620-79-1Relevant academic research and scientific papers
Identification of new 3-phenyl-1H-indole-2-carbohydrazide derivatives and their structure–activity relationships as potent tubulin inhibitors and anticancer agents: A combined in silico, in vitro and synthetic study
Saruengkhanphasit, Rungroj,Butkinaree, Chutikarn,Ornnork, Narittira,Lirdprapamongkol, Kriengsak,Niwetmarin, Worawat,Svasti, Jisnuson,Ruchirawat, Somsak,Eurtivong, Chatchakorn
, (2021/03/17)
Virtual screening of commercially available molecular entities by using CDRUG, structure-based virtual screening, and similarity identified eight new derivatives of 3-phenyl-1H-indole-2-carbohydrazide with anti-proliferative activities. The molecules were tested experimentally for inhibition of tubulin polymerisation, which revealed furan-3-ylmethylene-3-phenyl-1H-indole-2-carbohydrazide (27a) as the most potent candidate. Molecule 27a was able to induce G2/M phase arrest in A549 cell line, similar to other tubulin inhibitors. Synthetic modifications of 27a were focussed on small substitutions on the furan ring, halogenation at R1 position and alteration of furyl connectivity. Derivatives 27b, 27d and 27i exhibited the strongest tubulin inhibition activities and were comparable to 27a. Bromine substitution at R1 position showed most prominent anticancer activities; derivatives 27b-27d displayed the strongest activities against HuCCA-1 cell line and were more potent than doxorubicin and the parent molecule 27a with IC50 values 50 = 0.34 μM), while 27d displayed stronger activity against A549 cell line (IC50 = 0.43 μM) compared to doxorubicin and 27a. Fluorine substitutions at the R1 position tended to show more modest anti-tubulin and anticancer activities, and change of 2-furyl to 3-furyl was tolerable. The new derivatives, thiophenyl 26, displayed the strongest activity against A549 cell line (IC50 = 0.19 μM), while 1-phenylethylidene 21b and 21c exhibited more modest anticancer activities with unclear mechanisms of action; 26 and 21c demonstrated G2/M phase arrest, but showed weak tubulin inhibitory properties. Molecular docking suggests the series inhibit tubulin at the colchicine site, in agreement with the experimental findings. The calculated molecular descriptors indicated that the molecules obey Lipinski's rule which suggests the molecules are drug-like structures.
Pyrazole-Thiazole Core-Containing Analogs Exhibit Adjunctive Activity with Meropenem against Carbapenem-Resistant Enterobacteriaceae (CRE)
Kim, Chungsik,Kassu, Mintesinot,Smith, Kenneth P.,Kirby, James E.,Manetsch, Roman
supporting information, p. 2775 - 2780 (2021/07/02)
Pyrazole-thiazole core-containing compound KP-40 and 20 novel derivatives were designed and synthesized through traditional SAR analysis. These molecules displayed adjunctive activity with meropenem against Gram-negative bacteria evidenced by a range of fractional inhibitory concentration (FIC=0.5–0.25) and minimum adjunctive concentration (MAC=128–32 μM) values. Of this series of molecules, four compounds displayed notable adjunctive potential, with FIC and MAC values of 0.25 and 32 μM, respectively. Moreover, the solubility of these compounds was improved to an acceptable range. Further analysis using our “in house” permeation and efflux multi parameter optimization (PEMPO) algorithm revealed key physicochemical properties that may be critical for the development of active Gram-negative antibacterials. Taking PEMPO scores into consideration prior to executing synthesis of analogs may be a simple, yet rapid and effective strategy that can be used in conjunction with traditional SAR approaches to aid in the design of potent Gram-negative antibacterials.
Catalytic Asymmetric Homologation of Ketones with α-Alkyl α-Diazo Esters
Tan, Fei,Pu, Maoping,He, Jun,Li, Jinzhao,Yang, Jian,Dong, Shunxi,Liu, Xiaohua,Wu, Yun-Dong,Feng, Xiaoming
supporting information, p. 2394 - 2402 (2021/02/16)
The homologation of ketones with diazo compounds is a useful strategy to synthesize one-carbon chain-extended acyclic ketones or ring-expanded cyclic ketones. However, the asymmetric homologation of acyclic ketones with α-diazo esters remains a challenge due to the lower reactivity and complicated selectivity. Herein, we report the enantioselective catalytic homologation of acetophenone and related derivatives with α-alkyl α-diazo esters utilizing a chiral scandium(III) N,N′-dioxide as the Lewis acid catalyst. This reaction supplies a highly chemo-, regio-, and enantioselective pathway for the synthesis of optically active β-keto esters with an all-carbon quaternary center through highly selective alkyl-group migration of the ketones. Moreover, the ring expansion of cyclic ketones was accomplished under slightly modified conditions, affording a series of enantioenriched cyclic β-keto esters. Density functional theory calculations have been carried out to elucidate the reaction pathway and possible working models that can explain the observed regio- and enantioselectivity.
Discovery of remogliflozin etabonate: A potent and highly selective SGLT2 inhibitor
Shimizu, Kazuo,Fujikura, Hideki,Fushimi, Nobuhiko,Nishimura, Toshihiro,Tatani, Kazuya,Katsuno, Kenji,Fujimori, Yoshikazu,Watanabe, Shinjiro,Hiratochi, Masahiro,Nakabayashi, Takeshi,Kamada, Noboru,Arakawa, Koichi,Hikawa, Hidemasa,Azumaya, Isao,Isaji, Masayuki
, (2021/02/16)
We optimized the structure of an active metabolite (1) of WAY-123783, which was obtained from mouse urine after oral administration, to improve selectivity for SGLT2 and oral bioavailability. O-glucoside derivative 24 (remogliflozin etabonate) was subsequently identified as a potent, highly selective, and orally available SGLT2 inhibitor.
Reductive Knoevenagel Condensation with the Zn-AcOH System
Ivanov, Konstantin L.,Melnikov, Mikhail Ya.,Budynina, Ekaterina M.
, p. 1285 - 1291 (2020/11/13)
An efficient gram-scale one-pot approach to 2-substituted malonates and related structures is developed, starting from commercially available aldehydes and active methylene compounds. The technique combines Knoevenagel condensation with the reduction of the C=C bond in the resulting activated alkenes with the Zn-AcOH system. The relative ease with which the C=C bond reduction occurs can be traced to the accepting abilities of the substituents in the intermediate arylidene malonates.
REDUCTION METHOD AND REDUCTION PRODUCT OF ALKENYL ACTIVE METHYLENE COMPOUND
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Paragraph 0022-0023, (2021/07/02)
Disclosed are a reduction method and reduction product of an alkenyl active methylene compound. The reduction reaction comprises the following steps: taking an alkenyl active methylene compound as a substrate, a metal hydride as a reducing agent, and a palladium compound as a catalyst, performing a reduction reaction to obtain a reduction product, and then reducing the alkenyl active methylene compound. The reduction system is a simple method for reducing the alkenyl active methylene compound, and the used hydride and palladium compound catalyst are both reagents that could easily be obtained in a laboratory. Compared with conventional hydrogen hydrogenation methods and reduction methods of reducing agents, the method is easier to operate, higher in safety, mild in conditions, and high in reaction yield, a reaction in a one-pot two-step manner can be achieved, and high atom economy and step economy can be obtained.
Development of coumarine derivatives as potent anti-filovirus entry inhibitors targeting viral glycoprotein
Gao, Yinyi,Cheng, Han,Khan, Sameer,Xiao, Gaokeng,Rong, Lijun,Bai, Chuan
, (2020/07/23)
Filoviruses, including Ebolavirus (EBOV), Marburgvirus (MARV) and Cuevavirus, cause hemorrhagic fevers in humans with up to 90% mortality rates. In the 2014–2016 West Africa Ebola epidemic, there are 15,261 laboratory confirmed cases and 11,325 total deaths. The lack of effective vaccines and medicines for the prevention and treatment of filovirus infection in humans stresses the urgency to develop antiviral therapeutics against filovirus-associated diseases. Our previous study identified a histamine receptor antagonist compound CP19 as an entry inhibitor against both EBOV and MARV. The preliminary structure-activity relationship (SAR) studies of CP19 showed that its piperidine, coumarin and linker were related with its antiviral activities. In this study, we performed detailed SAR studies on these groups with synthesized CP19 derivatives. We discovered that 1) the piperidine group could be optimized with heterocycles, 2) the substitution groups of C3 and C4 of coumarin should be relatively large hydrophobic groups and 3) the linker part should be least substituted. Based on the SAR analysis, we synthesized compound 32 as a potent entry inhibitor of EBOV and MARV (IC50 = 0.5 μM for EBOV and 1.5 μM for MARV). The mutation studies of Ebola glycoprotein and molecular docking studies showed that the coumarin and its substituted groups of compound 32 bind to the pocket of Ebola glycoprotein in a similar way to the published entry inhibitor compound 118a. However, the carboxamide group of compound 32 does not have strong interaction with N61 as compound 118a does. The coumarin skeleton structure and the binding model of compound 32 elucidated by this study could be utilized to guide further design and optimization of entry inhibitors targeting the filovirus glycoproteins.
Anti-filamentous virus small molecule compound and application thereof
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Paragraph 0047; 0050; 0053-0054, (2021/01/04)
The invention discloses an anti-filamentous virus small molecule compound and application thereof. The small molecule compound has a structural formula shown as a formula I, and an R group of the small molecule compound is selected from structural formulas II-V. The four new compounds all have higher anti-filamentous virus activity and excellent filamentous virus treatment index, and the use of compounds with similar structures finds that the new compounds have better antiviral activity by 6-glycerol branched chain substitution on the basis of the original compounds; and the structural framework can become a basic skeleton of an anti-filamentous virus inhibitor.
Complementing Pyridine-2,6-bis(oxazoline) with Cyclometalated N-Heterocyclic Carbene for Asymmetric Ruthenium Catalysis
Li, Long,Han, Feng,Nie, Xin,Hong, Yubiao,Ivlev, Sergei,Meggers, Eric
supporting information, p. 12392 - 12395 (2020/06/10)
A strategy for expanding the utility of chiral pyridine-2,6-bis(oxazoline) (pybox) ligands for asymmetric transition metal catalysis is introduced by adding a bidentate ligand to modulate the electronic properties and asymmetric induction. Specifically, a ruthenium(II) pybox fragment is combined with a cyclometalated N-heterocyclic carbene (NHC) ligand to generate catalysts for enantioselective transition metal nitrenoid chemistry, including ring contraction to chiral 2H-azirines (up to 97 % ee with 2000 TON) and enantioselective C(sp3)?H aminations (up to 97 % ee with 50 TON).
Method for synthesizing beta-keto ester through copper catalysis
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Paragraph 0037-0039, (2019/12/02)
The invention relates to a method for synthesizing beta-keto ester by copper catalysis, which comprises the following steps of dissolving ethyl acylacetate and halogenated hydrocarbon in an organic solvent, adding a copper catalyst and alkali, reacting at 60-90 DEG C for 12-18 hours, and separating and purifying to obtain the beta-keto ester. Compared with the prior art, the method has the advantages of simple and green synthesis process, excellent selectivity, higher yield and wide substrate range, and has the wide application value in the fields of biology, pharmaceutical chemistry industryand the like.
