Kantevari, Srinivas
supporting information, p. 26 - 35 (2020/01/03)
(+)-Usnic acid, a product of secondary metabolism in lichens, has displayed a broad range of biological properties such as antitumor, antimicrobial, antiviral, anti-inflammatory, and insecticidal activities. Interested by these pharmacological activities and to tap into its potential, we herein present the synthesis and biological evaluation of new usnic acid enaminone-conjugated 1,2,3-triazoles 10-44 as antimycobacterial agents. (+)-Usnic acid was condensed with propargyl amine to give usnic acid enaminone 8 with a terminal ethynyl moiety. It was further reacted with various azides A1-A35 under copper catalysis to give triazoles 10-44 in good yields. Among the synthesized compounds, saccharin derivative 36 proved to be the most active analogue, inhibiting Mycobacterium tuberculosis (Mtb) at an MIC value of 2.5 μM. Analogues 16 and 27, with 3,4-difluorophenacyl and 2-acylnaphthalene units, respectively, inhibited Mtb at MIC values of 5.4 and 5.3 μM, respectively. Among the tested Gram-positive and Gram-negative bacteria, the new derivatives were active on Bacillus subtilis, with compounds 18 [3-(trifluoromethyl)phenacyl] and 29 (N-acylmorpholinyl) showing inhibitory concentrations of 41 and 90.7 μM, respectively, while they were inactive on the other tested bacterial strains. Overall, the study presented here is useful for converting natural (+)-usnic acid into antitubercular and antibacterial agents via incorporation of enaminone and 1,2,3-triazole functionalities.
Nickel-Catalyzed Asymmetric Addition of Aromatic Halides to Ketones: Highly Enantioselective Synthesis of Chiral 2,3-Dihydrobenzofurans Containing a Tertiary Alcohol
Li, Ying,Li, Wendian,Tian, Jiangyan,Huang, Guozheng,Lv, Hui
supporting information, p. 5353 - 5357 (2020/07/14)
A highly enantioselective and straightforward synthetic procedure to chiral 3-hydroxy-2,3-dihydrobenzofurans has been developed by nickel/bisoxazoline-catalyzed intramolecular asymmetric addition of aryl halides to unactivated ketones, giving 2,3-dihydrobenzofurans with a chiral tertiary alcohol at the C-3 position in good yields and excellent enantioselectivities (up to 92percent yield and 98percent ee). The gram-scale reaction also proceeded smoothly without a loss of yield and enantioselectivity.
Development of triazolothiadiazine derivatives as highly potent tubulin polymerization inhibitors: Structure-activity relationship, in vitro and in vivo study
Ma, Weifeng,Chen, Peng,Huo, Xiansen,Ma, Yufeng,Li, Yanhong,Diao, Pengcheng,Yang, Fang,Zheng, Shengquan,Hu, Mengjin,You, Wenwei,Zhao, Peiliang
, (2020/10/08)
Based on our prior work, we reported the design, synthesis, and biological evaluation of fifty-two new triazolothiadiazine-based analogues of CA-4 and their preliminary structure-activity relationship. Among synthesized compounds, Iab was found to be the most potent derivative possessing IC50 values ranging from single-to double-digit nanomolar in vitro, and also exhibited excellent selectivity over the normal human embryonic kidney HEK-293 cells (IC50 > 100 μM). Further mechanistic studies revealed that Iab significantly blocked tubulin polymerization and disrupted the intracellular microtubule network of A549 cells. Moreover, Iab induced G2/M cell cycle arrest by regulation of p-cdc2 and cyclin B1 expressions, and caused cell apoptosis through up-regulating cleaved PARP and cleaved caspase-3 expressions, and down-regulating of Bcl-2. Importantly, in vivo, Iab effectively suppressed tumor growth of A549 lung cancers in a xenograft mouse model without obvious signs of toxicity, confirming its potential as a promising candidate for cancer treatment.
Selective Debromination of α,α,α-Tribromomethylketones with HBr–H2O Reductive Catalytic System
Cheng, Zhao,Guo, Hongmei,Huang, Guozheng,Rexit, Abulikemu Abudu,Wang, Hui,Zheng, Meng-Xia
, p. 6455 - 6458 (2020/10/21)
A debromination of α,α,α-tribromomethylketones is developed for chemoselective synthesis of α-mono- and α,α-dibromomethylketones with high selectivity under H2O–HBr reductive conditions. This method offers an efficient and direct way to synthesize α-mono or α,α-dibromomethylketone compounds in high to excellent yields through the process of HBr self-circulation in water.
Facile Synthesis of α-Haloketones by Aerobic Oxidation of Olefins Using KX as Nonhazardous Halogen Source
Luo, Zhibin,Meng, Yunge,Gong, Xinchi,Wu, Jie,Zhang, Yulan,Ye, Long-Wu,Zhu, Chunyin
supporting information, p. 173 - 177 (2020/01/02)
An operationally simple and safe synthesis of α-haloketones using KBr and KCl as nonhazardous halogen sources is reported. It involves an iron-catalysed reaction of alkenes with KBr/KCl using O2 as terminal oxidant under the irradiation of visible-light. This strategy avoids the risks associated with handling halo-contained electrophiles (Cl2, Br2, NCS, NBS). The process is tolerant to several functional groups, and extended to a range of substituted styrenes in up to 89% yield. A radical reaction pathway is proposed based on control experiments and spectroscopy studies.
