- Antiprotozoal activity of bicyclic diamines with a N-methylpiperazinyl group at the bridgehead atom
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ω-Aminoacyl and -alkyl derivatives of 4-(4-methylpiperazin-1-yl) bicyclo[2.2.2]octan-2-amines and of 5-(4-methylpiperazin-1-yl)-2-azabicyclo[3.2. 2]nonanes were prepared and their activities were examined in vitro against the multiresistant K1 strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900). Some of the newly synthesized compounds showed very promising antiprotozoal activity and selectivity. A few of the alkylamino-2-azabicyclo[3.2.2]nonanes exhibited high antiplasmodial activity, whereas a single bicyclo[2.2.2]octane derivative was the most potent antitrypanosomal compound. The results of the newly synthesized compounds were compared with the activities of already synthesized compounds and of drugs in use. Structure-activity relationships were discussed.
- Faist, Johanna,Seebacher, Werner,Kaiser, Marcel,Brun, Reto,Saf, Robert,Weis, Robert
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Read Online
- Novel selective and sensitive optical chemosensor based on phenylfluorone derivative for detection of Ge(IV) ion in aqueous solution
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A water soluble chemosensor for Ge4+ ion based on fluorone derivative containing 3,4?bis(2?(diethylamino)?2?oxoethoxy)phenyl (R8) has been synthesized. The binding abilities between R8 and 10 equiv. of Na+, K+, Ca2+, Fe2+, Cu2+, Cd2+, Hg2+, Pb2+, Al3+, Cr3+, Fe3+ and Ge4+ ions in 1% v/v EtOH-water (tris-buffer pH 7.0) were studied using UV–vis and fluorescence spectrophotometry. When observed by naked-eyes, the color of R8 changed from yellow-orange to pink and the fluorescent color changed from green to non-fluorescence when complexed with Ge4+ ion. The spectral analysis showed that UV–vis absorption and fluorescence emission intensity of R8 decreased dramatically when Ge4+ ion was added comparing with other ions. To explain this behavior, the quantum calculation was performed using the hybrid density functional at B3LYP /LanL2DZ level of theory. The calculated orbital energies indicated that the decreasing of UV–vis absorption and the quenching of fluorescence were due to the complexation induced metal to ligand charge transfer. The association constants (Ka) of R8-Ge4+ complexes calculated from Benesi–Hildebrand equation was 6.21 × 105 M?1. The UV–vis detection limit for Ge4+ was 4.40 × 10?7 M which was three orders of magnitude lower than those of Al3+, Cd2+, Cu2+ and Na+ ion.
- Keawwangchai, Somchai,Morakot, Nongnit,Keawwangchai, Tasawan
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Read Online
- Prodrugs of scutellarin: Ethyl, benzyl and N,N-diethylglycolamide ester synthesis, physicochemical properties, intestinal metabolism and oral bioavailability in the rats
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In an effort to enhance the oral bioavailability of scutellarin, ethyl, benzyl and N,N-diethylglycolamide ester of scutellarin were synthesized. The hydrolysis of the prodrugs follows first-order kinetics in aqueous solution, and produced a V-shaped pH profile. The N,N-diethylglycolamide ester is highly susceptible to enzymatic hydrolysis in human plasma (t1/2 ≈ 7 min) with a high stability in aqueous solution (t1/2 ≈ 16 day, pH 4.2). Compared with the solubility of scutellarin, the solubility of glycolamide ester was about ten times in pH 4.0 buffer, and about thirty five times in water. Its apparent partition coefficient increased significantly from -2.56 to 1.48. Glycolamide ester of scutellarin was chosen to investigate the intestinal metabolism and in vivo bioavailability. Degradation studies in the intestinal tract content and homogenates indicated intestinal metabolism before absorption was a crucial obstacle for the prodrug. N,N-Diethylglycolamide ester can be protected from the degradation in the intestinal lumen by an emulsion. A significant increase in the plasma AUC and Cmax of the prodrug emulsion was observed in rats, compared with that of the scutellarin-cyclodextrin complex (P 0.01). The emulsion of N,N-diethylglycolamide ester produces a 1.58-fold enhancement in apparent bioavailability and 1.4-fold increase in the absolute bioavailability compared to the scutallarin-cyclodextrin complex.
- Cao, Feng,Guo, Jian-Xin,Ping, Qi-Neng,Liao, Zheng-Gen
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Read Online
- Preparation method of N,N-diethyl chloroacetamide
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The invention relates to a preparation method of N,N-diethyl chloroacetamide, which comprises the steps of adding 423+/-2 parts of dichloromethane into a reaction kettle, adding 90+/-0.5 parts of diethylamine, dropwisely adding 69.7+/-0.5 parts of chloroacetyl chloride into the reaction kettle under the temperature control condition of 5+/-5 DEG C, keeping the temperature at 5+/-5 DEG C, stirringfor 180+/-10 minutes, and adding 128.3+/-2 parts of water into the reaction kettle, stirring, standing for layering, taking an organic layer, adding 62.3+/-1 parts of water and 23.2+/-0.5 parts of sodium chloride, stirring, standing for layering, taking the organic layer, recovering dichloromethane, and discharging to obtain the product. The method for preparing N,N-diethyl chloroacetamide is simple and convenient to operate and high in yield, and the prepared finished product is high in purity and low in content of related substances.
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Paragraph 0052; 0055-0065
(2021/03/13)
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- De novo Design of SARS-CoV-2 Main Protease Inhibitors
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The COVID-19 pandemic prompted many scientists to investigate remedies against SARS-CoV-2 and related viruses that are likely to appear in the future. As the main protease of the virus, M Pro, is highly conserved among coronaviruses, it has emerged as a prime target for developing inhibitors. Using a combination of virtual screening and molecular modeling, we identified small molecules that were easily accessible and could be quickly diversified. Biochemical assays confirmed a class of pyridones as low micromolar noncovalent inhibitors of the viral main protease.
- Dovala, Dustin,Fischer, Christian,Nomura, Daniel K.,Peitsinis, Zisis,Spradlin, Jessica N.,Trauner, Dirk,Yang, Chao,Zhang, Yingkai,Rühmann, Klaus-Peter,Vep?ek, Nynke A.
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supporting information
(2021/10/16)
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- Palladium-Catalyzed β-C(sp3)-H Arylation of Aliphatic Ketones Enabled by a Transient Directing Group
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The direct arylation of aliphatic ketones has been developed via Pd-catalyzed β-C(sp3)-H bond functionalization with 2-(aminooxy)-N,N-dimethylacetamide as a novel transient directing group (TDG), which showed remarkable directing ability to generate arylated products in moderate to good yields. Furthermore, the reaction can tolerate abundant substrate of ketones and aryl iodides. This study expands the scope of applications for TDGs.
- Wang, Yangyang,Wu, Gaorong,Xu, Xiaobo,Pang, Binghan,Liao, Shaowen,Ji, Yafei
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p. 7296 - 7303
(2021/05/29)
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- Quinazoline derivative and application thereof as antitumor drug
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The invention belongs to the technical field of medicinal chemistry, and relates to a quinazoline derivative shown as a general formula (I), physiologically acceptable salt formed by the quinazoline derivative and inorganic or organic acid, a pharmaceutical composition containing the quinazoline derivative and the physiologically acceptable salt, and application of the quinazoline derivative and the pharmaceutical composition to preparation of drugs for treating tumor diseases, particularly drugs for treating abnormal EGFR family diseases. The compound has pharmacological properties with important values, and especially has an inhibition effect on signal transduction caused by tyrosine kinase.
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Paragraph 0102-0105
(2020/08/22)
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- Design and synthesis of some barbituric and 1,3-dimethylbarbituric acid derivatives: A non-classical scaffold for potential PARP1 inhibitors
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Six series based on barbituric acid 5a-e, 10a-d; thiobarbituric acid 6a-e, 11a-d and 1,3-dimethylbarbituric acid 7a-e, 12a-d were prepared and screened for their in vitro PARP1 inhibition. They revealed promising inhibition at nanomolar level especially compounds 5c, 7b, 7d and 7e (IC50 = 30.51, 41.60, 41.53 and 36.33 nM) with higher potency than olaparib (IC50 = 43.59 nM). Moreover, compounds 5b, 5d, 7a, 12a and 12c exhibited good comparable activity (IC50 = 65.93, 58.90, 66.57, 45.40 and 50.62 nM, respectively). Furthermore, the most active compounds 5c, 7b, 7d, 7e, 12a and 12c against PARP1 in vitro were evaluated in the BRCA1 mutated triple negative breast cancer cell line MDA-MB-436 where 5c and 12c showed higher potency compared to olaparib and result in cell cycle arrest at G2/M phase. 5c and 12c showed apoptotic effects in MDA-MB-436 and potentiated the cytotoxicity of temozolomide in A549 human lung epithelial cancer cell line. Compounds 5c and 12c represent interesting starting points towards PARP1 inhibitors.
- Eldin A. Osman, Essam,Hanafy, Noura S.,George, Riham F.,El-Moghazy, Samir M.
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- Discovery and Optimization of Glucose Uptake Inhibitors
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Aerobic glycolysis, originally identified by Warburg as a hallmark of cancer, has recently been implicated in immune cell activation and growth. Glucose, the starting material for glycolysis, is transported through the cellular membrane by a family of glucose transporters (GLUTs). Therefore, targeting glucose transporters to regulate aerobic glycolysis is an attractive approach to identify potential therapeutic agents for cancers and autoimmune diseases. Herein, we describe the discovery and optimization of a class of potent, orally bioavailable inhibitors of glucose transporters, targeting both GLUT1 and GLUT3.
- Liu, Kevin G.,Kim, Ji-In,Olszewski, Kellen,Barsotti, Anthony M.,Morris, Koi,Lamarque, Christophe,Yu, Xuemei,Gaffney, Jack,Feng, Xiao-Jiang,Patel, Jeegar P.,Poyurovsky, Masha V.
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supporting information
p. 5201 - 5211
(2020/07/10)
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- Catalytic hydrogenation of α,β-unsaturated carboxylic acid derivatives using copper(i)/N-heterocyclic carbene complexes
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A simple and air-stable copper(i)/N-heterocyclic carbene complex enables the catalytic hydrogenation of enoates and enamides, hitherto unreactive substrates employing homogeneous copper catalysis and H2 as a terminal reducing agent. This atom economic transformation replaces commonly employed hydrosilanes and can also be carried out in an asymmetric fashion.
- Zimmermann, Birte M.,Kobosil, Sarah C. K.,Teichert, Johannes F.
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supporting information
p. 2293 - 2296
(2019/02/27)
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- Design and synthesis of aminothiazolyl norfloxacin analogues as potential antimicrobial agents and their biological evaluation
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A series of aminothiazolyl norfloxacin analogues as a new type of potential antimicrobial agents were synthesized and screened for their antimicrobial activities. Most of the prepared compounds exhibited excellent inhibitory efficiencies. Especially, norfloxacin analogue II-c displayed superior antimicrobial activities against K. pneumoniae and C. albicans with MIC values of 0.005 and 0.010 mM to reference drugs, respectively. This compound not only showed broad antimicrobial spectrum, rapid bactericidal efficacy and strong enzymes inhibitory potency including DNA gyrase and chitin synthase (CHS), low toxicity against mammalian cells and no obvious propensity to trigger the development of bacterial resistance, but also exerted efficient membrane permeability, and could effectively intercalate into K. pneumoniae DNA to form a steady supramolecular complex, which might block DNA replication to exhibit their powerful antimicrobial activity. Quantum chemical studies were also performed to explain the high antimicrobial activities. Molecular docking showed that compound II-c could bind with gyrase–DNA and topoisomerase IV–DNA through hydrogen bonds and π-π stacking.
- Wang, Liang-Liang,Battini, Narsaiah,Bheemanaboina, Rammohan R.Yadav,Zhang, Shao-Lin,Zhou, Cheng-He
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p. 105 - 123
(2019/02/15)
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- Design and Synthesis of New Aryloxy-linked Dimeric 1,2,3-Triazoles via Click Chemistry Approach: Biological Evaluation and Molecular Docking Study
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A quest for more potent new antitubercular agents has prompted to design and synthesize aryloxy-linked dimeric 1,2,3-triazoles (4a–j), from azides (2a-e) and bis(prop-2-yn-1-yloxy)benzene (3a–b) on 1,3-dipolar cycloaddition reaction via copper (I)-catalyzed click chemistry approach with good to better yields. The titled compounds (4a–j) were designed using molecular hybridization approach by assembling various bioactive pharmacophoric fragments in a single molecular framework. All the synthesized compounds have been screened for their in vitro antitubercular, antifungal, and antioxidant activities against their respective strains. Among them, 4h and 4i show the highest antifungal activity, whereas compounds 4h, 4i, and 4j have revealed promising antitubercular activity against their respective strains. In addition to this, most of the synthesized compounds were found as potent antifungal and antioxidant agents. A significant network of bonded and non-bonded interactions stabilized these molecules into the active site of fungal CYP51 that is realized from the obtained well-placed docking poses and the associated thermodynamic interactions with the enzyme. The synthesized compounds have also been analyzed for absorption, distribution, metabolism, and excretion properties.
- Deshmukh, Tejshri R.,Khare, Smita P.,Krishna, Vagolu S.,Sriram, Dharmarajan,Sangshetti, Jaiprakash N.,Bhusnure, Omprakash,Khedkar, Vijay M.,Shingate, Bapurao B.
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p. 2144 - 2162
(2019/07/12)
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- Diphenylmorpholine CMPO: Synthesis, coordination behavior and extraction studies of actinides
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Carbamoylmethyl phosphine oxide (CMPO) derivatives are well known ligands in the separation and extraction of trivalent lanthanides and actinides from nuclear waste. The substituents of CMPO play major role in their selectivity and extractability. We report the synthesis and characterization of diphenylmorpholine carbamoylmethyl phosphine oxide (DPMCMPO) (L1) and diphenyl-N,N-diethyl carbamoylmethyl phosphine oxide (DPDECMPO) (L2) using various spectroscopic techniques, such as FT-IR, 1H, 13C, and 31P NMR. The molecular structure of DPMCMPO is confirmed by single crystal XRD analysis. The present study aims to understand the influence of substituents on ‘N’ atom of L1 (morpholine based DPMCMPO) and L2 (diethyl substituted DPDECMPO) ligands for the extraction of some selected actinide ions such as Th(IV), U(VI) and Am(III). The geometry and electronic structure of these ligands and their respective complexes with Th(NO3)4 and UO2(NO3)2 are further explored using density functional theory (DFT) calculations. The employed ligands (L1 and L2) show greater distribution values for Th(IV) over U(VI), due to strong “ligand-Th” complexation ability as suggested by DFT calculations.
- Das, Dhrubajyoti,Sivaramakrishna, Akella,Gopakumar, Gopinadhanpillai,Brahmmananda Rao,Sivaraman,Vijayakrishna, Kari
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p. 215 - 222
(2017/12/26)
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- 1,3-dimethyl-7-substituted-quinazolinyl-2,4-diones, and synthesis method and application thereof
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The invention discloses 1,3-dimethyl-7-substituted-quinazolinyl-2,4-diones. The structural general formula of the compounds is disclosed in the specification, wherein R1 is hydrogen or ethyl; and R2 is a benzene ring, benzene ring derivative, heterocyclic ring or aliphatic hydrocarbon. Part of compounds have favorable inhibiting activities for Candida albicans, Aspergillus flavus, Torula histolytica and Aspergillus fumigatus. The compounds have obvious inhibiting activities for chitin synthetase, have favorable antibacterial effects, and can be used for preparing drugs for anti-pathogenic microorganisms.
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Paragraph 0056; 0057; 0058; 0059; 0060; 0097; 0098
(2017/07/31)
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- Functionalized ion liquid for lithium extraction, and synthesis method thereof
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The invention discloses a functionalized ion liquid for lithium extraction, and a synthesis method thereof, and belongs to the field of chemical synthesis. According to the method, halogenated acyl chloride, disubstituted amine, 4-N,N-dimethylpyridine and potassium hexafluorophosphate are adopted as raw materials, and an amidation reaction, a salt formation reaction and an exchange reaction are performed to obtain the functionalized ion liquid having the amide group. Compared to the functionalized ion liquid and the synthesis method thereof in the prior art, the functionalized ion liquid and the synthesis method thereof of the present invention have characteristics of simple operation, industrial application, important application value, and the like.
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Paragraph 0060; 0062; 0063
(2017/08/28)
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- Interception of amide ylides with sulfonamides: Synthesis of (: E)- N -sulfonyl amidines catalyzed by Zn(OTf)2
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Through the interception of amide ylides with sulfonamides, we herein report the first general example of an intermolecular condensation reaction between sulfonamides and amides. Beyond formamides, this approach was successfully applied to a variety of lactams and linear amides, giving rise to a broad array of (E)-N-sulfonyl amidines.
- Chen, Jijun,Long, Wenhao,Fang, Shangwen,Yang, Yonggang,Wan, Xiaobing
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supporting information
p. 13256 - 13259
(2017/12/26)
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- Design, Synthesis, and Biological Evaluation of Scutellarein Derivatives Based on Scutellarin Metabolic Mechanism in Vivo
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Three series of scutellarein derivatives have been designed and synthesized based on metabolic mechanism of scutellarin (1) in vivo. Their thrombin inhibition activities were tested through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (FIB). The antioxidant activities of these target products were assessed by 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) assay and the ability to protect PC12 cells against H2O2-induced cytotoxicity, and their solubilities were evaluated by ultraviolet (UV) spectrophotometer. The results showed that the two isopropyl groups substituted derivative (18c) demonstrated stronger anticoagulant activity, better water solubility, and good antioxidant activity compared with scutellarein (2), which warrants further development of 18c as a promising agent for ischemic cerebrovascular disease treatment. Three series of scutellarein derivatives have been designed and synthesized based on metabolic mechanism of scutellarin (1) in vivo. The results of the biological evaluation showed that the two isopropyl groups substituted derivative (18c) demonstrated stronger anticoagulant activity, better water solubility, and good antioxidant activity compared with scutellarein (2), which warrants further development of 18c as a promising agent for ischemic cerebrovascular disease treatment.
- Dong, Ze-Xi,Shi, Zhi-Hao,Li, Nian-Guang,Zhang, Wei,Gu, Ting,Zhang, Peng-Xuan,Wu, Wen-Yu,Tang, Yu-Ping,Fang, Fang,Xue, Xin,Li, He-Min,Cheng, Hai-Bo,Yang, Jian-Ping,Duan, Jin-Ao
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p. 946 - 957
(2016/05/24)
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- 6-amino-4(3H)-quinazolinone derivatives and their synthesis method and use
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The invention discloses 6-amino-4(3H)-quinazolinone derivatives and their synthesis method and use and belongs to the technical field of drug synthesis. The invention also relates to a use of the 6-amino-4(3H)-quinazolinone derivatives with a general formula (I) and its synthesis method in medical science, wherein in the general formula (I), X represents (CH2)n-1, n=1 to 10 and R1, R2 and R3 represent different substituents. The invention discloses the compound structures and their synthesis method and external acetylcholinesterase inhibition activity. The 6-amino-4(3H)-quinazolinone derivatives can be further studied and developed to form novel drugs for treating Alzheimer disease.
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Paragraph 0113; 0114
(2016/12/22)
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- GLUCOSE UPTAKE INHIBITORS
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Provided hererin are compounds that modulate glucose uptake activityand are useful for treating cancer, autoimmune diseases, inflammation, infectious diseases, and metabolic diseases. In certain embodiments, the compounds modulate glucose uptake activity by modulating cellular components, including, but not limited to those related to glycolysis and known transporters/co-transporters of glucose such as GLUT1 and other GLUT family members/alternative hexose transporters. In certain embodiments, the compounds have the structure of formula I: Formula (I) wherein the variables have the values disclosed herein.
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Paragraph 0294-0295
(2017/01/09)
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- Synthesis of scutellarein derivatives to increase biological activity and water solubility
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In order to improve the biological activity and water solubility of scutellarin (1), some derivatives of its main metabolite (scutellarein) were designed and synthesized. All the compounds were tested for their thrombin inhibition activity through the analyzation of thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen (FIB). Their antioxidant activities were assessed by measuring their scavenging capacities toward 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and the ability to protect PC12 cells against H2O2-induced cytotoxicity, their water solubility were also assessed by ultraviolet (UV) spectrophotometer. The results showed that compound 8b demonstrated stronger anticoagulant and antioxidant activity, better water solubility compared with scutellarein (2), which warrants it as a promising agent for the treatment of ischemic cerebrovascular disease.
- Shi, Zhi-Hao,Li, Nian-Guang,Shi, Qian-Ping,Zhang, Wei,Dong, Ze-Xi,Tang, Yu-Ping,Zhang, Peng-Xuan,Gu, Ting,Wu, Wen-Yu,Fang, Fang,Xin-Xue,Li, He-Min,Yang, Jian-Ping,Duan, Jin-Ao
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p. 6875 - 6884
(2015/11/11)
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- Design, synthesis and evaluation of novel quinazoline-2,4-dione derivatives as chitin synthase inhibitors and antifungal agents
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A series of novel 1-methyl-3-substituted quinazoline-2,4-dione derivatives were designed, synthesized, and characterized by 1H NMR, 13C NMR and MS spectral data. Their inhibition against chitin synthase (CHS) and antifungal activities were evaluated in vitro. Results showed compounds 5b, 5c, 5e, 5f, 5j, 5k, 5l, and 5o had strong inhibitory potency against CHS. Compound 5c, which has the highest potency among these compounds, had a half-inhibition concentration (IC50) of 0.08 mmol/L, while polyoxin B as positive drug had IC50 of 0.18 mmol/L. These IC 50 values of compounds 5i, 5m, 5n, and 5s were greater than 0.75 mmol/L, which revealed that those compounds had weak inhibition activity against CHS. Moreover, most of these compounds exhibited moderate to excellent antifungal activities. In detail, to Candida albicans, the activities of compound 5g and 5k were 8-fold stronger than that of fluconazole and 4-fold stronger than that of polyoxin B; to Aspergillus flavus, the activities of 5g, 5l and 5o were16-fold stronger than that of fluconazole and 8-fold stronger than that of polyoxin B; to Cryptococcus neoformans, the minimum-inhibition- concentration (MIC) values of compounds 5c, 5d, 5e and 5l were comparable to those of fluconazole and polyoxin B. The antifungal activities of these compounds were positively correlated to their IC50 values against CHS. Furthermore, these compounds had negligible actions to bacteria. Therefore, these compounds were promising selective antifungal agents.
- Ji, Qinggang,Yang, Dan,Wang, Xin,Chen, Chunyan,Deng, Qiao,Ge, Zhiqiang,Yuan, Lvjiang,Yang, Xiaolan,Liao, Fei
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p. 3405 - 3413
(2014/06/23)
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- Synthesis of 3-(aminooxoethyl)-6-methyl-1-(thiethan-3-yl)-pyrimidine-2,4-(1H,3H)-diones
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A new approach to prepare 2-chloroacetamides has been developed, based on the reaction of chloroacetyl chloride with excess of secondary amines. Alkylation of 6-methyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione with the synthesized 2-chloroacetamides in the presence of potassium carbonate has afforded N 3-acetamido-substituted 6-methyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-diones.
- Meshcheryakova
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p. 1539 - 1542
(2015/02/19)
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- Synthesis of berberine bromide analogs containing tertiary amides of acetic acid in the 9-O-position
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9-O-Acetamide analogs of berberine bromide were prepared in 20-87% yields via reaction of the isoquinoline alkaloid berberrubine with tertiary amides of bromoacetic acid. Aminolysis did not occur during reaction of methyl-2-(9-demethoxyberberine bromide-9-yl)hydroxyacetate with secondary amines. The corresponding acid or its ethyl ester was isolated.
- Nechepurenko,Komarova,Vasil'ev,Salakhutdinov
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p. 1047 - 1053
(2013/04/23)
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- In vitro antimalarial activity, β-haematin inhibition and structure-activity relationships in a series of quinoline triazoles
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A novel series of quinoline triazole amide analogues (38-51) has been synthesized. Analogues 38-44 had a Cl substituent at the 7-position of the quinoline ring, while 45-51 had a CN substituent at this position. Compounds 40, 45 and 49 were found to be the most active in the series against the Plasmodium falciparum chloroquine-sensitive D10 strain, with IC50 values in the range of 349-1247 nM, with 40 and 45, but not 49 also exhibiting similar activity against the chloroquine-resistant K1 strain of parasite. Quinoline triazoles 40 and 44 were the most active β-haematin inhibitors, with 50% inhibitory concentrations of 14.7 and 8.9 μM respectively. In vitro antimalarial activity of the 7-Cl bearing analogues 38-44 exhibited a strong linear dependence of log(1/IC50) on log P. Thus, the more lipophilic, the more active it was found be. The 7-CN series 45-51 showed no such dependence. The resistance index (IC50 K1/IC50 D10) also exhibited a linear dependence on log P, with a substantially steeper slope in the case of the 7-Cl series. The findings demonstrate the feasibility of producing hydrophilic analogues with strong activity and low cross-resistance with chloroquine.
- Joshi, Mukesh C.,Wicht, Kathryn J.,Taylor, Dale,Hunter, Roger,Smith, Peter J.,Egan, Timothy J.
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p. 338 - 347
(2013/10/21)
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- 1-(Carbamoylmethyl)-3H-indolium squaraine dyes: Synthesis, spectra, photo-stability and association with BSA
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Novel, squarylium dyes containing 1-(alkylcarbamoylmethyl)-2,3,3-trimethyl- 3H-indolium groups were synthesized and their UV/Vis and fluorescence spectra, aggregation, photo-stability and association with bovine serum albumin were studied. The absorption and emission max wavelengths of the dyes in different solvents were in the range 619-653?nm. Compared to a typical ethyl squarylium dye, the introduction of alkylcarbamoylmethyl groups reduced aggregation and improved molar extinction coefficient, fluorescence quantum yield and photo-stability in water. Moreover, the fluorescence intensity of the dyes increased upon the addition of BSA in pH 7.0 phosphate buffer solution. An excellent linear relationship (r2?=?0.9982) was obtained between fluorescence intensity and bovine serum albumin concentration.
- Wang, Bingshuai,Fan, Jiangli,Sun, Shiguo,Wang, Li,Song, Bo,Peng, Xiaojun
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experimental part
p. 43 - 50
(2010/11/02)
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- Bis(dialkylaminethiocarbonyl)disulfides as potent and selective monoglyceride lipase inhibitors
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Monoglyceride lipase (MGL) inhibition may offer an approach in treating diseases in which higher 2-arachidonoyglycerol activity would be beneficial. We report here the synthesis and pharmacological evaluation of bis(dialkylaminethiocarbonyl)disulfide derivatives as irreversible MGL inhibitors. Inhibition occurs through interactions with MGL C208 and C242 residues, and these derivatives exhibit high inhibition selectivity over fatty acid amide hydrolase, another endocannabinoid-hydrolyzing enzyme. 2009 American Chemical Society.
- Kapanda, Coco N.,Muccioli, Giulio G.,Labar, Geoffray,Poupaert, Jacques H.,Lambert, Didier M.
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supporting information; experimental part
p. 7310 - 7314
(2010/07/14)
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- Synthesis, pharmacology and?molecular modeling of?N-substituted 2-phenyl-indoles and?benzimidazoles as?potent GABAA agonists
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Among the known non-benzodiazepine hypnotic drugs, Zolpidem (1a), Indiplon (2a) and Zaleplon (2b) have shown high affinity and selectivity for the α1 subunit of the GABA-A receptor. Our group has performed pharmacophoric and ADMET-prediction studies to evaluate a virtual library of new molecules based on privileged structures. Among these, we have synthesized a library of N-substituted indoles and a library of N-substituted benzimidazoles. Afterwards, in vitro screening and in vivo spontaneous motor activity in mice has revealed molecules with good in vitro affinities for the α1 receptor and potent in vivo induction of sedation.
- Falcó, José Luis,Piqué, Maria,González, Miguel,Buira, Irma,Méndez, Eva,Terencio, Jose,Pérez, Cristina,Príncep, Marta,Palomer, Albert,Guglietta, Antonio
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p. 985 - 990
(2007/10/03)
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- Observations on the reactivity of thiyl radicals derived from 3,6-epidithiodiketopiperazine-2,5-diones and related congeners
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A range of thiyl radicals derived from the reduced form of epidithiodiketopiperazines (ETPs) act as polarity reversal catalysts for the hydrosilylation of an enol lactone but not for H-atom abstraction from a model ribose ester.
- Hilton,Motherwell,Potier,Pradet,Selwood
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p. 2239 - 2242
(2007/10/03)
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- Synthesis, spectral studies and anti-inflammatory activity of glycolamide esters of niflumic acid as potential prodrugs
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In order to reduce the gastric irritation caused by direct contract mechanism of the carboxylic acid group, a series of glycolamide esters of niflumic (CAS 4394-00-7) (1) have been prepared as biolabile prodrugs by reacting appropriate 2-chloroacetamides with niflumic acid. The required 2-chloroacetamides were obtained by the condensation of chloroacetyl chloride and corresponding amine. Their structures were confirmed by UV, IR and 1H NMR spectra. Selected compounds were evaluated for anti-inflammatory activity in carrageenan induced paw oedema in rats at the doses of 45, 90 and 150 mg/kg b.w. Prodrugs showed comparable anti-inflammatory activity (67.1-79.4%) at 150 mg/kg b.w. with respect to niflumic acid (70.3%) at 45 mg/kg b.w., indicating moderate release of niflumic acid in vivo. The highest activity was observed with diethylamine (4) and pyrrolidine (9) derivatives.
- Gadad, Andanappa K.,Bhat, Shailija,Tegeli, Varsha S.,Redasani, Vivek V.
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p. 817 - 821
(2007/10/03)
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- Biphenyl-substituted quinoline derivatives
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Compounds of the formula wherein X, R1, R2, R3, R4, R5, R6, A, B, D and E are as defined herein. These compounds inhibit the action of angiotensin II and are useful, therefore, for example, as antihypertensive agents.
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- A general method for the synthesis of N,N-dialkylaminobutylamines
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A general method for the synthesis of N,N-dialkylaminobutylamines 4 from readily available chloroacetamides 6 is described.
- Seguin, Helene,Gardette, Daniel,Moreau, Marie-France,Madelmont, Jean-Claude,Gramain, Jean-Claude
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p. 4257 - 4272
(2007/10/03)
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- Indole- and benzimidazole-substituted imidazole and benzimidazole derivatives
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Novel compounds are disclosed having the formula STR1 wherein X, R1, R2, R3, R4, and R5 are substituents. These compounds inhibit the action of angiotensin II and are useful, therefore, for example, as antihypertensive agents.
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- Synthesis of Dibenzocrown Ethers with Pendent Amide Groups
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Synthetic routes to twenty six crown ether compounds with pendent amide, N-alkylamide, or N,N-dialkylamide groups are reported.The new crown ether compounds are based on sym-dibenzo-16-crown-5-oxyacetamide and sym-(propyl)-dibenzo-16-crown-5-oxyacetamide and are obtained in high yields.
- Kasprzyk, Stanislaw P.,Bartsch, Richard A.
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p. 119 - 123
(2007/10/02)
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- Equilibrium Acidities and Homolytic Bond Dissociation Energies of the Acidic C-H Bonds in N-Substituted Trimethylammonium and Pyridinium Cations
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Equilibrium acidities (pKHAs) of the cations in sixteen N-substituted trimethylammonium salts, one N-phenacylquinuclidinium salt, eight N-substituted pyridinium salts, and N-(ethoxycarbonyl)-isoquinolinium bromide, together with the oxidation potentials of their conjugate bases, have been determined in dimethyl sulfoxide (DMSO) solution.The acidifying effects of the α-trimethylammonium groups (α-Me3N+) and the α-pyridinium groups (α-PyN+) on the adjacent acidic C-H bonds in these cations were found to average about 10 and 18 pKHA units, respectively, in DMSO.The homolytic bond dissociation energies of the acidic C-H bonds in these cations, estimated by the combination of the equilibrium acidities with the oxidation potentials of their corresponding conjugate bases (ylides), show that the α-trimethylammonium groups destabilize adjacent radicals by 2-6 kcal/mol, whereas α-pyridinium groups stabilize adjacent radicals by 3-6 kcal/mol.The effects of α-pyridinium groups on the stabilization energies of the radicals derived from these cations were found to be ca. 4-10 kcal/mol smaller than those of the corresponding phenyl groups, whereas their effects on the equilibrium acidities of the cations were 5.4-13.1 pKHA units larger.The pKHA value of tetramethylammonium cation (Me4N+) was estimated by extrapolation to be about 42 in DMSO.
- Zhang, Xian-Man,Bordwell, Frederick G.,Puy, Michael Van Der,Fried, Herbert E.
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p. 3060 - 3066
(2007/10/02)
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- Heterocyclic diamides and method for improving feed utilization and lactation in ruminant animals
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Novel diamides having a nitrogen-containing heterocyclic moiety such as pyridyl are disclosed that are useful for improving feed utilization efficiency of ruminants and for improving lactation of lactating ruminants.
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- Quinolylglycinamide derivatives, the process for preparation thereof and their therapeutic application as psychotropic drugs
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The present invention relates to new quinolylglycinamide derivatives corresponding to the following general formula: STR1 The invention also relates to a process for preparing these compounds and their therapeutic application as a psychotropic agent.
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- Amide phosphorothiolate herbicides
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The present invention relates to new herbicidal phosphorothioate (phosphorodithioate) derivatives and to preparation thereof.
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- Azabicyclononanecarbodithioic acid
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Compounds of the formula EQU1 where R is an ester forming radical, salt forming radical, --SCCl3 or Y--Sx where x is an integer from 0 to 3 and Y is the radical in parentheses. The compounds accelerate vulcanization of natural and synthetic rubber and some have the property of inhibiting oxidation of rubber.
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