- Corrosion inhibition performance of a structurally well-defined 1,2,3-triazole derivative on mild steel-hydrochloric acid interface
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In the present work, a new 1,4-disubstituted-1,2,3-triazole product, named 4-[1-(4-methoxy-phenyl)-1H-[1,2,3]triazol-4-ylmethyl]-morpholine (MPTM) was successfully synthesized under click chemistry regime. The structure of the new compound that has a rigi
- Hrimla, Meryem,Bahsis, Lahoucine,Boutouil, Aziz,Laamari, My Rachid,Julve, Miguel,Stiriba, Salah-Eddine
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Read Online
- Discovery of fast-acting dual-stage antimalarial agents by profiling pyridylvinylquinoline chemical space via copper catalyzed azide-alkyne cycloadditions
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To identity fast-acting, multistage antimalarial agents, a series of pyridylvinylquinoline-triazole analogues have been synthesized via CuAAC. Most of the compounds display significant inhibitory effect on the drug-resistant malarial Dd2 strain at low submicromolar concentrations. Among the tested analogues, compound 60 is the most potent molecule with an EC50 value of 0.04 ± 0.01 μM. Our current study indicates that compound 60 is a fast-acting antimalarial compound and it demonstrates stage specific action at the trophozoite phase in the P. falciparum asexual life cycle. In addition, compound 60 is active against both early and late stage P. falciparum gametocytes. From a mechanistic perspective, compound 60 shows good activity as an inhibitor of β-hematin formation. Collectively, our findings suggest that fast-acting agent 60 targets dual life stages of the malarial parasites and warrant further investigation of pyridylvinylquinoline hybrids as new antimalarials.
- Huang, Guang,Solano, Claribel Murillo,Melendez, Joel,Yu-Alfonzo, Sabrina,Boonhok, Rachasak,Min, Hui,Miao, Jun,Chakrabarti, Debopam,Yuan, Yu
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supporting information
(2020/10/13)
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- A click chemistry approach to pleuromutilin derivatives, evaluation of anti-MRSA activity and elucidation of binding mode by surface plasmon resonance and molecular docking
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Novel series of pleuromutilin analogs containing substituted 1,2,3-triazole moieties were designed, synthesised and assessed for their in vitro antibacterial activity against Methicillin-resistant Staphylococcus aureus (MRSA). Initially, the in vitro antibacterial activities of these derivatives against 4 strains of S. aureus (MRSA ATCC 43300, ATCC 29213, AD3, and 144) were tested by the broth dilution method. Most of the synthesised pleuromutilin analogs displayed potent activities. Among them, compounds 50, 62, and 64 (MIC = 0.5～1 μg/mL) showed the most effective antibacterial activity and their anti-MRSA activity were further studied by the time-killing kinetics approach. Binding mode investigations by surface plasmon resonance (SPR) with 50S ribosome revealed that the selected compounds all showed obvious affinity for 50S ribosome (KD = 2.32 × 10?8～5.10 × 10?5 M). Subsequently, the binding of compounds 50 and 64 to the 50S ribosome was further investigated by molecular modelling. Compound 50 had a superior docking mode with 50S ribosome, and the binding free energy of compound 50 was calculated to be ?12.0 kcal/mol.
- Zhang, Zhe,Zhang, Zhao-Sheng,Wang, Xiao,Xi, Gao-Lei,Jin, Zhen,Tang, You-Zhi
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p. 2087 - 2103
(2021/12/02)
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- MONOCARBOXYLIC ACID TRANSPORTER 4 (MCT4) MODULATORS AND USES THEREOF
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Disclosed herein are compounds, compositions, and methods for modulating the monocarboxylic acid transporter 4 (MCT4) with the compounds and compositions disclosed herein. Also described are methods of treating diseases or conditions that are mediated by
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Paragraph 0248-0249
(2021/11/26)
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- BTK Inhibitors and uses thereof
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The invention discloses a bruton's tyrosine kinase (BTK) inhibitor and use thereof. Specifically, the invention provides heteroaromatic compounds or stereoisomers, geometrical isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutical compositions containing the heteroaromatic compounds; the invention also discloses use of the heteroaromatic compounds or the pharmaceutical compositions containing the heteroaromatic compounds in preparation of medicines; the medicines can be used for treating autoimmune diseases, inflammatory diseases or proliferative diseases.
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Paragraph 1368-1373; 1812-1817
(2020/05/02)
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- Diazabicyclooctane Functionalization for Inhibition of β-Lactamases from Enterobacteria
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Second-generation β-lactamase inhibitors containing a diazabicyclooctane (DBO) scaffold restore the activity of β-lactams against pathogenic bacteria, including those producing class A, C, and D enzymes that are not susceptible to first-generation inhibitors containing a β-lactam ring. Here, we report optimization of a synthetic route to access triazole-containing DBOs and biological evaluation of a series of 17 compounds for inhibition of five β-lactamases representative of enzymes found in pathogenic Gram-negative bacteria. A strong correlation (Spearman coefficient of 0.87; p = 4.7 × 10-21) was observed between the inhibition efficacy of purified β-lactamases and the potentiation of β-lactam antibacterial activity, indicating that DBO functionalization did not impair penetration. In comparison to reference DBOs, avibactam and relebactam, our compounds displayed reduced efficacy, likely due to the absence of hydrogen bonding with a conserved asparagine residue at position 132. This was partially compensated for by additional interactions involving certain triazole substituents.
- Bouchet, Flavie,Atze, Heiner,Fonvielle, Matthieu,Edoo, Zainab,Arthur, Michel,Ethève-Quelquejeu, Mélanie,Iannazzo, Laura
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supporting information
p. 5257 - 5273
(2020/06/10)
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- 1,5,7-TRISUBSTITUTED ISOQUINOLINE DERIVATIVES, PREPARATION THEREOF, AND USE THEREOF IN MEDICINES
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The present disclosure relates to 1,5,7-trisubstituted isoquinoline derivatives, their preparation and pharmaceutical use. In particular, the present disclosure discloses a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and a preparation method and use thereof. The definitions of the groups in the formula can be found in the specification and claims.
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Paragraph 0166-0167
(2020/08/30)
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- Design, synthesis and biological activities of novel pleuromutilin derivatives with a substituted triazole moiety as potent antibacterial agents
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A series of novel pleuromutilin derivatives possessing 1,2,3-triazole moieties were synthesized via click reactions under mild conditions. The in vitro antibacterial activities of these derivatives against 4 strains of S. aureus (MRSA ATCC 43300, ATCC 29213, AD 3, and 144) and 1 strain of E. coli (ATCC 25922) were tested by the broth dilution method. The majority of the synthesized derivatives displayed potent antibacterial activities against MRSA (MIC = 0.125–2 μg/mL). It was also found that most compounds had no significant inhibitory effect on the proliferation of RAW264.7 cells at the concentration of 8 μg/mL. Among these derivatives, compound 32 (～1.71 log10 CFU/g) containing dimethylamine group side chain displayed more effective than tiamulin (～0.77 log10 CFU/g) at the dose of 20 mg/kg in reducing MRSA load in thigh infected mice. Additionally, compound 32 (the survival rate was 50%) also displayed superior in vivo efficacy to that of tiamulin (the survival rate was 20%) in the mouse systemic model. Structure-activity relationship (SAR) studies resulted in compound 32 with the most potent in vitro and in vivo antibacterial activity among the series. Moreover, compound 32 was evaluated in CYP450 inhibition assay and showed moderate in vitro inhibition of CYP3A4 (IC50 = 6.148 μM).
- Zhang, Zhe,Li, Kang,Zhang, Guang-Yu,Tang, You-Zhi,Jin, Zhen
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- Design, synthesis and biological evaluation of novel pleuromutilin derivatives containing piperazine and 1,2,3-triazole linker
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A series of novel pleuromutilin derivatives containing piperazine ring, 1, 2, 3-triazoles and secondary amines on the side chain of C14 were synthesized under mild conditions via click reaction. The in vitro antibacterial activities of the synthesized derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, ATCC 29213, 144 and AD3) and one strain of Escherichia coli (ATCC 25922) were evaluated by the broth dilution method. Among these derivatives, 22–[2-(4-((4-nitrophenyl piperazine)methyl)-1,2,3-triazol-1-yl)-1-(piperazine-1-yl) ethyl-1-one] deoxy pleuromutilin (compound 59) showed the most prominent in vitro antibacterial effect against MRSA (MIC = 1 μg/mL). Furthermore, compound 59 displayed more rapid bactericidal kinetic than tiamulin time-kill studies and possessed a longer PAE than tiamulin against MRSA in vitro. In addition, in vivo antibacterial activities of compound 59 against MRSA were further evaluated employing thigh infection model. And compound 59 (-8.89 log10 CFU/mL) displayed superior activities than tiamulin. Compound 59 was further evaluated in CYP450 inhibition assay and the results showed that it exhibited low to moderate inhibitory effects on CYP1A2, CYP2E1, CYP2D6 and CYP3A4 enzymes. The PK properties of compound 59 were then measured. The half-life (t1/2), clearance rate (Cl) and the area under the plasma concentration time curve (AUC0→∞) of compound 59 were 0.74 h, 0.29 L/h/kg and 46.28 μg·h/mL, respectively.
- Zhang, Guang-Yu,Zhang, Zhe,Li, Kang,Liu, Jie,Li, Bo,Jin, Zhen,Liu, Ya-Hong,Tang, You-Zhi
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- Dioxane quinazoline and dioxane quinazoline type compound, and preparation method and application thereof
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The invention relates to a dioxane quinazoline and dioxane quinazoline type compound having a formula (I) as described in the specification or a pharmaceutically acceptable salt thereof. The inventionalso provides preparation of the compound having the formula (I) and the pharmaceutically acceptable salt and application of the compound and the pharmaceutically acceptable salt as a medicine. The medicine is used as a tyrosine kinase (such as VEGFR-2, c-MET and RET) inhibitor for treating diseases relevant to tyrosine kinases.
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Paragraph 0075-0076; 0077-0078
(2020/03/17)
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- NEW BETA-LACTAMASE INHIBITORS TARGETING GRAM NEGATIVE BACTERIA
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The present invention relates to a compound of the following formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, notably for use as β-lactamase inhibitors, notably in the treatment of a disease caused by gram negative bacteria, in particular enterobacteria, as well as pharmaceutical compositions containing such a compound and a process to prepare such a compound.
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Page/Page column 27; 29-31
(2019/07/13)
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- NEW ANTIBIOTICS TARGETING MYCOBACTERIA
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The present invention relates to a compound of the following formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, notably for use as a drug, notably in the treatment of a disease caused by mycobacteria, as well as pharmaceutical compositions containing such a compound and a process to prepare such a compound.
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Page/Page column 28-30
(2019/07/13)
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- One-pot facile synthesis, crystal structure and antifungal activity of 1,2,3-triazoles bridged with amine-amide functionalities
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A library of twenty five 1,2,3-triazoles bridged with amine-amide functionalities have been synthesized from reaction of N-substituted(prop-2-yn-1-yl)amines (2a–2e), 2-bromo-N-arylacetamides (4a–4e) and sodium azide through copper(I)-catalyzed alkyne-azide cycloaddition. The synthesized compounds were characterized by using FTIR, 1H NMR, 13C NMR, and HRMS techniques. The structures of synthesized 5a (CCDC 1569245) and 5h (CCDC 1569249) were also confirmed by X-ray crystallography. Antifungal evaluation of newly synthesized triazoles was carried out against–Candida albicans and Aspergillus niger. Biological screening of synthesized 1,2,3-triazoles revealed moderate to good antifungal activity against tested strains.
- Kaushik,Luxmi, Raj,Kumar, Mukesh,Singh, Dharmendra,Kumar, Krishan,Pahwa, Ashima
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supporting information
p. 118 - 128
(2019/01/24)
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- One-pot synthesis of substituted-amino triazole-glycosides
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This work combined three classes of compounds in the same molecule “amino triazole-glycoside” and developed a convenient method for the synthesis of this type of compound via a one-pot two step reaction. Alkylation of amine derivatives with propargyl bromide to give propargylamine was performed in the first step subsequently followed by a ‘click’ reaction with various β-azido-glycosides in the presence of CuI in aqueous solution to provide β-amino triazole-glycosides. Thirty-two examples of glycosides were obtained in moderate to good yield using this one-pot procedure.
- Sutcharitruk, Warapond,Sirion, Uthaiwan,Saeeng, Rungnapha
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- Design, synthesis,: In silico docking studies and biological evaluation of novel quinoxaline-hydrazide hydrazone-1,2,3-triazole hybrids as α-glucosidase inhibitors and antioxidants
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A new series of quinoxaline-hydrazidehydrazone-1,2,3-triazole hybrids, 14a-j, 15a-j and 16a-e, was designed, synthesized and screened for in vitro α-glucosidase and antioxidant activities. For the synthesis of the target compounds, quinoxaline hydrazides were condensed with benzaldehyde triazoles in the presence of AcOH (cat) in ethanol. The key step in the preparation of compounds 8a-j was the Cu(i)-catalyzed [3+2] cycloaddition reaction (CuAAC) with appropriate alkynes (6, 7) and azides, and 13a-j were prepared from simple aldehydes utilizing the same click reaction as the final step. Quinoxaline hydrazides (3, 3a) were synthesized from o-phenylenediamine and pyruvic acid via three-step reactions comprising cyclization, alkylation and hydrazidation. Among these hybrids, 14a (IC50 = 21.92 μg mL-1), 14b (IC50 = 22.32 μg mL-1), 14c (IC50 = 23.58 μg mL-1) and 15a (IC50 = 24.50 μg mL-1) showed good α-glucosidase inhibition compared with the standard acarbose (IC50 = 22.32 μg mL-1). Further, the scavenging abilities of the synthesized compounds as antioxidants were studied using the DPPH, H2O2, and NO methods; as per the obtained results, compounds 14a, 14b, 14c and 15a displayed good antioxidant activity. Docking studies of the active compounds and acarbose as a standard with α-glucosidase (PDB ID: 2ZEO) were performed to determine the molecular interactions between the inhibitors and the active site of the enzyme. Better binding energies of the active compounds than of the standard acarbose were observed. Therefore, our new hybrid molecules may be useful for further optimization in developing new lead molecules with both α-glucosidase inhibition and antioxidant activities.
- Settypalli, Triloknadh,Chunduri, Venkata Rao,Maddineni, Aruna Kumari,Begari, Nagaraju,Allagadda, Rajasekhar,Kotha, Peddanna,Chippada, Appa Rao
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p. 15435 - 15452
(2019/10/08)
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- Pleuromutilin derivative with 2-aminothiophenol and 1,2,3-triazole side chain, preparation and application
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The invention belongs to the field of medicinal chemistry, and particularly relates to a pleuromutilin derivative with 2-aminothiophenol and a 1,2,3-triazole side chain, preparation and application. The pleuromutilin derivative with 2-aminothiophenol and the 1,2,3-triazole side chain is a compound of a formula 2 or a pharmaceutically acceptable salt of the compound, and a solvent compound, an enantiomer, a diastereomer and a tautomer of the compound of the formula 2 or the pharmaceutically acceptable salt of the compound or a mixture of the compound of the formula 2 or the pharmaceutically acceptable salt of the compound in any ratio, and includes a racemic mixture, and the compound has good inhibition to methicillin-resistant staphylococcus aureus activity, and is especially suitable forbeing used as a novel antibacterial drug for prevention and treatment of infectious diseases caused by human or animals or methicillin-resistant staphylococcus aureus or multi-drug resistant bacteria.(Please see the specification for the formula).
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Paragraph 0101-0103
(2019/11/12)
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- Pleuromutilin derivative containing piperazine and 1, 2, 3-triazole secondary amine side chains, and preparation and applications thereof
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The invention belongs to the field of pharmaceutical chemistry, and especially relates to a pleuromutilin derivative containing piperazine and 1, 2, 3-triazole secondary amine side chains, and preparation and applications thereof. The pleuromutilin derivative containing piperazine and 1, 2, 3-triazole secondary amine side chains is a compound represented by formula 2 or a pharmaceutically acceptable salt of the compound, or a solvate, an enantiomer, a diastereomer, a tautomer of the compound represented by formula 2 or the pharmaceutically acceptable salt of the compound, or a mixture of the above substances at a random ratio comprising a racemic mixture. The compound possesses excellent in vitro antibacterial activity, the cost is lower than that of valnemulin and retapamulin, so that thecompound is especially suitable to be taken as a novel antibacterial drug in prevention and treatment of human or animal bacterial infectious diseases, especially infectious diseases caused by medicine resistant Staphylococcus aureus.
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Paragraph 0104-0106
(2019/11/29)
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- Balancing Physicochemical Properties of Phenylthiazole Compounds with Antibacterial Potency by Modifying the Lipophilic Side Chain
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Bacterial resistance to antibiotics is presently one of the most pressing healthcare challenges and necessitates the discovery of new antibacterials with unique chemical scaffolds. However, the determination of the optimal balance between structural requirements for pharmacological action and pharmacokinetic properties of novel antibacterial compounds is a significant challenge in drug development. The incorporation of lipophilic moieties within a compound's core structure can enhance biological activity but have a deleterious effect on drug-like properties. In this Article, the lipophilicity of alkynylphenylthiazoles, previously identified as novel antibacterial agents, was reduced by introducing cyclic amines to the lipophilic side chain. In this regard, substitution with methylpiperidine (compounds 14-16) and thiomorpholine (compound 19) substituents significantly enhanced the aqueous solubility profile of the new compounds more than 150-fold compared to the first-generation lead compound 1b. Consequently, the pharmacokinetic profile of compound 15 was significantly enhanced with a notable improvement in both half-life and the time the compound's plasma concentration remained above its minimum inhibitory concentration (MIC) against methicillin-resistant Staphylococcus aureus (MRSA). In addition, compounds 14-16 and 19 were found to exert a bactericidal mode of action against MRSA and were not susceptible to resistance formation after 14 serial passages. Moreover, these compounds (at 2× MIC) were superior to the antibiotic vancomycin in the disruption of the mature MRSA biofilm. The modifications to the alkynylphenylthiazoles reported herein successfully improved the pharmacokinetic profile of this new series while maintaining the compounds' biological activity against MRSA.
- Abdel-Aleem, Jelan A.,Abutaleb, Nader S.,Ali, Alsagher O.,Elsebaei, Mohamed M.,Kotb, Ahmed,Mancy, Ahmed,Mayhoub, Abdelrahman S.,Mohammad, Haroon,Saad, Abdullah Y.,Seleem, Mohamed N.
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- Series of Alkynyl-Substituted Thienopyrimidines as Inhibitors of Protozoan Parasite Proliferation
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Discovery of new chemotherapeutic lead agents can be accelerated by optimizing chemotypes proven to be effective in other diseases to act against parasites. One such medicinal chemistry campaign has focused on optimizing the anilinoquinazoline drug lapatinib (1) and the alkynyl thieno[3,2-d]pyrimidine hit GW837016X (NEU-391, 3) into leads for antitrypanosome drugs. We now report the structure-activity relationship studies of 3 and its analogs against Trypanosoma brucei, which causes human African trypanosomiasis (HAT). The series was also tested against Trypanosoma cruzi, Leishmania major, and Plasmodium falciparum. In each case, potent antiparasitic hits with acceptable toxicity margins over mammalian HepG2 and NIH3T3 cell lines were identified. In a mouse model of HAT, 3 extended life of treated mice by 50%, compared to untreated controls. At the cellular level, 3 inhibited mitosis and cytokinesis in T. brucei. Thus, the alkynylthieno[3,2-d]pyrimidine chemotype is an advanced hit worthy of further optimization as a potential chemotherapeutic agent for HAT.
- Woodring, Jennifer L.,Behera, Ranjan,Sharma, Amrita,Wiedeman, Justin,Patel, Gautam,Singh, Baljinder,Guyett, Paul,Amata, Emanuele,Erath, Jessey,Roncal, Norma,Penn, Erica,Leed, Susan E.,Rodriguez, Ana,Sciotti, Richard J.,Mensa-Wilmot, Kojo,Pollastri, Michael P.
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supporting information
p. 996 - 1001
(2018/09/21)
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- Supported copper (I) catalyst from fish bone waste: An efficient, green and reusable catalyst for the click reaction toward N-substituted 1,2,3-TRIAZOLES
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An eco-efficient, green, and multi-gram procedure is presented for one-pot multicomponent synthesis of N-substituted 1,2,3-triazoles by using waste fishbone powders supported CuBr (FBPs-CuBr) as catalyst. FBPs-CuBr is found to be an efficient heterogeneous catalyst and a series of 1,2,3-triazoles are obtained in moderate to excellent yields in water under MW irradiation (70–98%). It can be separated conveniently by a simple filtration and reused at least seven consecutive runs with a slight drop in the product yields. Furthermore, the desired product still could be obtained in 80% yield when the scale of the reaction was increased to 40.0 mmol.
- Xiong, Xingquan,Tang, Zhongke,Sun, Zhaohong,Meng, Xiaoqing,Song, Sida,Quan, Zhilong
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- N-Propargylation of secondary amines directly using calcium carbide as an acetylene source
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A one-pot N-propargylation of secondary amines has been achieved by heating the amine with formaldehyde and calcium carbide in DMSO in the presence of CuCl as a catalyst. Fifteen examples of propargylic tertiary amines, 12 of which are novel, were efficiently prepared in yields of 65-84%. The advantages of the method are broad substrate scope and a simple work-up procedure.
- Fu, Rugang,Li, Zheng
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p. 341 - 345
(2017/06/19)
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- Design, synthesis, and evaluation of hinge-binder tethered 1,2,3-triazolylsalicylamide derivatives as Aurora kinase inhibitors
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A series of hinge-binder tethered 1,2,3-triazolylsalicylamide derivatives were designed, synthesized, and evaluated for the Aurora kinase inhibitory activities. The novel hinge-binder tethered 1,2,3-triazolylsalicylamide scaffold was effectively assembled by Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC). A variety of alkynes with hinge binders were used to search proper structures-binding relationship to the hinge region. The synthesized 1,2,3-triazolylsalicylamide derivatives showed significant Aurora kinase inhibitory activity. In particular, 8a inhibited Aurora A kinase with an IC50 value of 0.284 μM, whereas 8m inhibited Aurora B kinase with an IC50 value of 0.364 μM.
- Jeong, Yunkyung,Lee, Jooyeon,Ryu, Jae-Sang
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supporting information
p. 2114 - 2124
(2016/04/20)
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- Aryl alkynyl hydrocarbon compound and preparation method and application thereof
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The invention relates to an aryl alkynyl hydrocarbon compound and a medicine compound containing the compound. The compound or the medicine compound can serve as an inhibitor of Retinoid-related orphan receptor gamma t (RORyt). The invention further relates to a method for preparing the compound and the medicine compound and application thereof to mammal treatment or prevention, especially RORyt mediated inflammation of humans or autoimmune diseases.
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Paragraph 0379; 0380; 0381
(2017/02/17)
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- Copper catalysed alkynylation of tertiary amines with CaC2: Via sp3 C-H activation
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A mild and easy-to-handle protocol to produce propargylamines with a terminal alkyne through catalytic cross-coupling of tertiary amines and calcium carbide has been developed. The reaction proceeds via sp3 C-H bond activation and C-C coupling. Good to excellent yields were obtained for the corresponding propargylamines with both alkyl and aryl substitutions. The development of these functionalized propargylamines with a terminal alkyne group will offer a wider application for the synthesis of natural or pharmaceutical products due to their unique sp C-H reactivity.
- Teong, Siew Ping,Yu, Dingyi,Sum, Yin Ngai,Zhang, Yugen
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supporting information
p. 3499 - 3502
(2016/07/06)
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- RAFAMYCIN ANALOGS AND METHODS FOR MAKING SAME
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A semi-synthetic rapamycin analog with a triazole moiety or a pharmaceutically acceptable salt or prodrug thereof, is a broad-spectrum cytostatic agent and a mTOR inhibitor, and is useful in the treatment of various cancers, or tumors in organs such as kidney, liver, breast, head and neck, lung, prostate, and restenosis in coronary arteries, peripheral arteries, and arteries in the brain, immune and autoimmune diseases. Also disclosed are fungal growth-, restenosis-, post-transplant tissue rejection- and immune- and autoimmune disease-inhibiting compositions and a method of inhibiting cancer, fungal growth, restenosois, post-transplant tissue rejection, and immune and autoimmune disease in a mammal. One particular preferred application of such triazole-moiety containing rapamycin analog is in treating renal carcinoma, lung cancer, colon cancer, and breast cancers wherein potency of the drug, its half-life, tissue distribution properties, and its pharmacokinetic properties including bioavailability through oral and intravenous routes are essential to the clinical outcomes.
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Paragraph 0102
(2015/02/25)
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- Synthesis of polyfunctional triethoxysilanes by 'click silylation'
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The copper-catalyzed 'click silylation' has been exploited for the chemical modification of γ-azidopropyltriethoxysilane (AzPTES) with a wide range of terminal alkynes (1a-1v) in a one-pot operation. The novel 1,2,3-triazole-triethoxysilane derivatives (2a-2v) were synthesized by this procedure and comprehensively characterized by IR spectra, 1H and 13C NMR, and HRMS studies.
- Singh, Gurjaspreet,Mangat, Satinderpal Singh,Singh, Jandeep,Arora, Aanchal,Sharma, Ramesh K.
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supporting information
p. 903 - 909
(2015/03/03)
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- HETEROCYCLIC COMPOUNDS AND USES THEREOF
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Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.
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Paragraph 00656; 00659
(2015/04/22)
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- EPZ011989, A potent, orally-available EZH2 inhibitor with robust in vivo activity
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Inhibitors of the protein methyltransferase Enhancer of Zeste Homolog 2 (EZH2) may have significant therapeutic potential for the treatment of B cell lymphomas and other cancer indications. The ability of the scientific community to explore fully the spectrum of EZH2-associated pathobiology has been hampered by the lack of in vivo-active tool compounds for this enzyme. Here we report the discovery and characterization of EPZ011989, a potent, selective, orally bioavailable inhibitor of EZH2 with useful pharmacokinetic properties. EPZ011989 demonstrates significant tumor growth inhibition in a mouse xenograft model of human B cell lymphoma. Hence, this compound represents a powerful tool for the expanded exploration of EZH2 activity in biology.
- Campbell, John E.,Kuntz, Kevin W.,Knutson, Sarah K.,Warholic, Natalie M.,Keilhack, Heike,Wigle, Tim J.,Raimondi, Alejandra,Klaus, Christine R.,Rioux, Nathalie,Yokoi, Akira,Kawano, Satoshi,Minoshima, Yukinori,Choi, Hyeong-Wook,Porter Scott, Margaret,Waters, Nigel J.,Smith, Jesse J.,Chesworth, Richard,Moyer, Mikel P.,Copeland, Robert A.
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supporting information
p. 491 - 495
(2015/05/27)
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- Discovery of highly potent renin inhibitors potentially interacting with the S3' subsite of renin
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To exploit the S3′ subsite of renin active site for renin inhibitor design, 42 aliskiren derivatives with modified P2' portion were designed, synthesized and biologically evaluated. Some highly potent renin inhibitors (IC50 50 Combining double low line 0.9 nM) and 39 (IC50 Combining double low line 0.7 nM) were over 2.5-fold more potent than aliskiren (IC50 Combining double low line 2.3 nM). SAR analysis indicated that incorporation of polar hydrophilic moieties into the P2' portion of renin inhibitors generally enhanced the potency. Consistently with this, molecular modeling study revealed that the triazole part of 39 could provide additional interactions to the S3' subsite of renin active site. Moreover, in vivo evaluation in the double transgenic mouse hypertension model demonstrated that 39 produced greater reduction of the mean arterial blood pressure than ariskiren at the doses of 17.0 and 34.0 1/4mol/kg, respectively. Taken together, the S3' subsite of renin active site merits further consideration for renin inhibitor design.
- Sun, Xiaowei,Wen, Xiaoan,Chen, Yan-Yan,Shi, Chen,Gao, Chengzhe,Wu, Yong,Wang, Li-Jun,Yang, Xiu-Hong,Sun, Hongbin
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supporting information
p. 269 - 288
(2015/09/21)
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- HETEROCYCLIC COMPOUNDS FOR USE IN THE TREATMENT OF PI3K-GAMMA MEDIATED DISORDERS
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Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.
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Paragraph 001312
(2015/11/10)
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- Alkoxyboration: Ring-closing addition of B-O σ bonds across alkynes
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For nearly 70 years, the addition of boron-X σ bonds to carbon-carbon multiple bonds has been employed in the preparation of organoboron reagents. However, the significantly higher strength of boron-oxygen bonds has thus far precluded their activation for addition, preventing a direct route to access a potentially valuable class of oxygen-containing organoboron reagents for divergent synthesis. We herein report the realization of an alkoxyboration reaction, the addition of boron-oxygen σ bonds to alkynes. Functionalized O-heterocyclic boronic acid derivatives are produced using this transformation, which is mild and exhibits broad functional group compatibility. Our results demonstrate activation of this boron-O σ bond using a gold catalysis strategy that is fundamentally different from that used previously for other boron addition reactions.
- Hirner, Joshua J.,Faizi, Darius J.,Blum, Suzanne A.
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supporting information
p. 4740 - 4745
(2014/04/17)
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- A 1,3-amino group migration route to form acrylamidines
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A novel 1,3-amino group migration strategy for the synthesis of acrylamidines is presented. Cu(i) catalyzed reaction of N,N-disubstituted propargylamine with tosylazide generates a highly reactive ketenimine intermediate which is trapped by a tethered amino group leading to the rearrangement reaction.
- Chauhan, Dinesh Pratapsinh,Varma, Sreejith Jayasree,Vijeta, Arjun,Banerjee, Pallavi,Talukdar, Pinaki
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supporting information
p. 323 - 325
(2014/01/06)
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- Design and synthesis of novel 2H-chromen-2-one derivatives bearing 1,2,3-triazole moiety as lead antimicrobials
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A series of novel 2H-chromen-2-one derivatives decorated with 1,2,3-triazole moiety were designed and synthesized using the click reaction of azidoalkyloxy-2H-chromen-2-ones with different propargylamines. Propargylamines were obtained by alkylation of various heterocyclic amines with propargyl bromide. Newly synthesized compounds and intermediates were evaluated for their antifungal activity against four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus and Candida albicans). Antibacterial studies were also carried out against three Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis and Staphylococcus epidermis) and four Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi and Klebsiella pneumoniae). In vitro, bioassay results showed that all the synthesized compounds exhibited excellent activity against fungal strains Aspergillus fumigatus, Aspergillus flavus and Candida albicans. Interestingly, all the compounds have shown even superior activity than the reference drug miconazole against Aspergillus fumigatus. Morpholine and N-acetyl piperazine containing compounds 10c and 10e have shown promising activity against various bacterial strains. Compound 10e was found to be most active against Pseudomonas aeruginosa. Based on, in silico pharmacokinetic studies, compounds 10a-e were identified as lead compounds for future investigation due to their lower toxicity, high drug score values and good oral bioavailability as per OECD guidelines.
- Kushwaha, Khushbu,Kaushik, Nagendra,Lata,Jain, Subhash C.
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supporting information
p. 1795 - 1801
(2014/04/17)
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- RAFAMYCIN ANALOGS AND METHODS FOR MAKING SAME
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A semi-synthetic rapamycin analog with a triazole moiety or a pharmaceutically acceptable salt or prodrug thereof, is a broad-spectrum cytostatic agent and a m TOR inhibitor, and is useful in the treatment of various cancers, or tumors in organs such as kidney, liver, breast, head and neck, lung, prostate, and restenosis in coronary arteries, peripheral arteries, and arteries in the brain, immune and autoimmune diseases. Also disclosed are fungal growth-, restenosis-, post- transplant tissue rejection- and immune- and autoimmune disease- inhibiting compositions and a method of inhibiting cancer, fungal growth, restenosois, post-transplant tissue rejection, and immune and autoimmune disease in a mammal. One particular preferred application of such triazole-moiety containing rapamycin analog is in treating renal carcinoma, lung cancer, colon cancer, and breast cancers wherein potency of the drug, its half-life, tissue distribution properties, and its pharmacokinetic properties including bioavailability through oral and intravenous routes are essential to the clinical outcomes.
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Paragraph 60
(2014/06/23)
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- Synthesis of polyfunctional triethoxysilanes by 'click silylation'
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The copper-catalyzed 'click silylation' has been exploited for the chemical modification of γ-azidopropyltriethoxysilane (AzPTES) with a wide range of terminal alkynes (1a-1v) in a one-pot operation. The novel 1,2,3-triazole-triethoxysilane derivatives (2a-2v) were synthesized by this procedure and comprehensively characterized by IR spectra, 1H and 13C NMR, and HRMS studies.
- Singh, Gurjaspreet,Mangat, Satinderpal Singh,Singh, Jandeep,Arora, Aanchal,Sharma, Ramesh K.
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supporting information
p. 903 - 909
(2014/02/14)
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- 7-Chloroquinolinotriazoles: Synthesis by the azide-alkyne cycloaddition click chemistry, antimalarial activity, cytotoxicity and SAR studies
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Twenty-seven 7-chloroquinolinotriazole derivatives with different substituents in the triazole moiety were synthesized via copper-catalyzed cycloaddition (CuAAC) click chemistry between 4-azido-7-chloroquinoline and several alkynes. All the synthetic compounds were evaluated for their in vitro activity against Plasmodium falciparum (W2) and cytotoxicity to Hep G2A16 cells. All the products disclosed low cytotoxicity (CC50 > 100 μM) and five of them have shown moderate antimalarial activity (IC50 from 9.6 to 40.9 μM). As chloroquine analogs it was expected that these compounds might inhibit the heme polymerization and SAR studies were performed aiming to explain their antimalarial profile. New structural variations can be designed on the basis of the results obtained.
- Pereira, Guilherme R.,Brand?o, Geraldo Célio,Arantes, Lucas M.,De Oliveira Jr., Háliton A.,De Paula, Renata Cristina,Do Nascimento, Maria Fernanda A.,Dos Santos, Fábio M.,Da Rocha, Ramon K.,Lopes, Júlio César D.,De Oliveira, Alaíde Braga
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p. 295 - 309
(2014/02/14)
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- Substituted Benzene Compounds
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The present invention relates to substituted benzene compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for research or other non-therapeutic purposes.
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Paragraph 0179; 0180
(2014/05/07)
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- PROCESS FOR PRODUCING AN AMINOPROPYNE OR ENAMINONE
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There is provided a process for producing an aminopropyne or an enaminone comprising the step of reacting a metal acetylide, an amine and a carbonyl-containing compound in the presence of a transition metal catalyst. There is also provided a process for producing an aminopropyne comprising the step of reacting a metal acetylide, an amine and a halide-containing compound in the presence of a transition metal catalyst at a reaction temperature of 50°C to 150°C. There are also provided processes to further synthesize the aminopropyne produced to obtain a butyneamine, another aminopropyne or a triazol.
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Page/Page column 24
(2013/03/26)
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- Synthesis of functional acetylene derivatives from calcium carbide
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AHA Erlebnis: CaC2, used to produce acetylene until several decades ago, is re-emerging as a cheap, sustainable resource synthesized from coal and lignocellulosic biomass. We report efficient catalytic protocols for the synthesis of functional acetylene derivatives from CaC2 through aldehyde, alkyne, and amine (AAA) as well as alkyne, haloalkane, and amine (AHA) couplings, and in addition demonstrate its use in click and Sonogashira chemistry, showing that calcium carbide is a sustainable and cost-efficient carbon source.
- Lin, Zhewang,Yu, Dingyi,Sum, Yin Ngai,Zhang, Yugen
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scheme or table
p. 625 - 628
(2012/06/04)
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- SUBSTITUTED PARA-BIPHENYLOXYMETHYL DIHYDRO OXAZOLOPYRIMIDINONES, PREPARATION AND USE THEREOF
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The present invention relates to a series of substituted para-biphenyloxymethyl dihydro oxazolopyrimidinones of formula (I) as defined herein. This invention also relates to methods of making these compounds including novel intermediates. The compounds of
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Page/Page column 61
(2011/04/19)
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- CuAAC macrocyclization: High intramolecular selectivity through the use of copper-tris(triazole) ligand complexes
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A range of multivalent heteroaryl ligands, copper sources, and solvent systems have been investigated for use in CuAAC-mediated macrocyclization reactions. These studies have revealed the key factors governing selectivity for macrocyclization versus dimerization and identified a simple but specific set of reaction conditions capable of efficiently generating a diverse series of drug-like macrocycles at modest dilution in up to 95% yield.
- Chouhan, Gagan,James, Keith
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supporting information; experimental part
p. 2754 - 2757
(2011/06/26)
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- Library of 1,4-disubstituted 1,2,3-triazole analogs of oxazolidinone RNA-binding agents
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The design and synthesis of small molecules that target RNA is immensely important in antibacterial therapy. We had previously reported on the RNA binding of a series of 4,5-disubstituted 2-oxazolidinones that bind to a highly conserved bulge region of bacterial RNA. This biological target T box antitermination system, which is found mainly in Gram-positive bacteria, regulates the expression of several amino acid related genes. In an effort to amplify our library, we have prepared a library of 1,4-disubstituted 1,2,3-triazole analogs that entails an isosteric replacement of the oxazolidinone nucleus. The synthesis of the new analogs was enhanced via copper(I) catalysis of an azide and alkyne cycloaddition reaction. A total of 108 1,4-disubstituted 1,2,3-triazole compounds have been prepared. All compounds were evaluated as RNA binding agents.
- Acquaah-Harrison, George,Zhou, Shu,Hines, Jennifer V.,Bergmeier, Stephen C.
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scheme or table
p. 491 - 496
(2010/09/15)
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- Modifications of C-2 on the pyrroloquinoline template aimed at the development of potent herpesvirus antivirals with improved aqueous solubility
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A series of C-2 pyrroloquinoline analogs designed to improve aqueous solubility were examined for herpesvirus polymerase and antiviral activity. Several analogs were identified that maintained the antiviral activity of the previous development candidate against HCMV, HSV-1 and VZV, but with significantly improved aqueous solubility.
- Nieman, James A.,Nair, Sajiv K.,Heasley, Steven E.,Schultz, Brenda L.,Zerth, Herbert M.,Nugent, Richard A.,Chen, Ke,Stephanski, Kevin J.,Hopkins, Todd A.,Knechtel, Mary L.,Oien, Nancee L.,Wieber, Janet L.,Wathen, Michael W.
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supporting information; experimental part
p. 3039 - 3042
(2010/07/03)
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- Design, synthesis and antimicrobial activities of some new quinoline derivatives carrying 1,2,3-triazole moiety
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A new series of [1-(6-methoxy-2-methylquinolin-4-yl)-1H-1,2,3-triazol-4-yl] methanamine derivatives were synthesized starting from 4-methoxyaniline through multi-step reactions. The title compounds 5a-y were prepared by treating the azide intermediate 4 with propargyl bromide and different alkyl/heterocyclic amines in a sequential three component synthesis. All the new compounds were characterized by spectral and elemental analyses. The newly synthesized final compounds were evaluated for their in vitro antibacterial and antifungal activities against pathogenic strains. The preliminary screening results indicated that most of the compounds demonstrated moderate to very good antibacterial and antifungal activities, comparable to the first-line drugs. Twenty five new derivatives of [1-(6-methoxy-2-methylquinolin-4-yl)-1H-1,2,3- triazol-4-yl] methanamine have been synthesized and the most effective compounds have MIC of 6.25 μg/mL, which are in comparable with present antibiotics.
- Thomas,Adhikari, Airody Vasudeva,Shetty, N. Suchetha
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experimental part
p. 3803 - 3810
(2010/09/15)
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- Highly selective N-Alkylation of amines promoted on silica: An efficient and recyclable surface
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N-Alkylation of amines suffers from competing over alkylations. At the same time, use of strong base and other harsh conditions greatly limits providing a practical, generalized and selective procedure. Activated silica gel has been found to promote N-alkylations of amines. Here, we studied N-alkylation of amines with various types of alkyl halides, which finally constitute practical, highly selective and eco-friendly conditions for mono- or bis-alkylated amines at ambient temperature with recyclability of silica.
- Basu, Basudeb,Paul, Susmita,Nanda, Ashis K.
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experimental part
p. 1115 - 1120
(2010/05/02)
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- Quinazolinones and pyrido[3,4-d]pyrimidin-4-ones as orally active and specific matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis
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Quinazolinones 8 and pyrido[3,4-d]pyrimidin-4-ones 9 as orally active and specific matrix metalloproteinase-13 inhibitors were discovered for the treatment of osteoarthritis. Starting from a high-through-put screening (HTS) hit thizolopyrimidin-dione 7, w
- Jie, Jack Li,Nahra, Joe,Johnson, Adam R.,Bunker, Amy,O'Brien, Patrick,Yue, Wen-Song,Ortwine, Daniel F.,Man, Chiu-Fai,Baragi, Vijay,Kilgore, Kenneth,Dyer, Richard D.,Han, Hyo-Kyung
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p. 835 - 841
(2008/09/20)
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- Natural products in parallel synthesis: Triazole libraries of nonactic acid
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The synthesis of a library of nonactic acid-derived triazoloamide derivatives and their evaluation as antimicrobial agents is described.
- Luesse, Sarah B.,Wells, Gregg,Nayek, Abhijit,Smith, Adrienne E.,Kusche, Brian R.,Bergmeier, Stephen C.,McMills, Mark C.,Priestley, Nigel D.,Wright, Dennis L.
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body text
p. 3946 - 3949
(2009/04/07)
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- Highly flexible and efficient synthesis of the GABAB enhancer 4-(2-hexylsulfanyl-6-methyl-pyrimidin-4-ylmethyl)-morpholine
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In the course of establishing a flexible synthesis of 2,4,6-substituted pyrimidines, we discovered that 2-hexyl-isothiourea hydrobromide reacts at ambient temperature and in a mildly exothermic fashion with 5,5-diethoxy-pent-3-yn-2-one upon treatment with 2 equiv of triethylamine in tetrahydrofuran to afford 4-diethoxymethyl-2-hexylsulfanyl-6-methyl-pyrimidine in 80% isolated yield. The methodology was developed in the search for an improved synthesis of the GABAB enhancer 4-(2-hexylsulfanyl-6-methyl-pyrimidin-4-ylmethyl)-morpholine.
- Verron, Julien,Malherbe, Paricher,Prinssen, Eric,Thomas, Andrew W.,Nock, Nadine,Masciadri, Raffaello
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p. 377 - 380
(2007/10/03)
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- Heterobicyclic thiophene compounds and methods of use
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Compounds of Formula I and pharmaceutically acceptable salts thereof, are useful for inhibiting receptor tyrosine kinases and for treating disorders mediated thereby. Methods of using compounds of Formula I and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.
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Page/Page column 58
(2008/06/13)
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- AMIDE DERIVATIVES
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The invention concerns a compound of the Formula I (A chemical formula should be inserted here - please see paper copy enclosed herewith) wherein m is 0-2 and each R1 is a group such as hydroxy, halogeno, trifluoromethyl heterocyclyl and heterocyclyloxy; R2 is halogeno, trifluoromethyl or (1-6C)alkyl; R3 is hydrogen, halogeno or (1-6C)alkyl; and R4 is (3-6C)cycloalkyl;or pharmaceutically-acceptable salts thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical condions mediated by cytokines.
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Page/Page column 87-89
(2008/06/13)
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