- Sulfonamide-based ring-fused analogues for CAN508 as novel carbonic anhydrase inhibitors endowed with antitumor activity: Design, synthesis, and in vitro biological evaluation
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In the present study, we report the design and synthesis of novel CAN508 sulfonamide-based analogues (4, 8a-e, 9a-h and 10a-e) as novel carbonic anhydrase (CA) inhibitors with potential CDK inhibitory activity. A bioisosteric replacement approach was adop
- Said, Mohamed A.,Eldehna, Wagdy M.,Nocentini, Alessio,Fahim, Samar H.,Bonardi, Alessandro,Elgazar, Abdullah A.,Kry?tof, Vladimír,Soliman, Dalia H.,Abdel-Aziz, Hatem A.,Gratteri, Paola,Abou-Seri, Sahar M.,Supuran, Claudiu T.
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- Synthesis, characterization, antimicrobial activity, 3D-QSAR, DFT, and molecular docking of some ciprofloxacin derivatives and their copper(II) complexes
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Six new derivatives of ciprofloxacin compounds and their copper(II) complexes were synthesized, characterized by spectroscopic methods (ultraviolet–visible [UV–vis], Fourier transform infrared [FTIR], nuclear magnetic resonance [NMR], mass spectrometry [M
- Khalil, Tarek E.,El-Dissouky, Ali,Al-Wahaib, Dhuha,Abrar, Nada M.,El-Sayed, Doaa S.
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- Design and synthesis of novel benzenesulfonamide containing 1,2,3-triazoles as potent human carbonic anhydrase isoforms I, II, IV and IX inhibitors
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In a quest to discover new biologically active compounds, a series of twenty novel heterocyclic derivatives substituted at position 5 with -H (7a-7j) or -CF3 (8a-8j), bearing benzenesulfonamide at N-1 position and various aroyl groups at position 4 of the 1,2,3-triazole ring was synthesized and screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibition potential against four human (h) isoforms hCA I, II, IV and IX. All the compounds (7a-7j and 8a-8j) were synthesized via [3+2] cycloaddition reaction from 4-azidobenzenesulfonamide. Interestingly, compounds 7a-7j were prepared in one pot manner via enaminone intermediate using novel methodology. All the newly synthesized compounds (7a-7j & 8a-8j) were found to be excellent inhibitors of edema related isoform hCA I with their inhibition constant (Ki) ranging from 30.1 to 86.8 nM as compared to standard drug acetazolamide (AAZ) with Ki = 250 nM. Further it was found that most of tested compounds were weaker inhibitors of isoform, hCA II although compounds 7b, 7d-7e, 8a, 8d-8f, 8i (mostly with electron withdrawing substituents) have shown better inhibition potential (Ki i = 52.4 nM) than AAZ (Ki = 74 nM) while against tumor associated hCA IX, all the compounds have shown moderate inhibition potential. Present study have added one more step in exploring the 1,2,3-triazlole moiety in the medicinal field.
- Kumar, Rajiv,Vats, Lalit,Bua, Silvia,Supuran, Claudiu T.,Sharma, Pawan K.
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- SLC-0111 enaminone analogs, 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides, as novel selective subnanomolar inhibitors of the tumor-associated carbonic anhydrase isoform IX
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SLC-0111, an ureido substituted benzenesulfonamide, is a selective carbonic anhydrase (CA, EC 4.2.1.1) IX inhibitor that is currently in Phase I/II clinical trials for the treatment of advanced hypoxic tumors complicated with metastases. Herein we report
- Eldehna, Wagdy M.,Abo-Ashour, Mahmoud F.,Berrino, Emanuela,Vullo, Daniela,Ghabbour, Hazem A.,Al-Rashood, Sara T.,Hassan, Ghada S.,Alkahtani, Hamad M.,Almehizia, Abdulrahman A.,Alharbi, Amal,Abdel-Aziz, Hatem A.,Supuran, Claudiu T.
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- Synthesis and Biological Activity of Some Novel Aryl-Substituted 1,3,4-Oxadiazole Mannich Bases Containing Pyrimidine Rings
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A series of novel Mannich base derivatives (E1-E15) of 5-aryl-1,3,4-oxadiazole-2-thione with substituted pyrimidine were synthesized and characterized by elemental analysis, IR, 1H-NMR. The antifungal activities of these compounds were also originally studied. The results showed that most of the title compounds exhibited relatively good fungicidal activities. Especially compounds E8 and E13 showed better antifungal activity than comparison compound hymexazol. The relationship of structure and activity revealed that the presence of the methyl group at four and six positions of pyrimidine ring remarkably enhanced the antifungal activity of title compounds.
- Shen, Shengqiang,Sun, Xiaohong,Liu, Yuanfa,Chen, Bang,Jin, Ruyi,Ma, Haixia
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- Synthesis and Cation Recognition Study of Novel Benzo Crown Ether Functionalized Enamine Derivatives
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A novel series of benzo crown ether (dibenzo 18-crown-6 ether, benzo 18-crown-6 ether, and benzo 15-crown-5 ether) functionalized enamines derivatives from amino benzo crown ether (4-amino dibenzo 18-crown-6 ether, 4-amino benzo 18-crown-6 ether, 4-amino
- Patil, Dayanand R.,Chandam, Dattatraya R.,Mulik, Abhijeet G.,Jagdale, Suryabala D.,Patil, Prasad P.,Deshmukh, Madhukar B.
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- Facile Synthesis of Some New Pyrazole-Based 2-Thioxo-4-thiazolidinone
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5-Ethoxymethylene-2-thioxo-4-thiazolidinone (1) reacts with hydrazine hydrate at room temperature to afford 5-(hydrazinylmethylene)-2-thioxo-4-thiazolidinone (3). Compound 3 condensed with different aromatic aldehydes 6a-d in ethanol in the presence of a few drops of piperidine to give the corresponding Schiffs bases 7a-d. On the other hand, compound 3 reacts with o-hydroxybenzaldehyde derivatives 8a and 8b in refluxing ethanol catalyzed by a few drops of piperidine to yield 1H-inadzolyl-2-thioxo-4-thiazolidinones 9a and 9b. Reaction of compound 3 with α-ketoesters 10a and 10b or α-diketones 10c-e in refluxing glacial acetic acid furnished the pyrazolyl-2-thioxo-4-thiazolidinone derivatives 11a-e. Also, compound 3 reacts with some different enaminones 12a-f in refluxing glacial acetic acid to afford the new pyrazolyl-2-thioxo-4-thiazolidinone derivatives 13a-f. Pyrazoles 15a-d was obtained via reaction of compound 3 with chalcones 14a-d in dimethylformamide (DMF). The structures of all the newly synthesized products were confirmed on the basis of their elemental and spectral data, and a plausible mechanism has been postulated to account for their formation.
- Metwally, Nadia Hanafy,El-Doseky, Ibrahim Adel
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- One-pot synthesis of enaminones using gold's reagent
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Enaminones were efficiently prepared via modification for Gupton method, which depends on carrying out the latter procedure in one step reaction, avoiding the isolation of [3-(dimethylamino)-2-azaprop-2-en-1-ylidene] dimethylammonium chloride (Gold's reag
- Saleh, Tamer S.,Al-Omar, Mohamed A.,Abdel-Aziz, Hatem A.
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- Efficient synthesis, structure elucidation, and anti-parasitic activities of novel quinolinyl β–enaminones
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In the present study, a novel series of side chain-modified quinoline β-enaminones were synthesized in good-to-excellent yields. The structures of all the synthesized compounds have been established with the help of spectral and analytical data and also b
- Khanikar, Shilpika,Kaping, Shunan,Helissey, Philippe,Joshi, Prince,Shaham, Salique Hassan,Mishra, Shikha,Srivastava, Mrigank,Tripathi, Renu,Vishwakarma, Jai N.
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- Access to α,α-dihaloacetophenones through anodic C[dbnd]C bond cleavage in enaminones
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We have developed a method to synthesize α,α-dihaloketones under electrochemical conditions. In this reaction, the Cl- or Br- is oxidized to Cl2 or Br2 at the anode, which undergoes two-step addition reactions with the N,N-dimethyl enaminone, and finally breaks C[dbnd]C of the N,N-dimethyl enaminone to generate α,α-dihaloketones. The electrosynthesis reaction can be conveniently carried out in an undivided electrolytic cell at room temperature. In addition, various functional groups are compatible with this green protocol which can be applied simultaneously to the gram scale without significantly lower yield.
- Zhang, Zhenlei,Yang, Jiusi,Wu, Kairui,Yu, Renjie,Bu, Jiping,Huang, Zijun,Li, Shaoke,Ma, Xiantao
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supporting information
(2021/12/20)
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- DDQ-mediated oxidative coupling reaction of N,N-dimethyl enaminones with cycloheptatriene
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An efficient 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-mediated oxidative coupling reaction of N,N-dimethyl enaminones with cycloheptatriene is developed. It provides a variety of α-alkenylated 1,3-dicarbonyl compounds in moderate to good yields under mild conditions.
- Cheng, Dongping,Yu, Chenze,Pu, Yueqi,Xu, Xiaoliang
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supporting information
(2022/01/23)
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- Metal-free synthesis of β-aminoketones by the reductive hydroamination of ynones
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This study describes a cascade method for the synthesis of β-aminoketones through the reductive hydroamination of alkynes under very mild metal-free conditions. It allows for the rapid conversion of ynones and amines into corresponding β-aminoketones with a broad substrate scope and diverse functionalities. This straightforward and easy-to-handle reaction process can be successfully applied for the synthesis of Proroxan and Propipocaine, offering a potential option for the synthesis of drug molecules with the β-aminoketone skeleton.
- Fu, Rui,Liu, Yu,Wu, Tao,Zhang, Xinyu,Zhu, Yang,Luo, Jiangbin,Zhang, Zhengyu,Jiang, Yaojia
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p. 3525 - 3528
(2022/03/31)
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- Microscale Parallel Synthesis of Acylated Aminotriazoles Enabling the Development of Factor XIIa and Thrombin Inhibitors
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Herein we report a microscale parallel synthetic approach allowing for rapid access to libraries of N-acylated aminotriazoles and screening of their inhibitory activity against factor XIIa (FXIIa) and thrombin, which are targets for antithrombotic drugs. This approach, in combination with post-screening structure optimization, yielded a potent 7 nM inhibitor of FXIIa and a 25 nM thrombin inhibitor; both compounds showed no inhibition of the other tested serine proteases. Selected N-acylated aminotriazoles exhibited anticoagulant properties in vitro influencing the intrinsic blood coagulation pathway, but not extrinsic coagulation. Mechanistic studies of FXIIa inhibition suggested that synthesized N-acylated aminotriazoles are covalent inhibitors of FXIIa. These synthesized compounds may serve as a promising starting point for the development of novel antithrombotic drugs.
- Platte, Simon,Korff, Marvin,Imberg, Lukas,Balicioglu, Ilker,Erbacher, Catharina,Will, Jonas M.,Daniliuc, Constantin G.,Karst, Uwe,Kalinin, Dmitrii V.
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supporting information
p. 3672 - 3690
(2021/08/07)
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- MODULATORS OF HSD17B13 AND METHODS OF USE THEREOF
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The disclosure relates to compounds and pharmaceutical compositions capable of modulating the hydroxysteroid 17-beta dehydrogenase (HSD17B) family member proteins including inhibiting the HSD17B member proteins, e.g. HSD17B13. The disclosure further relates to methods of treating liver diseases, disorders, or conditions with the compounds and pharmaceutical compositions disclosed herein, in which the HSD17B family member protein plays a role.
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Paragraph 0705
(2021/01/23)
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- Synthesis, characterization, and antimicrobial activity investigations of ruthenium (II)–bipyridine complexes of ciprofloxacin derivatives
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A series of ruthenium (II) complexes derived from the reaction between cis-bis (2,2′-bipyridine) dichloro ruthenium (II) dihydrate and enaminone derivatives of ciprofloxacin were synthesized and fully characterized using elemental analysis, cyclic voltammetry and different spectroscopic techniques (Uv–vis, FTIR, NMR, mass spectroscopy, and X-ray photoelectron spectrometry (XPS)). The isolated compounds were tested for their antibacterial and antifungal activities against gram-negative and gram-positive bacteria. The FTIR data revealed that ciprofloxacin derivatives act as bidentate ligands through the pyridone carbonyl and the carboxylate oxygen atom. The UV–visible data showed that the charge transfer CT band is blue shifted upon the coordination of the ciprofloxacin derivatives compared to the CT band of the parent complex. The XPS results revealed the characteristic peaks of Ru3p3/2 and Ru3p1/2 as well as Ru3d5/2 and Ru3d3/2, which confirmed the assembly of the ruthenium (II) ciprofloxacin derivative complexes. Cyclic voltammetry data showed that the ciprofloxacin enaminone derivatives have a similar reduction potential for the Ru (II)/Ru (III) redox couple, and it revealed that the coordination of the ruthenium (II) ion altered the redox property of the ligands and enhanced their electron transfer rate. The electrochemical and the UV–visible results suggest that the ciprofloxacin derivative ligands are (Formula presented.) -acceptor ligands. Further, the complexes showed higher antibacterial activities than the parent ciprofloxacin antibiotic and did not show antifungal activities among the tested fungi strains.
- Al-Wahaib, Dhuha,El-Dissouky, Ali,Abrar, Nada M.,Khalil, Tarek E.
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- A new approach for the synthesis of novel naphthoquinone chalcone hybrid compounds
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A facile and efficient synthesis of novel naphthoquinone-based chalcone hybrids (7 and 24) via the microwave-assisted one-pot three-component reactions of 2-substituted-1,4-naphthoquinones, N,N-dimethylformamide dimethyl acetal (DMF-DMA), and acetophenone derivatives has been reported. Whereas the synthesis of hybrids 7 proceeded via a condensation, 1,4-addition, rotation, elimination, and [1,3]-H shift sequence of steps, the synthesis of hybrids 24 were formed through a three-step sequence including condensation, 1,4-addition, and elimination reactions.
- Nguyen, Ha-Thanh,Dang Thi, Tuyet Anh,Hoang Thi, Phuong,Le-Nhat-Thuy, Giang,Nguyen Thi, Quynh Giang,Nguyen Tuan, Anh,Le Thi, Tu Anh,Van Nguyen, Tuyen
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supporting information
(2021/08/27)
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- Stable monovalent aluminum(i) in a reduced phosphomolybdate cluster as an active acid catalyst
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Low-valent aluminum Al(i) chemistry has attracted extensive research interest due to its unique chemical and catalytic properties but is limited by its low stability. Herein, a hourglass phosphomolybdate cluster with a metal-center sandwiched by two benzene-like planar subunits and large steric-hindrance is used as a scaffold to stabilize low-valent Al(i) species. Two hybrid structures, (H3O)2(H2bpe)11[AlIII(H2O)2]3{[AlI(P4MoV6O31H6)2]3·7H2O (abbr. Al6{P4Mo6}6) and (H3O)3(H2bpe)3[AlI(P4MoV6O31H7)2]·3.5H2O (abbr. Al{P4Mo6}2) (bpe =trans-1,2-di-(4-pyridyl)-ethylene) were successfully synthesized with Al(i)-sandwiched polyoxoanionic clusters as the first inorganic-ferrocene analogues of a monovalent group 13 element with dual Lewis and Br?nsted acid sites. As dual-acid catalysts, these hourglass structures efficiently catalyze a solvent-free four-component domino reaction to synthesize 1,5-benzodiazepines. This work provides a new strategy to stabilize low-valent Al(i) species using a polyoxometalate scaffold.
- Zhang, Ya-Qi,Zhou, Lai-Yun,Ma, Yuan-Yuan,Dastafkan, Kamran,Zhao, Chuan,Wang, Lan-Zhi,Han, Zhan-Gang
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p. 1886 - 1890
(2021/02/22)
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- 1,2,4-Triazolo[1,5-a]pyrimidines: Efficient one-step synthesis and functionalization as influenza polymerase PA-PB1 interaction disruptors
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In the search for new anti-influenza virus (IV) compounds, we have identified the 1,2,4-triazolo[1,5-a]pyrimidine (TZP) as a very suitable scaffold to obtain compounds able to disrupt IV RNA-dependent RNA polymerase (RdRP) PA-PB1 subunits heterodimerization. In this work, in order to acquire further SAR insights for this class of compounds and identify more potent derivatives, we designed and synthesized additional series of analogues to investigate the role of the substituents around the TZP core. To this aim, we developed four facile and efficient one-step procedures for the synthesis of 5-phenyl-, 6-phenyl- and 7-phenyl-2-amino-[1,2,4]triazolo[1,5-a]pyrimidines, and 2-amino-5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-ol. Two analogues having the ethyl carboxylate moiety at the C-2 position of the TZP were also prepared in good yields. Then, the scaffolds herein synthesized and two previous scaffolds were functionalized and evaluated for their anti-IAV activity, leading to the identification of compound 22 that showed both anti-PA-PB1 (IC50 = 19.5 μM) and anti-IAV activity (EC50 = 16 μM) at non-toxic concentrations, thus resulting among the most active TZP derivatives reported to date by us. A selection of the synthesized compounds, along with a set of in-house available analogues, was also tested against SARS-CoV-2. The most promising compound 49 from this series displayed an EC50 value of 34.47 μM, highlighting the potential of the TPZ scaffold in the search for anti-CoV agents.
- Pismataro, Maria Chiara,Felicetti, Tommaso,Bertagnin, Chiara,Nizi, Maria Giulia,Bonomini, Anna,Barreca, Maria Letizia,Cecchetti, Violetta,Jochmans, Dirk,De Jonghe, Steven,Neyts, Johan,Loregian, Arianna,Tabarrini, Oriana,Massari, Serena
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- An expedient synthesis of highly functionalized 1,3-dienes by employing cyclopropenes asC4units
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An efficient method has been described to synthesize dicarbonyl functionalized 1,3-dienes by cleaving the CC bond of enaminones with cyclopropenes in the presence of a rhodium catalyst. The acetate-substituted cyclopropenes are judiciously chosen as standardC4units of 1,3-diene precursors. The reactions are believed to undergo a unique cutting and insertion process, involving a CC bond cleavage of the enaminone and insertion of a newC(sp2) source with the formation of two C-C single bonds. A broad range of substrates can be used to synthesize the corresponding 1,3-dienes under very mild reaction conditions, including low catalyst-loading, ambient temperature, and a neutral reaction solvent.
- Jiang, Chengzhou,Wu, Jiamin,Han, Jiabin,Chen, Kai,Qian, Yang,Zhang, Zhengyu,Jiang, Yaojia
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supporting information
p. 5710 - 5713
(2021/06/16)
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- Structure-Based Discovery of Pyrimidine Aminobenzene Derivatives as Potent Oral Reversal Agents against P-gp- And BCRP-Mediated Multidrug Resistance
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Overexpression of ATP binding cassette (ABC) transporters, including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), is an important factor leading to multidrug resistance (MDR) in cancer treatments. Three subclasses of dual inhibitors of P-gp and BCRP were designed based on the active moieties of BCRP inhibitors, tyrosine kinase inhibitors, and P-gp inhibitors, of which compound 21 possessed low cytotoxicity, high reversal potency, and good lipid distribution coefficient. 21 also increased the accumulation of Adriamycin (ADM) and Mitoxantrone (MX), blocked Rh123 efflux, and made no change in the protein expression of P-gp and BCRP. Importantly, coadministration of 21 can significantly improve the oral bioavailability of paclitaxel (PTX). It was also demonstrated that 21 significantly inhibited the growth of K562/A02 xenograft tumors by increasing the sensitivity of ADM in vivo. In summary, 21 has the potential to overcome MDR caused by P-gp and BCRP and to improve the oral bioavailability of PTX.
- Qiu, Qianqian,Zou, Feng,Li, Huilan,Shi, Wei,Zhou, Daoguang,Zhang, Ping,Li, Teng,Yin, Ziyu,Cai, Zilong,Jiang, Yuxuan,Huang, Wenlong,Qian, Hai
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p. 6179 - 6197
(2021/06/01)
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- Synthesis of a new series of pyrazolo[1,5-a]pyrimidines as CDK2 inhibitors and anti-leukemia
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Based on the structural study of previously known CDK2 inhibitors, a new series of pyrazolo[1,5-a]pyrimidine derivatives was designed and synthesized. The target compounds were biologically assessed as potent CDK2 inhibitors and promising anti-leukemia hi
- Almehmadi, Samar J.,Alsaedi, Amani M.R.,Harras, Marwa F.,Farghaly, Thoraya A.
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- One-Pot Synthesis of Symmetrical and Asymmetrical 3-Amino Diynes via Cu(I)-Catalyzed Reaction of Enaminones with Terminal Alkynes
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An economical and efficient protocol for the direct construction of amino skipped diynes through the Cu(I)-catalyzed reaction of enaminones and terminal alkynes has been described. Different kinds of symmetrical and asymmetrical 3-amino diynes could be ob
- Zhang, Changyuan,Guo, Huosheng,Chen, Lulu,Zhang, Jiantao,Guo, Mengping,Zhu, Xuncheng,Shen, Chan,Li, Zeng
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supporting information
p. 8169 - 8173
(2021/11/01)
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- Modification on the 1,2-dihydro-2-oxo-pyridine-3-carboxamide core to obtain multi-target modulators of endocannabinoid system
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Several preclinical evidence indicate that the modulation of the endocannabinoid system (ECS) represents a promising therapeutic approach for different diseases. However, only few modulators of this system have reached so far an advanced stage of clinical development, mainly due to limited efficacy and CB1 receptor-dependent side effects. Those limitations might be overcome by multi-target compounds that exert pro-cannabinoid activities through the modulation of two or more targets in the ECS. This approach can offer a safer and more effective pharmacological strategy as compared to the modulation of a single target. In this work, we report the synthesis and biological characterization of new 6-aryl-1,2-dihydro-2-oxo-pyridine-3-carboxamide derivatives. Our results identified several compounds exhibiting interesting multi-target profiles within the ECS. In particular, compound B1 showed moderate-to-high affinity for cannabinoid receptors (Ki CB1R = 304 nM, partial agonist, Ki CB2R = 3.1 nM, inverse agonist) and a potent inhibition of AEA uptake (IC50 = 62 nM) with moderate inhibition of FAAH (IC50 = 2.9 μM). The corresponding 2-alkoxypyridine analogue B14 exhibited significant inhibitor activity on both FAAH (IC50 = 69 nM) and AEA uptake (IC50 = 76 nM) without significantly binding to both cannabinoid receptor subtypes. Molecular docking analysis was carried out on the three-dimensional structures of CB1R and CB2R and of FAAH to rationalize the structure-activity relationships of this series of compounds.
- Gado, Francesca,Arena, Chiara,Fauci, Cristiana La,Reynoso-Moreno, Ines,Bertini, Simone,Digiacomo, Maria,Meini, Serena,Poli, Giulio,Macchia, Marco,Tuccinardi, Tiziano,Gertsch, Jürg,Chicca, Andrea,Manera, Clementina
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- Stereoselective synthesis of trifluoromethyl-substituted 2: H -furan-amines from enaminones
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A straightforward strategy for synthesis of highly functionalized trifluoromethyl 2H-furans is described. The copper catalyzed method relies on a cascade cyclic reaction between enaminones and N-tosylhydrazones. This method allows the synthesis of 2-amino
- Liang, Xiaoyu,Guo, Pan,Yang, Wenjie,Li, Meng,Jiang, Chengzhou,Sun, Wangbin,Loh, Teck-Peng,Jiang, Yaojia
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supporting information
p. 2043 - 2046
(2020/02/22)
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- I2-Promoted [4 + 2] cycloaddition of: In situ generated azoalkenes with enaminones: Facile and efficient synthesis of 1,4-dihydropyridazines and pyridazines
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A facile and efficient strategy for the synthesis of 1,4-dihydropyridazines and pyridazines through I2-promoted [4 + 2] cycloaddition of in situ generated azoalkenes with enaminones has been developed. The switch in selectivity is attributed to the judici
- Baell, Jonathan B.,Feng, Jiajun,He, Tiantong,Huang, Fei,Xie, Yuxing,Yu, Yang
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supporting information
p. 9483 - 9493
(2020/12/15)
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- Design, diversity-oriented synthesis and biological evaluation of novel heterocycle derivatives as non-nucleoside HBV capsid protein inhibitors
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The capsid assembly is a significant phase for the hepatitis B virus (HBV) lifespan and is an essential target for anti-HBV drug discovery and development. Herein, we used scaffold hopping, bioisosterism, and pharmacophore hybrid-based strategies to design and synthesize six series of various heterocycle derivatives (pyrazole, thiazole, pyrazine, pyrimidine, and pyridine) and screened for in vitro anti-HBV non-nucleoside activity. Drug candidate NZ-4 and AT-130 were used as lead compounds. Several compounds exhibited prominent anti-HBV activity compared to lead compound NZ-4 and positive drug Lamivudine, especially compound II-8b, showed the most prominent anti-HBV DNA replication activity (IC50 = 2.2 ± 1.1 μM). Also compounds IV-8e and VII-5b showed the best in vitro anti-HBsAg secretion (IC50 = 3.8 ± 0.7 μM, CC50 > 100 μM) and anti-HBeAg secretion (IC50 = 9.7 ± 2.8 μM, CC50 > 100 μM) respectively. Besides, II-8b can interact HBV capsid protein with good affinity constants (KD = 60.0 μM), which is equivalent to lead compound NZ-4 ((KD = 50.6 μM). The preliminary structure-activity relationships (SARs) of the newly synthesized compounds were summarized, which may help researchers to discover more potent anti-HBV agents.
- Jia, Haiyong,Yu, Ji,Du, Xianhong,Cherukupalli, Srinivasulu,Zhan, Peng,Liu, Xinyong
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- Cyclometalated pt complexes of cnc pincer ligands: Luminescence and cytotoxic evaluation
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In the framework of our attempts to develop cyclometalated Pt(II) complexes toward bifunctional targeting inhibitors or agents for photodynamic therapy, diagnostics, and bioimaging, a series of bis-cyclometalated Pt(II) complexes [Pt(CNC)(L)] (L = DMSO, MeCN) containing various (CNC)2- ligands based on 2,6-diphenylpyridine were synthesized and characterized analytically and spectroscopically, focusing on their electrochemical, luminescence, and antiproliferative properties. Electrochemical experiments and UV-vis absorption spectroscopy suggest ligand-centered LUMOs and metal-centered HOMOs in line with DFT calculations. Extension of the ancillary phenyl to naphthyl cores and a central 4-phenylpyridine group instead of pyridine results in bathochromic shifts of the long-wavelength absorption bands ranging from 420 to 440 nm, with the latter shift being more pronounced. The complexes of the fused CNC heterocyclic systems dba (H2dba = dibenzo[c,h]acridine), db(ph)a (H2db(ph)a = 7-phenyldibenzo[c,h]acridine), and bzqph (HbzqphH = 2-phenylbenzo[h]quinoline) absorb far more red-shifted in the range 500-530 nm. All complexes show reversible first electrochemical reductions and irreversible oxidations with an electrochemical gap of about 3 V, roughly in line with the absorption energies. While the 2,6-diphenylpyridine complexes [Pt(CNC)(DMSO)] show no luminescence at ambient temperature in solution, the fused dba, db(ph)a, and bzqph derivatives are efficient triplet emitters at ambient temperature with emission wavelengths in the region 575-600 nm and quantum yields ranging from 7 to 23%. Vibrationally resolved emission spectra calculated in the framework of DFT faithfully reproduce the experimental data. TD-DFT calculations at the excited-state T1 geometry reveal intraligand π-π*/MLCT character of the emission for all three investigated complexes. Antiproliferative tests on selected complexes gave very different toxicities, ranging from lower than 1 μM to virtually nontoxic. The data allowed drawing some structure-activity relationships (SAR), even though variations in solubility could also significantly account for the different toxicities.
- Garbe, Simon,Krause, Maren,Klimpel, Annika,Neundorf, Ines,Lippmann, Petra,Ott, Ingo,Brünink, Dana,Strassert, Cristian A.,Doltsinis, Nikos L.,Klein, Axel
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supporting information
p. 746 - 756
(2020/03/30)
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- Sulfonamide/sulfamate switch with a series of piperazinylureido derivatives: Synthesis, kinetic and in silico evaluation as carbonic anhydrase isoforms I, II, IV, and IX inhibitors
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We report here a thorough structure-activity relationship (SAR) with piperazinylureido sulfamates as inhibitors of human (h) carbonic anhydrase (CA, EC 4.2.1.1). A SAR investigation over the structure of reported anti-cancer zinc-binder CAIs such as SLC-0
- Nocentini, Alessio,Moi, Davide,Deplano, Alessandro,Osman, Sameh M.,AlOthman, Zeid A.,Balboni, Gianfranco,Supuran, Claudiu T.,Onnis, Valentina
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- Synthesis and biological evaluation of (3/4-(pyrimidin-2-ylamino)benzoyl)-based hydrazine-1-carboxamide/carbothioamide derivatives as novel RXRα antagonists
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Abnormal alterations in the expression and biological function of retinoid X receptor alpha (RXRα) have a key role in the development of cancer. Potential modulators of RXRα as anticancer agents are explored in growing numbers of studies. A series of (4/3-(pyrimidin-2-ylamino)benzoyl)hydrazine-1-carboxamide/carbothioamide derivatives are synthesised and evaluated for anticancer activity as RXRα antagonists in this study. Among all synthesised compounds, 6A shows strong antagonist activity (half maximal effective concentration (EC50) = 1.68 ± 0.22 μM), potent anti-proliferative activity against human cancer cell lines HepG2 and A549 cells (50% inhibition of cell viability (IC50) values 50 values > 100 μM). Further bioassays indicate that 6A inhibits 9-cis-RA-induced activity in a dose-dependent manner, and selectively binds to RXRα-=LΒD with submicromolar affinity (Kd = 1.20 × 10?7 M). 6A induces time-and dose-dependent cleavage of poly ADP-ribose polymerase, and significantly stimulates caspase-3 activity, leading to RXRα-dependent apoptosis. Finally, molecular docking studies predict the binding modes for RXRα-LBD and 6A.
- Chen, Xiaohui,Fang, Meijuan,Guo, Kaiqiang,Liu, Jie,Liu, Weihao,Qin, Jingbo,Tang, Bowen,Wu, Chunxiao,Wu, Tong,Wu, Zhen,Xu, Jianwen,Zhou, Hu
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p. 880 - 896
(2020/04/07)
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- Microwave-Assisted Synthesis of Fluorescent Pyrido[2,3-b]indolizines from Alkylpyridinium Salts and Enaminones
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Pyridinium ylides are well recognized as dipoles for cycloaddition reactions. In its turn, the microwave-assisted interaction of N-(cyanomethyl)-2-alkylpyridinium salts with enaminones unexpectedly proceeds as a domino sequence of cycloisomerization and cyclocondensation reactions, instead of a 1,3-dipolar cycloaddition. The reaction takes place in the presence of sodium acetate as base and employs benign solvents. The optical properties of the resulting pyrido[2,3-b]indolizines were studied, showing green light emission with high fluorescence quantum yields.
- Festa, Alexey A.,Rybakov, Victor B.,Sokolova, Ekaterina A.,Subramani, Karthikeyan,Varlamov, Alexey V.,Voskressensky, Leonid G.,van der Eycken, Erik V.
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- Multi-substituted pyrrole derivative and preparation method thereof
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The invention discloses a multi-substituted pyrrole derivative and a preparation method thereof, and relates to the field of organic synthesis. According to the preparation method, diazonium or phenylhydrazone reacts with amino substituted unsaturated car
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Paragraph 0029
(2020/02/27)
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- Trifluoromethyl-substituted dihydrofuranamine compound, and preparation method and application thereof
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The invention discloses a trifluoromethyl-substituted dihydrofuranamine compound, and a preparation method and an application thereof. The method comprises the steps: under the condition of inert gasprotection, mixing a compound A, a compound B, copper ch
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Paragraph 0041-0043
(2020/04/06)
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- 1,8-NAPHTHYRIDINONE COMPOUNDS AND USES THEREOF
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1,8-naphthyridinone compounds as modulators of an adenosine receptor are provided. The compounds may find use as therapeutic agents for the treatment of diseases mediated through a G-protein-coupled receptor signaling pathway and may find particular use i
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Paragraph 0144-0145
(2020/07/31)
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- Synthesis and in-vitro anti-proliferative evaluation of some pyrazolo[1,5-a]pyrimidines as novel larotrectinib analogs
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A series of 2-phenyl-7-(aryl)pyrazolo[1,5-a]pyrimidine-3-carbonitriles 11a–j and 2-phenyl-7-(aryl)pyrazolo[1,5-a]pyrimidine-3,6-dicarbonitriles 16a–c was synthesized by the reaction of 5-amino-3-phenyl-1H-pyrazole-4-carbonitrile (5) with 3-(dimethylamino)
- Attia, Mohamed H.,Elrazaz, Eman Z.,El-Emam, Soad Z.,Taher, Azza T.,Abdel-Aziz, Hatem A.,Abouzid, Khaled A.M.
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- Synthesis, in vitro, and in vivo (Zebra fish) antitubercular activity of 7,8-dihydroquinolin-5(6H)-ylidenehydrazinecarbothioamides
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We, herein, describe the synthesis of a series of novel aryl tethered 7,8-dihydroquinolin-5(6H)-ylidenehydrazinecarbothioamides 4a–v, which showed in vitro and in vivo antimycobacterial activity against Mycobacterium tuberculosis (Mtb) H37Rv. The intermed
- Kantevari, Srinivas,Krishna, Vagolu Siva,Marvadi, Sandeep kumar,Sridhar, Balasubramanian,Srilakshmi Reshma, Rudraraju,Sriram, Dharmarajan,Surineni, Goverdhan
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- Aromatic ketone compound and organic light-emitting device thereof
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The invention provides an aromatic ketone compound and an organic light-emitting device. thereof, wherein the aromatic ketone compound has the structure (I) shown, in a formula shown in the description . X1 And X2 The lines are the s
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Paragraph 0101-0103
(2020/03/12)
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- Copper-catalyzed carbene insertion and ester migration for the synthesis of polysubstituted pyrroles
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Copper-catalyzed carbene insertion/ester migration/cyclization of enaminones and α-diazo compounds occurred efficiently to afford 2-ester polysubstituted pyrroles under mild conditions in moderate-to-good yields. Substituent functionality was well tolerated and13C-labelled experiments demonstrated 1,2-ester migration during the reaction.
- Li, Mingrui,Sun, Yiming,Xie, Yuxing,Yu, Yang,Huang, Fei,Huang, He
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supporting information
p. 11050 - 11053
(2020/10/05)
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- Design, synthesis, and biological evaluation of triazolyl- and triazinyl-quinazolinediones as potential antitumor agents
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Novel 6(3-1H-1,2,4-triazol-1-yl)-3-phenylquinazoline-2,4(1H,3H)-diones (7a-e) were synthesized from different enaminones (6a-e) with 6-hydrazinyl-3-phenylquinazoline-2,4(1H,3H)-dione. 2,6(4-2-Substituted-1,3,5-triazin-1(2H)-yl)-3-phenylquinazoline-2,4(1H,3H)-diones (8a-k) were synthesized from the reaction of 1-(2,4-dioxo-3-phenyl-1,2,3,4-tetrahydroquinazolin-6-yl)thiourea, urea, or guanidine (3a-c) with enaminones (6a-e), and a series from 3-substituted-2-imino-1,3,5-triazin-1(2H)-yl-sulfonyl-phenyl-1-methylquinazoline-2,4(1H,3H)-dione (12a-j) were obtained from the reaction of N-(diaminomethylene)-4-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzenesulfonamide (11) with the enaminone (6a-j). The antitumor activity of the synthesized compounds was evaluated against two human cell lines: human colon carcinoma HCT116 and human hepatocellular carcinoma HEP-G2. Some of the tested compounds showed significant potency compared to the reference drug staurosporin.
- Al-Romaizan, Abeer N.,Ahmed, Nesreen S.,Elfeky, Sherin M.
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- Rhodium-catalyzed C–H activation/cyclization of enaminones with sulfoxonium ylides toward polysubstituted naphthalenes
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A rhodium-catalyzed ortho-C–H functionalization and annulation between enaminones and sulfoxonium ylides was developed, affording a series of multi-substituted naphthalenes in good to moderate yields with excellent functional group compatibility. The proc
- Wang, Zhenlian,Xu, Huang
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supporting information
p. 664 - 667
(2019/02/06)
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- 1,8-NAPHTHYRIDINONE COMPOUNDS AND USES THEREOF
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1,8-naphthyridinone compounds as modulators of an adenosine receptor are provided. The compounds may find use as therapeutic agents for the treatment of diseases mediated through a G-protein-coupled receptor signaling pathway and may find particular use in oncology.
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Paragraph 0026; 0027
(2019/02/05)
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- COMPOUNDS AND METHODS FOR HEMATOPOIETIC REGENERATION
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The invention relates to compounds that promote hematopoietic regeneration. The invention further relates to methods of promoting hematopoietic regeneration using the novel compounds of the invention.
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Page/Page column 39-40
(2019/06/17)
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- The use of enaminones and enamines as effective synthons for MSA-catalyzed regioselective synthesis of 1,3,4-tri- And 1,3,4,5-tetrasubstituted pyrazoles
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In the present work, an efficient regioselective synthesis of 1,3,4-tri- and 1,3,4,5-tetrasubstituted pyrazoles via a methanesulfonic acid (MSA)-catalyzed reaction of hydrazones with enaminones or enamines is reported. Mechanistically, the formation of the title compounds involves the [2+3] cycloaddition of hydrazones with enaminones or enamines followed by aromatization with acid and oxygen. This convenient method under mild conditions with various hydrazones, enaminones, and enamines was well-tolerated to afford products in good to excellent yields. Compared with the literature methods, this strategy has advantages such as materials that are available economically, metal-free catalysis, excellent regioselectivity, and high efficiency.
- Duan, Liancheng,Zhou, Hui,Gu, Yucheng,Gong, Ping,Qin, Mingze
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supporting information
p. 16131 - 16137
(2019/11/03)
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- A catalyst-free four-component domino reaction for the synthesis of functionalized 3-acyl-1,5-benzodiazepines
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Various functional 3-acyl-1,5-benzodiazepines containing carboxyl, ester and acyl groups at the 2-position were synthesized via an efficient, sustainable and catalyst-free domino reaction. During the synthesis process, one new cycle and four new bonds (on
- Sun, Yue-Wei,Bei, Yue-Ming,Wang, Lan-Zhi
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p. 930 - 938
(2019/01/30)
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- Harnessing Stereospecific Z-Enamides through Silver-Free Cp?Rh(III) Catalysis by Using Isoxazoles as Masked Electrophiles
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The stereospecific synthesis of Z-enamides is described in this paper. For the first time, isoxazoles have been employed as electrophiles in C-H functionalization to afford thermodynamically less stable Z-enamides utilizing salicylaldehydes in an atom- and step-economic fashion. The stereochemistry of enamides might originate from the relative disposition of atoms present in isoxazole and the intramolecular hydrogen bonding. The reaction showed excellent scope as several structurally and electronically diverse salicylaldehydes and isoxazoles reacted efficiently.
- Debbarma, Suvankar,Bera, Sourav Sekhar,Maji, Modhu Sudan
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supporting information
p. 835 - 839
(2019/01/26)
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- [3+2] Anionic Cycloaddition of Isocyanides to Acyclic Enamines and Enaminones: A New, Simple, and Convenient Method for the Synthesis of 2,4-Disubstituted Pyrroles
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We herein demonstrate a new approach for the synthesis of 2,4-disubstituted pyrroles by [3+2] cycloaddition reaction of isocyanides to the activated double bond of various enamines and enaminones. This process paved the way for the synthesis a series of 2,4-disubstituted pyrroles, which are known to be intermediates in the synthesis of biologically active compounds, in good to excellent yields from simple and commercially available starting materials. The process is carried out efficiently using a strong base, tBuOK, at low temperatures (0 °C). The described method is simple, proceeds in one step, does not require additional catalysts and hence, has a wide scope.
- Bakulev, Vasiliy A.,Efimov, Ilya V.,Luque, Rafael,Matveeva, Maria D.,Voskressensky, Leonid G.
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supporting information
(2020/02/27)
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- Synthesis of Functionalized α-Vinyl Aldehydes from Enaminones
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An efficient RhII-catalyzed synthesis of functionalized α-vinyl aldehydes with high E/Z stereoselectivity was developed. The reaction mediates the cyclopropanation of enaminones with vinyl carbenoids that are generated from cyclopropenes in situ to give the aminocyclopropane intermediates. Selective C?C bond cleavage of the cyclopropane intermediates leads to formation of α-vinyl aldehyde derivatives with high E/Z selectivity. This method proceeds at room temperature under very mild reaction conditions and works with a broad substrate scope.
- Chen, Jie,Guo, Pan,Zhang, Jianguo,Rong, Jiaxin,Sun, Wangbin,Jiang, Yaojia,Loh, Teck-Peng
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supporting information
p. 12674 - 12679
(2019/08/07)
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- Highly Site-Selective Metal-Free C-H Acyloxylation of Stable Enamines
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A highly site-selective acyloxylation of stable enamines with PhI(OAc)2 under metal-free conditions to afford (E)-vinyl acetate derivatives in good to excellent yields is described. Depending on the judicious choice of the solvent system, either the α- or β-site-selective product could be obtained with high selectivity. For the α-site-selective product, the rearranged amide compound is obtained as the major product. This reaction proceeds under mild reaction conditions (room temperature, metal-free, and open-flask) and features a broad substrate scope.
- Wang, Fei,Sun, Wangbing,Wang, Yixin,Jiang, Yaojia,Loh, Teck-Peng
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supporting information
p. 1256 - 1260
(2018/02/23)
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- Synthesis of Polyaromatic Rings: Rh(III)-Catalyzed [5 + 1] Annulation of Enaminones with Vinyl Esters through C-H Bond Functionalization
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An expedient [5 + 1] annulation method via Rh(III)-catalyzed C-H bond functionalization of enaminones to synthesize polyaromatic rings is described. The reaction tolerates a broad range of functional groups and offers a new entry to construct polycyclic a
- Liang, Gaohui,Rong, Jiaxin,Sun, Wangbin,Chen, Gengjia,Jiang, Yaojia,Loh, Teck-Peng
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supporting information
(2018/11/23)
-
- Synthesis of Polyaromatic Rings: Rh(III)-Catalyzed [5 + 1] Annulation of Enaminones with Vinyl Esters through C-H Bond Functionalization
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An expedient [5 + 1] annulation method via Rh(III)-catalyzed C-H bond functionalization of enaminones to synthesize polyaromatic rings is described. The reaction tolerates a broad range of functional groups and offers a new entry to construct polycyclic a
- Liang, Gaohui,Rong, Jiaxin,Sun, Wangbin,Chen, Gengjia,Jiang, Yaojia,Loh, Teck-Peng
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supporting information
p. 7326 - 7331
(2018/11/25)
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- Rh(III)-Catalyzed Enaminone-Directed C-H Coupling with α-Diazo-α-phosphonoacetate for Reactivity Discovery: Fluoride-Mediated Dephosphonation for C-C Coupling Reactions
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Rh(III)-catalyzed enaminone-directed C-H coupling with α-diazo-α-phosphonoacetate has been used for the identification of fluoride-mediated dephosphonation C-C coupling reactivity for the synthesis of 4-hydroxy-1-naphthoates. Intermolecular C-C coupling of α-phosphonoacetate and benzaldehyde for (E)-selective α,β-unsaturated ester synthesis has also been achieved.
- Song, Chao,Yang, Chen,Zeng, Hua,Zhang, Wenjing,Guo, Shan,Zhu, Jin
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supporting information
p. 3819 - 3823
(2018/07/22)
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- 3-Formylpyrazolo[1,5- a]pyrimidines as Key Intermediates for the Preparation of Functional Fluorophores
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A one-pot route for the regioselective synthesis of 3-formylpyrazolo[1,5-a]pyrimidines 4a-k in good yields through a microwave-assisted process is provided. The synthesis proceeds via a cyclocondensation reaction between β-enaminones 1 with NH-3-aminopyrazoles 2, followed by formylation with an iminium salt moiety (Vilsmeyer-Haack reagent). These N-heteroaryl aldehydes 4 were successfully used as strategic intermediates for the preparation of novel functional fluorophores with yields up to 98%. The structures of the products obtained and regioselectivity of the reactions were determined on the basis of NMR measurements and X-ray diffraction analysis. Since pyrazolo[1,5-a]pyrimidines (PPs) 3 have shown an important fluorescence, photophysical properties of four 2-methylderivatives substituted at position 7 with different acceptor (A) or donor (D) groups were investigated. The compounds evaluated exhibited large Stokes shift in different solvents, but only the substituted p-methoxyphenyl (4-An) showed a strong fluorescence intensity with quantum yields up to 44% due to its greater ICT. Therefore, hybrid systems based on pyrazolo[1,5-a]pyrimidines could be used as fluorescent probes to detect biologically or environmentally relevant species.
- Castillo, Juan-Carlos,Tigreros, Alexis,Portilla, Jaime
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p. 10887 - 10897
(2018/08/11)
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- Metal-free TBAI-catalyzed oxidative Csp3–S bond formation through Csp2–Csp2 bond and S–N bond cleavage: A new route to β-keto-Sulfones
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A novel TBAI-catalyzed radical sulfonylation of readily available N,N-dimethylenaminones with sulfonylhydrazides to afford functionalized β-keto-sulfones has been developed. Various functional groups were tolerated well under the present oxidative conditions and the corresponding β-keto-sulfone compounds were obtained in moderate to good yields. Importantly, this transformation offered the first protocol for Csp3–S bond formation by oxidative Csp2–Csp2 bond cleavage in one step.
- Tang, Yucai,Chen, Ying,Liu, Hui,Guo, Min
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supporting information
p. 3703 - 3705
(2018/09/14)
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- Synthesizing method of beta-keto sulfone compound
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The invention discloses a synthesizing method of a beta-keto sulfone compound. The synthesizing method includes: mixing a compound I as shown in formula I and a compound II as shown in formula II withan oxidizing agent to obtain mixed liquid, and adding a copper catalyst into the mixed liquid by three times; sequentially subjecting the mixture obtained after the reaction to cation exchange membrane processing and post-processing to obtain the beta-keto sulfone compound as shown in formula III. The synthesizing method has the advantages that the compound I is used as the raw material, the rawmaterial is simple and easy to obtain, the synthesizing route is simple, side reaction is reduced, and high product purity and yield are achieved; the used copper catalyst is cheap and has high specificity to the reaction of the method, the copper catalyst is added by three times and coordinated with the other raw materials, the mixture obtained after the reaction is sequentially subjected to cation exchange membrane processing and post-processing, and the problem that a metal catalyst is hard to separate in the prior art can be well solved.
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Paragraph 0044; 0046
(2018/09/08)
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- COMPOUND OF 5-HYDROXYL-1,7-NAPHTHYRIDINE SUBSTITUTED BY ARYL OR HETEROARYL, PREPARATION METHOD THEREOF AND PHARMACEUTICAL USE THEREOF
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Disclosed are a compound of the following formula (I) or a pharmaceutically acceptable salt thereof, a preparation method thereof, pharmaceutical compositions and uses thereof in the preparation of a medicine for inhibiting HIF prolyl hydroxylase or a medicine for promoting the generation of endogenous EPO, wherein in the formula (I), R1 and R2 are each independently hydrogen; R3 is hydrogen or C1-3 alkyl; and Ar is an aromatic ring or an heteroaromatic ring selected from a naphthalene ring, a pyridine ring, a thiophene ring, a furan ring and a substituted benzene ring.
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Paragraph 0175
(2018/03/25)
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