- Design, synthesis and antifungal evaluation of borrelidin derivatives
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Borrelidin, a nitrile containing 18-membered polyketide macrolide, display potent antifungal activity. In this study, a library of borrelidin derivatives were synthesized. Their structures were elucidated by detailed spectroscopic data analysis. The antifungal activity and cytotoxicity of these target compounds were evaluated by broth microdilution and 3-(4,5-dimethylthiazol-2-yl)-3,5-phenytetrazoliumromide (MTT) methods. Among forty-seven prepared analogues, compound 3b had the inhibitory effect on Candida albicans and Candida parapsilosis (MIC: 50 and 12.5 μg/mL, respectively). Furthermore, compounds 4n and 4r presented better antifungal activity against Aspergillus fumigatus with 12.5 μg/mL MIC value, which were insensitive to borrelidin. Preliminary structure-activity relationships (SAR) revealed that the ester analogues containing fragment -OCH2CH2N- had an important effect on the antifungal activity. Meanwhile, the molecular docking study indicated the carboxyl substituents in BN could provide extra interaction with pathogenic fungal threonyl-tRNA synthetase (ThrRS).
- Hu, Caijuan,Su, Hao,Luo, Jinghan,Han, Li,Liu, Qingyin,Wu, Wenxi,Mu, Yu,Guan, Peipei,Sun, Tiemin,Huang, Xueshi
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Read Online
- Synthesis and antifungal photodynamic activities of a series of novel zinc(II) phthalocyanines substituted with piperazinyl moieties
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A series of novel zinc(II) phthalocyanines tetra-substituted or mono-substituted with piperazinyl moieties linked by different ethoxy chains has been prepared and characterized. The effects of the N-protecting group of piperazinyl moiety, length of ethoxy chains and number of substitutes on the photophysical, photochemical properties, cellular uptakes and in vitro photodynamic antifungal activities have also been examined. All of these compounds are essentially non-aggregated and good singlet oxygen generators with quantum yields (ΦΔ) of 0.54-0.77 in N,N-dimethylformamide. The photodynamic activity of these compounds against Candida albicans follows the order: 7 > 5a > 5b > 4a ≈ 4b. The mono-substituted phthalocyanine 7 exhibits the highest photodynamic inactivation of C. albicans with an IC90 value of 9 μM, which can be attributed to its better amphiphilicity and even higher cellular uptake. The results suggest that phthalocyanine 7 is a potential photosensitizer for antifungal photodynamic therapy.
- Zheng, Bi-Yuan,Zhang, Hong-Peng,Ke, Mei-Rong,Huang, Jian-Dong
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Read Online
- FUSED PYRIMIDINE PYRIDINONE COMPOUNDS AS JAK INHIBITORS
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The disclosure provides compounds of formula (I), or a pharmaceutically-acceptable salt thereof, wherein the variables are defined in the specification, that are inhibitors of JAK kinases, particularly JAK3. The disclosure also provides pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat gastrointestinal inflammatory diseases.
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Page/Page column 45
(2021/06/04)
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- METHODS FOR DELAYING, PREVENTING, AND TREATING ACQUIRED RESISTANCE TO RAS INHIBITORS
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The present disclosure relates to compositions and methods for the treatment of diseases or disorders (e.g., cancer) with bi-steric inhibitors of mTOR in combination with RAS inhibitors. Specifically, in some embodiments this disclosure includes compositions and methods for inducing apoptosis of tumor cells and/or for delaying, preventing, or treating acquired resistance to RAS inhibitors using bi-steric mTOR inhibitors.
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Paragraph 00611
(2022/01/04)
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- TRICYCLIC COMPOUNDS ACTING ON CRBN PROTEINS
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The present invention discloses a series of tricyclic compounds and use thereof in preparing a medicament for treating a disease related to CRBN protein. Specifically, the present invention discloses a derivative compound of formula (1) or a pharmaceutically acceptable salt thereof.
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Paragraph 0231-0232
(2021/07/17)
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- Structure-Activity Relationship Studies Reveal New Astemizole Analogues Active against Plasmodium falciparum in Vitro
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In the context of drug repositioning and expanding the existing structure-activity relationship around astemizole (AST), a new series of analogues were designed, synthesized, and evaluated for their antiplasmodium activity. Among 46 analogues tested, compounds 21, 30, and 33 displayed high activities against asexual blood stage parasites (PfNF54 IC50 = 0.025-0.043 μM), whereas amide compound 46 additionally showed activity against late-stage gametocytes (stage IV/V; PfLG IC50 = 0.6 ± 0.1 μM) and 860-fold higher selectivity over hERG (46, SI = 43) compared to AST. Several analogues displaying high solubility (Sol > 100 μM) and low cytoxicity in the Chinese hamster ovary (SI > 148) cell line have also been identified.
- Birkholtz, Lyn-Marie,Chibale, Kelly,Coertzen, Dina,Ferger, Richard,Kumar, Malkeet,Mambwe, Dickson,Njoroge, Mathew,Reader, Janette,Taylor, Dale,Van Der Watt, Mari?tte
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supporting information
p. 1333 - 1341
(2021/08/24)
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- TAU-PROTEIN TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
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The present disclosure relates to bifunctional compounds, which find utility as modulators of tan protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tan protein, such that tan protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tan. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tan protein. Diseases or disorders that result from aggregation or accumulation of tan protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 0397; 0398
(2021/02/12)
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- WEE1 inhibitors as well as preparation and application thereof
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The invention relates to WEE1 inhibitors as well as preparation and application thereof. The present invention relates to compounds of formula (I), or pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof, and their use in the preparation of medicaments for the treatment of diseases associated with WEE1 activity.
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Paragraph 0430-0436
(2020/10/14)
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- TARGETING DNA REPAIR IN TUMOR CELLS VIA INHIBITION OF ERCC1-XPF
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The current application relates to pyronaridine or 6-chloro-2-methoxyacridine analogs having binding affinity for the ERCC1-XPF hetero-dimerization interface. The compounds can be used for targeting DNA repair in tumor cells via ERCC1-XPF inhibition, ther
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Paragraph 00234; 00444-00446
(2020/12/30)
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- ACTIVATORS OF THE RETINOIC ACID INDUCIBLE GENE "RIG-I' PATHWAY AND METHODS OF USE THEREOF
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The present invention is directed to compounds of Formula (I), which are activators of the RIG-I pathway.
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Page/Page column 78
(2020/03/05)
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- ACTIVATORS OF THE RETINOIC ACID INDUCIBLE GENE "RIG-I" PATHWAY AND METHODS OF USE THEREOF
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The present invention is directed to compounds of Formula (I), which are activators of the RIG-I pathway.
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Paragraph 0513
(2020/03/01)
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- Nonclassical Phenyl Bioisosteres as Effective Replacements in a Series of Novel Open-Source Antimalarials
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The replacement of one chemical motif with another that is broadly similar is a common method in medicinal chemistry to modulate the physical and biological properties of a molecule (i.e., bioisosterism). In recent years, bioisosteres such as cubane and bicyclo[1.1.1]pentane (BCP) have been used as highly effective phenyl mimics. Herein, we show the successful incorporation of a range of phenyl bioisosteres during the open-source optimization of an antimalarial series. Cubane (19) and closo-carborane (23) analogues exhibited improved in vitro potency against Plasmodium falciparum compared to the parent phenyl compound; however, these changes resulted in a reduction in metabolic stability; unusually, enzyme-mediated oxidation was found to take place on the cubane core. A BCP analogue (22) was found to be equipotent to its parent phenyl compound and showed significantly improved metabolic properties. While these results demonstrate the utility of these atypical bioisosteres when used in a medicinal chemistry program, the search to find a suitable bioisostere may well require the preparation of many candidates, in our case, 32 compounds.
- Tse, Edwin G.,Houston, Sevan D.,Williams, Craig M.,Savage, G. Paul,Rendina, Louis M.,Hallyburton, Irene,Anderson, Mark,Sharma, Raman,Walker, Gregory S.,Obach, R. Scott,Todd, Matthew H.
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p. 11585 - 11601
(2020/12/04)
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- Development of dual inhibitors targeting pyruvate dehydrogenase kinases and human lactate dehydrogenase A: High-throughput virtual screening, synthesis and biological validation
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Most cancer cells feature an altered glucose metabolism from oxidative phosphorylation to cytoplasmic glycolysis. Pyruvate dehydrogenase kinases (PDKs) and lactate dehydrogenase A (LDHA) play crucial roles in promotion of glycolysis, thus the inhibition of both enzymes is considered a promising strategy for developing of anticancer therapeutics. Herein, we describe the first discovery of series novel dual inhibitors targeting PDKs and LDHA. We identified 6 hits from a library database containing 485465 compounds through a high-throughput virtual screening assay. Hit-to-lead optimization enabled us to discover two compounds, namely 20e and 20k, which inhibited PDKs with IC50 values of 0.8, and 1.6 μM, respectively, and inhibited LDHA with IC50 values of 0.15 and 0.7 μM, respectively. Meanwhile, the two compounds reduced A549 cell proliferation with EC50 values of 13.2, and 15.7 μM. Furthermore, 20e and 20k decreased the lactate formation, and increased oxygen consumption, suggesting the two compounds modulated the glucose metabolic pathways in cancer cells.
- Xiang, Sichuan,Huang, Ding,He, Qiaolin,Li, Jie,Tam, Kin Yip,Zhang, Shao-Lin,He, Yun
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- Double-target inhibitor targeting pyruvate dehydrogenase kinase and human lactate dehydrogenase A
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The invention relates to compounds represented by formulas (5) and (11) or pharmaceutically acceptable salts thereof, which can simultaneously inhibit pyruvate dehydrogenase kinase and lactate dehydrogenase, and are useful, but not limited to, in the treatment of cancer diseases, wherein R1 is independently selected from phenyl, pyrimidinyl, pyridyl, heterocyclic group, alkenyl, halogen substituted alkyl and benzhydryl, and phenyl is optionally substituted by one or more substituents independently selected from fluorine, chlorine, bromine, alkyl, alkoxy, nitro and trifluoromethyl. R2 is independently selected from phenyl, pyridyl, dichloroacetyl and furyl, wherein phenyl is optionally substituted by one or more substituents independently selected from fluorine, chlorine, bromine, alkyl, alkoxy, nitro and trifluoromethyl.
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Paragraph 0023-0027
(2020/09/30)
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- Diaminodiphosphine tetradentate ligand and ruthenium complex thereof, and preparation methods and applications of ligand and complex
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The invention discloses a diaminodiphosphine tetradentate ligand and a ruthenium complex thereof, and preparation methods and applications of the ligand and the complex, and provides a ruthenium complex represented by a formula I, wherein L is a diaminodiphosphine tetradentate ligand represented by a formula II, and X and Y are respectively and independently chlorine ion, bromine ion, iodine ion,hydrogen negative ion or BH4. According to the present invention, the ruthenium complex exhibits excellent catalytic activity in the catalytic hydrogenation reactions of ester compounds, has high yield and high chemical selectivity, is compatible with conjugated and non-conjugated carbon-carbon double bond, carbon-carbon triple bond, epoxy, halogen, carbonyl and other functional groups, and hasgreat application prospects.
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Paragraph 0301-0303; 0306
(2019/11/04)
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- C26-LINKED RAPAMYCIN ANALOGS AS MTOR INHIBITORS
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The present disclosure relates to mTOR inhibitors. Specifically, the embodiments are directed to compounds and compositions inhibiting mTOR, methods of treating diseases mediated by mTOR, and methods of synthesizing these compounds.
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Paragraph 00599
(2019/11/21)
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- C40-, C28-, AND C-32-LINKED RAPAMYCIN ANALOGS AS MTOR INHIBITORS
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The present disclosure relates to mTOR inhibitors. Specifically, the embodiments are directed to compounds and compositions inhibiting mTOR, methods of treating diseases mediated by mTOR, and methods of synthesizing these compounds.
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Paragraph 00664
(2019/11/19)
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- PYRIDAZINE DERIVATIVES AS SMARCA2/4 DEGRADERS
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The present invention provides pyridazine derivatives of formula (I), which are therapeutically useful as SMARCA2/4 degraders. These compounds are useful in the treatment and/or prevention of diseases or disorders dependent upon SMARCA2/4 in a mammal. The present invention also provides preparation of the compounds and pharmaceutical compositions comprising at least one of the pyridazine derivatives of formula (I) or a pharmaceutically acceptable salt, or a stereoisomer thereof.
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Page/Page column 157-158
(2019/11/12)
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- TAU-PROTEIN TARGETING PROTACS AND ASSOCIATED METHODS OF USE
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The present disclosure relates to bifunctional compounds, which find utility as modulators of tau protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tau protein, such that tau protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tau. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tau protein. Diseases or disorders that result from aggregation or accumulation of tau protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 0690-091
(2018/05/24)
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- Novel Compounds as Autotaxin Inhibitors and Pharmaceutical Compositions Comprising the Same
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The present invention relates to a novel autotaxin inhibitor compound for preventing and treating disease or symptoms due to an increase in concentration of lysophosphatidic acid or activation of autotaxin. The present invention further relates to a pharmaceutical composition containing the same. The novel compound of the present invention is an autotaxin inhibitor which inhibits production of lysophosphatidic acid, and thus is useful for treating or preventing cardiovascular disease, cancer, metabolic disease, kidney disease, liver disease, inflammatory diseases, nervous disease, respiratory disease, desmoid disease, eye disease, cholestatic symptoms, other types of chronic pruritus or acute, or chronic rejection of transplanted organs.COPYRIGHT KIPO 2017
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Paragraph 0457-0458; 0463-0464
(2018/05/17)
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- 1,3,4-OXADIAZOLE SULFAMIDE DERIVATIVE COMPOUNDS AS HISTONE DEACETYLASE 6 INHIBITOR, AND THE PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention relates to novel compounds having histone deacetylase 6 (HDAC6) inhibitory activity, stereoisomers thereof or pharmaceutically acceptable salts thereof, the use thereof for the preparation of therapeutic medicaments, pharmaceutical c
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Paragraph 714-716
(2017/02/24)
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- A anthraquinone and thiazole compounds, its preparation method and use thereof
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The invention relates to a compound which takes 5,7-dihydroxyanthraquinone [2,1-d]thiazole as a mother nucleus, which has a following general formula, and relates to a preparation method and an application of the compound in an antitumor drug. The compound takes a traditional natural product rheinic acid as an initial raw material, and a series of compound with high antineoplastic activity is synthesized through mild reaction condition. The antitumor activity in vitro of the preferable compound is stronger by more than 30 times by comparing with rheinic acid.
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Paragraph 0151-0153
(2017/08/10)
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- Compound and application of compound to treating colon cancer
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The invention discloses a compound and application of the compound to treating the colon cancer. The structural formula of the compound is shown in the formula I, wherein R1, R2, R3 and R4 in the formula I are respectively independently chosen from alkyl groups and alkoxy groups, the number of hydrogen atoms, halogen, nitro and carbon atoms in the alkyl group is 1-6, the number of carbon atoms in the alkoxy group is 1-6, R5 is chosen from nitro and -NR6R7, wherein R6 and R7 are respectively independently the hydrogen atom or CH2Ar, the Ar represents a phenyl group or an aryl group, the para-position of the aryl group is substituted by R8, the aryl group is a phenyl group, the R8 is an alkoxy group or the following shown groups, and the number of halogen, hydroxyl and carbon atoms in the R8 is 1-6. The compound also has an obvious effect on inhibiting a tumor sphere from a cancer patient with the colon cancer. In addition, the compound also has an obvious effect on inhibiting the migration and the moving ability of a colon cancer cell line. A novel medicine for treating the colon cancer is expected to be developed on the basis of the compound.
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Paragraph 0209-0210
(2017/11/04)
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- Quinoline or quinazoline derivatives, its preparation process and its use in medicine
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The invention relates to a quinoline or quinazoline derivative, its preparation method and an application in medicines, specifically to new quinoline or quinazoline derivative as shown in a general formula (I) and its medicinal salt or a pharmaceutical composition containing the derivative and a preparation method thereof. The invention further relates to an application of the quinoline or quinazoline derivative and its medicinal salt or the pharmaceutical composition containing the derivative in the preparation of a therapeutic agent, especially a protein kinase inhibitor. Each substituent group in the general formula (I) has the same definition as in the specification.
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Paragraph 0365-0370
(2018/01/19)
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- Dual stimuli-responsive polyamines derived from modified N-vinylpyrrolidones through CuAAC click chemistry
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The synthesis via copper(I)-catalyzed azide alkyne cycloaddition (CuAAC) of three new monomer derivatives of N-vinyl-2-pyrrolidone (VP) carrying cyclic pyrrolidine, piperidine, and piperazine groups and the corresponding copolymers with unmodified VP is s
- Del Prado, Anselmo,Navarro, Rodrigo,Levkin, Pavel,Gallardo, Alberto,Elvira, Carlos,Reinecke, Helmut
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p. 1098 - 1108
(2016/03/12)
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- Mild deprotection of PMB ethers using tert-butyl bromide
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A convenient and high yielding method for the cleavage and scavenging of p-methoxybenzyl protecting group of several alcohols using tert-butyl bromide in refluxing acetonitrile is described. Under these mild conditions other protecting groups such as acid sensitive allyl, benzyl, and Me3CPh2Si ethers, or isopropylidene acetals were unchanged. Interestingly, a selective alkoxy-PMB cleavage was observed in the presence of a PMB phenoxy ether.
- Rival, Nicolas,Albornoz Grados, Arantxa,Schiavo, Lucie,Colobert, Fran?oise,Hanquet, Gilles
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p. 6823 - 6826
(2015/11/27)
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- DERIVATIVES OF 6-(2,3-DICHLOROPHENYL)-1,2,4-TRIAZIN-5- AMINE
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The instant disclosure relates to (among other things) compounds that are derivatives of 6-(2,3-dichlorophenyl)-1,2,4-triazin-5-amine. The compounds provided possess unique effects and differences over other phenyltriazines known in the art.
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Paragraph 0250; 0251
(2015/07/07)
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- Novel bicyclic nitroimidazole carbamate compounds, process for preparation thereof and pharmaceutical composition for preventing or treating tuberculosis containing the same as an active ingredient
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A bicyclic nitroimidazole carbamate compound represented by chemical formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing or treating tuberculosis disease containing the same as an active ingredient. Chemical Formula 1. In Chemical Formula 1, R. 1 And R2 Are as defined in the description of the invention. The bicyclic nitroimidazole carbamate compounds of the present invention exhibit excellent inhibitory effects on vitality and non-active tuberculosis. The compounds can be useful in the treatment of tuberculosis.
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Paragraph 0222-0226
(2021/06/01)
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- ANTIBODY-DRUG-CONJUGATE AND ITS USE FOR THE TREATMENT OF CANCER
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The present invention relates to an antibody-drug-conjugate. From one aspect, the invention relates to an antibody-drug-conjugate comprising an antibody capable of binding to a Target, said antibody being conjugated to at least one drug selected from derivatives of dolastatin 10 and auristatins. The invention also comprises method of treatment and the use of said antibody-drug-conjugate for the treatment of cancer.
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Page/Page column 198
(2015/11/10)
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- DERIVATIVES OF DOLASTATIN 10 AND AURISTATINS
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The present invention concerns a compound of following formula (I): where: - R1 is H or OH, - R2 is a (C1-C6)alkyl, COOH, COO-((C1-C6)alkyl) or thiazolyl group, - R3 is H or a (C1-C6)alkyl group, and - R4 is: ■ a straight-chain or branched, saturated or unsaturated hydrocarbon group having 1 to 8 carbon atoms substituted by one or more groups chosen from among OH and NR5R6, ■ -(CH2CH2X1)(CH2CH2X2)a2(CH2CH2X3)a3(CH2CH2X4)a4(CH2CH2X5)a5R7, ■ an aryl-(C1-C8)alkyl group substituted by one or more groups chosen from among OH and NR9R10 groups, or ■ a heterocycle-(C1-C8)alkyl group optionally substituted by one or more groups chosen from among (C1-C6)alkyl, OH and NR12R13 groups, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and its uses in particular for the treatment of cancer, pharmaceutical compositions containing the same and the preparation methods thereof.
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Page/Page column 101
(2014/11/13)
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- DERIVATIVES OF DOLASTATIN 10 AND AURISTATINS
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The present invention concerns a compound of following formula (I) where: - R1 is H or OH, - R2 is a (C1-C6)alkyl, COOH, COO-((C1-C6)alkyl) or thiazolyl group, - R3 is H or a (C1-C6)alkyl group, and - R4 is: - an aryl-(C1-C8)alkyl group substituted by one or more groups chosen from among OH and NR9R10 groups, or - a heterocycle-(C1-C8)alkyl group optionally substituted by one or more groups chosen from among (C1-C6)alkyl, OH and NR12R13 groups, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and its uses in particular for the treatment of cancer, pharmaceutical compositions containing the same and the preparation methods thereof.
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Page/Page column 74
(2014/11/13)
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- Natural product-based design, synthesis and biological evaluation of anthra[2,1-d]thiazole-6,11-dione derivatives from rhein as novel antitumour agents
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Two series of novel 2-substituted 5,7-dihydroxyanthra[2,1-d]thiazole-6,11- dione derivatives from natural rhein were designed, synthesized and evaluated for their antitumour activities against human cancer cell lines A549 and HeLa in vitro.
- Liang, Yu-Kun,Yue, Zhi-Zhou,Li, Jia-Xin,Tan, Cun,Miao, Ze-Hong,Tan, Wen-Fu,Yang, Chun-Hao
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p. 505 - 515
(2014/08/05)
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- IMIDAZOPYRIDAZINE COMPOUNDS
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The present invention relates to the use of novel compounds of formula I: wherein all variable substituents are defined as described herein, which are SYK inhibitors and are useful for the treatment of auto-immune and inflammatory diseases.
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Paragraph 0620-0621
(2013/05/09)
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- Aminolysis of benzyl 2-pyridyl thionocarbonate and t-butyl 2-pyridyl thionocarbonate: Effects of nonleaving groups on reactivity and reaction mechanism
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A kinetic study is reported for nucleophilic substitution reactions of benzyl 2-pyridyl thionocarbonate (5b) and t-butyl 2-pyridyl thionocarbonate (6b) with a series of alicyclic secondary amines in H2O at 25.0 °C. Generalbase catalysis, which has often been reported to occur for aminolysis of esters possessing a C=S electrophilic center, is absent for the reactions of 5b and 6b. The Bronsted-type plots for the reactions of 5b and 6b are linear with ssnuc = 0.29 and 0.43, respectively, indicating that the reactions of 5b proceed through a stepwise mechanism with formation of a zwitterionic tetrahedral intermediate (T±) being the rate-determining step while those of 6b proceed through a concerted mechanism. The reactivity of 5b and 6b is similar to that of their oxygen analogues (i.e., benzyl 2-pyridyl carbonate 5a and t-butyl 2-pyridyl carbonate 6a, respectively), indicating that the effect of modification of the electrophilic center from C=O to C=S (i.e., from 5a to 5b and from 6a to 6b) on reactivity is insignificant. In contrast, 6b is much less reactive than 5b, indicating that the replacement of the PhCH2 in 5b by the t-Bu in 6b results in a significant decrease in reactivity as well as a change in the reaction mechanism (i.e., from a stepwise mechanism to a concerted pathway). It has been concluded that the contrasting reactivity and reaction mechanism for the reactions of 5b and 6b are not due to the electronic effects of PhCH2 and t-Bu but are caused by the large steric hindrance exerted by the bulky t-Bu in 6b.
- Kim, Min-Young,Lee, Jae-In,Um, Ik-Hwan
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p. 1115 - 1119
(2013/07/28)
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- Selective inhibitors of bacterial t-RNA-(N1G37) methyltransferase (TrmD) that demonstrate novel ordering of the lid domain
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The tRNA-(N1G37) methyltransferase (TrmD) is essential for growth and highly conserved in both Gram-positive and Gram-negative bacterial pathogens. Additionally, TrmD is very distinct from its human orthologue TRM5 and thus is a suitable target for the design of novel antibacterials. Screening of a collection of compound fragments using Haemophilus influenzae TrmD identified inhibitory, fused thieno-pyrimidones that were competitive with S-adenosylmethionine (SAM), the physiological methyl donor substrate. Guided by X-ray cocrystal structures, fragment 1 was elaborated into a nanomolar inhibitor of a broad range of Gram-negative TrmD isozymes. These compounds demonstrated no activity against representative human SAM utilizing enzymes, PRMT1 and SET7/9. This is the first report of selective, nanomolar inhibitors of TrmD with demonstrated ability to order the TrmD lid in the absence of tRNA.
- Hill, Pamela J.,Abibi, Ayome,Albert, Robert,Andrews, Beth,Gagnon, Moriah M.,Gao, Ning,Grebe, Tyler,Hajec, Laurel I.,Huang, Jian,Livchak, Stephania,Lahiri, Sushmita D.,McKinney, David C.,Thresher, Jason,Wang, Hongming,Olivier, Nelson,Buurman, Ed T.
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supporting information
p. 7278 - 7288
(2013/10/21)
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- IMIDAZOPYRIDAZINE COMPOUNDS
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The present invention relates to the use of novel compounds of formula (I): wherein all variable substituents are defined as described herein, which are SYK inhibitors and are useful for the treatment of auto-immune and inflammatory diseases.
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Page/Page column 169
(2013/05/22)
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- {[[K.18-Crown-6]Br3}n: A tribromide catalyst for the catalytic protection of amines and alcohols
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{[K.18-Crown-6]Br3}n, a unique tribromide-type catalyst, was utilized for the N-boc protection of amines and trimethylsilylation (TMS) and tetrahydropyranylation (THP) of alcohols. The method is general for the preparation of N-boc derivatives of aliphatic (acyclic and cyclic) and aromatic, and primary and secondary amines and also various TMS-ethers and THP-ethers. The simple separation of the catalyst from the product is one of the many advantages of this method.
- Chehardoli, Gholamabbas,Zolfigol, Mohammad Ali,Derakhshanpanah, Fateme
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p. 1730 - 1733
(2013/10/21)
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- NOVEL BETULINIC ACID DERIVATIVES AS HIV INHIBITORS
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(I)The invention relates to novel novel betulinic acid derivatives and related compounds, and pharmaceutical compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
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Paragraph 0277
(2013/11/18)
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- Enzyme-controllable delivery of nitric oxide from a molecular hydrogel
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A β-galactosidase-responsive molecular hydrogelator of a nitric oxide (NO) donor can release NO in a controllable manner to improve wound healing.
- Gao, Jie,Zheng, Wenting,Zhang, Jimin,Guan, Di,Yang, Zhimou,Kong, Deling,Zhao, Qiang
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supporting information
p. 9173 - 9175
(2013/09/24)
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- A kinetic study on aminolysis of t-butyl 4-pyridyl carbonate and related compounds: Effect of leaving and nonleaving groups on reaction mechanism
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Second-order rate constants kN have been measured spectrophotometrically for nucleophilic substitution reactions of t-butyl 4-pyridyl carbonate 8 with a series of alicyclic secondary amines in H 2O at 25.0 ± 0.1 °C. The Bronsted-type plot for the reactions of 8 is linear with βnuc = 0.84. The βnuc value obtained for the reactions of 8 is much larger than that reported for the corresponding reactions of t-butyl 2-pyridyl carbonate 6 (i.e., βnuc = 0.44), which was proposed to proceed through a forced concerted mechanism. Thus, the aminolysis of 8 has been concluded to proceed through a stepwise mechanism with a zwitterionic tetrahedral intermediate T±, in which expulsion of the leaving-group from T± occurs at the rate-determining step (RDS). In contrast, aminolysis of benzyl 4-pyridyl carbonate 7 has been reported to proceed through two intermediates, T± and its deprotonated form T- on the basis of the fact that the plots of pseudo-first-order rate constant kobsd vs. amine concentration curve upward. The current study has demonstrated convincingly that the nature of the leaving and nonleaving groups governs the reaction mechanism. The contrasting reaction mechanisms have been rationalized in terms of an intramolecular H-bonding interaction, steric acceleration, and steric inhibition.
- Kang, Ji-Sun,Lee, Jae-In,Um, Ik-Hwan
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p. 2971 - 2975
(2012/10/29)
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- Kinetics and reaction mechanism of aminolyses of benzyl 2-pyridyl carbonate and t-butyl 2-pyridyl carbonate in acetonitrile
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Second-order rate constants (kN) have been measured spectrophotometrically for the reactions of benzyl 2- pyridyl carbonate 3 and t-butyl 2-pyridyl carbonate 4 with a series of alicyclic secondary amines in MeCN at 25.0 ± 0.1 ° C. Substrate 4 is much less reactive than 3 and the steric hindrance exerted by the bulky t-Bu group in 4 has been attributed to its decreased reactivity. The Bronsted-type plots for the reactions of 3 and 4 are linear with ssnuc = 0.57 and 0.45, respectively. Thus, the reactions have been concluded to proceed through a concerted mechanism, although the current reactions were expected to proceed through a stepwise mechanism with a zwitterionic tetrahedral intermediate T±. It has been proposed that the rate of leaving-group expulsion is accelerated by the intramolecular H-bonding interaction in T± and the "push" provided by the RO group through the resonance interaction. Thus, the enhanced nucleofugality forces the reactions to proceed through a concerted mechanism. The reactivity-selectivity principle (RSP) is not applicable to the current reaction systems, since the reaction of the less reactive 4 results in a smaller ssnuc than that of the more reactive 3. Steric hindrance exerted by the bulky t-Bu group in 4 has been suggested to be responsible for the failure of the RSP. Copyright
- Bae, Ae Ri,Um, Ik-Hwan
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scheme or table
p. 1547 - 1550
(2012/07/28)
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- SUBSTITUTED PYRIDAZINE CARBOXAMIDE COMPOUNDS
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The new pyridazine derivatives have unexpected drug properties as inhibitors of protein kinases especially against ALK and are useful in treating disorders related to abnormal protein kinase activities such as cancer, neurological and psychiatric diseases
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Page/Page column 41
(2012/04/23)
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- Structure-activity relationship study of N 6-(2-(4-(1 H -Indol-5-yl)piperazin-1-yl)ethyl)- N 6-propyl-4,5,6,7- tetrahydrobenzo[ d ]thiazole-2,6-diamine analogues: Development of highly selective D3 dopamine receptor agonists along with a highly potent D2/D3 agonist and their pharmacological characterization
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In our effort to develop multifunctional drugs against Parkinson's disease, a structure-activity-relationship study was carried out based on our hybrid molecular template targeting D2/D3 receptors. Competitive binding with [ 3H]spiroperidol was used to evaluate affinity (Ki) of test compounds. Functional activity of selected compounds in stimulating [ 35S]γS binding was assessed in CHO cells expressing either human D2 or D3 receptors. Our results demonstrated development of highly selective compounds for D3 receptor (for (-)-40Ki, D3 = 1.84 nM, D2/D3 = 583.2; for (-)-45Ki, D3 = 1.09 nM, D2/D3 = 827.5). Functional data identified (-)-40 (EC50, D2 = 114 nM, D3 = 0.26 nM, D2/D3 = 438) as one of the highest D3 selective agonists known to date. In addition, high affinity, nonselective D3 agonist (-)-19 (EC50, D2 = 2.96 nM and D3 = 1.26 nM) was also developed. Lead compounds with antioxidant activity were evaluated using an in vivo PD animal model.
- Johnson, Mark,Antonio, Tamara,Reith, Maarten E. A.,Dutta, Aloke K.
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experimental part
p. 5826 - 5840
(2012/07/30)
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- PHOSPHONATED RIFAMYCINS AND USES THEREOF FOR THE PREVENTION AND TREATMENT OF BONE AND JOINT INFECTIONS
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The present invention relates to phosphonated Rifamycins, and methods of making and using such compounds. These compounds are useful as antibiotics for prophylaxis and/or the treatment of bone and joint infections, especially for the prophylaxis and/or treatment of osteomyelitis.
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Page/Page column 89
(2011/11/06)
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- Mepyramine-JNJ7777120-hybrid compounds show high affinity to hH 1R, but low affinity to hH4R
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In literature, a synergism between histamine H1 and H 4 receptor is discussed. Furthermore, it was shown, that the combined application of mepyramine, a H1 antagonist and JNJ7777120, a H 4 receptor ligand leads to a synergistic effect in the acute murine asthma model. Thus, the aim of this study was to develop new hybrid ligands, containing one H1 and one H4 pharmacophor, connected by an appropriate spacer, in order to address both, H1R and H 4R. Within this study, we synthesized nine hybrid compounds, which were pharmacologically characterized at hH1R and hH4R. The new compounds revealed (high) affinity to hH1R, but showed only low affinity to hH4R. Additionally, we performed molecular dynamic studies for some selected compounds at hH1R, in order to obtain information about the binding mode of these compounds on molecular level.
- Wagner, Eva,Wittmann, Hans-Joachim,Elz, Sigurd,Strasser, Andrea
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supporting information; experimental part
p. 6274 - 6280
(2011/11/29)
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- Synthesis and crystal structure determination of [H2-cryptand 222](Br3)2: A unique tribromide catalyst for the catalytic chemoselective N-boc protection of amines
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The organic tribromide, [H2-cryptand 222](Br3) 2 was synthesized and characterized by X-ray crystallography, and was utilized as an active catalyst for the N-boc protection of amines. The method is general for the preparation of N-boc derivatives of aliphatic (acyclic and cyclic), aromatic, primary and secondary amines. We also applied our new reaction protocols for the N-boc protection of some new amines and spectral and physical data for the obtained products are reported.
- Chehardoli, Gholamabbas,Zolfigol, Mohammad Ali,Khakyzadeh, Vahid,Golbedaghi, Reza,Hall, Nikita A.,Blackman, Allan G.
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experimental part
p. 538 - 543
(2012/01/03)
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- Falcipain inhibitors: Optimization studies of the 2-pyrimidinecarbonitrile lead series
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Falcipain-2 and falcipain-3 are papain-family cysteine proteases of the malaria parasite Plasmodium falciparum that are responsible for host hemoglobin hydrolysis to provide amino acids for parasite protein synthesis. Different heteroarylnitrile derivatives were studied as potential falcipain inhibitors and therefore potential antiparasitic lead compounds, with the 5-substituted-2- cyanopyrimidine chemical class emerging as the most potent and promising lead series. Through a sequential lead optimization process considering the different positions present in the initial scaffold, nanomolar and subnanomolar inhibitors at falcipains 2 and 3 were identified, with activity against cultured parasites in the micromolar range. Introduction of protonable amines within lead molecules led to marked improvements of up to 1000 times in activity against cultured parasites without noteworthy alterations in other SAR tendencies. Optimized compounds presented enzymatic activities in the picomolar to low nanomolar range and antiparasitic activities in the low nanomolar range.
- Coterón, Jose M.,Catterick, David,Castro, Julia,Chaparro, María J.,Díaz, Beatriz,Fernández, Esther,Ferrer, Santiago,Gamo, Francisco J.,Gordo, Mariola,Gut, Jiri,De Las Heras, Laura,Legac, Jennifer,Marco, Maria,Miguel, Juan,Mu?oz, Vicente,Porras, Esther,De La Rosa, Juan C.,Ruiz, Jose R.,Sandoval, Elena,Ventosa, Pilar,Rosenthal, Philip J.,Fiandor, Jose M.
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supporting information; experimental part
p. 6129 - 6152
(2010/10/21)
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- Investigation of various N-heterocyclic substituted piperazine versions of 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol: Effect on affinity and selectivity for dopamine D3 receptor
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Here we report on the design and synthesis of several heterocyclic analogues belonging to the 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol series of molecules. Compounds were subjected to [3H]spiperone binding assays, carried out with HEK-293 cells expressing either D2 or D3 dopamine receptors, in order to evaluate their inhibition constant (Ki) at these receptors. Results indicate that N-substitution on the piperazine ring can accommodate various substituted indole rings. The results also show that in order to maintain high affinity and selectivity for the D3 receptor the heterocyclic ring does not need to be connected directly to the piperazine ring as the majority of compounds included here are linked either via an amide or a methylene linker to the heterocyclic moiety. The enantiomers of the most potent racemic compound 10e exhibited differential activity with (-)-10e (Ki; D2 = 47.5 nM, D3 = 0.57 nM) displaying higher affinity at both D2 and D3 receptors compared to its enantiomer (+)-10e (Ki; D2 = 113 nM, D3 = 3.73 nM). Additionally, compound (-)-10e was more potent and selective for the D3 receptor compared to either 7-OH-DPAT or 5-OH-DPAT. Among the bioisosteric derivatives, the indazole derivative 10g and benzo[b]thiophene derivative 10i exhibited the highest affinity for D2 and D3 receptors. In the functional GTPγS binding study, one of the lead molecules, (-)-15, exhibited potent agonist activity at both D2 and D3 receptors with preferential affinity at D3.
- Brown, Dennis A.,Mishra, Manoj,Zhang, Suhong,Biswas, Swati,Parrington, Ingrid,Antonio, Tamara,Reith, Maarten E.A.,Dutta, Aloke K.
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experimental part
p. 3923 - 3933
(2009/10/10)
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- Structure-activity relationships of adenine and deazaadenine derivatives as ligands for adenine receptors, a new purinergic receptor family
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Adenine derivatives bearing substituents in the 2-, N6-, 7-, 8-, and/or 9-position and a series of deazapurines were synthesized and investigated in [3H]adenine binding studies at the adenine receptor in rat brain cortical membrane preparations (rAde1R). Steep structure-activity relationships were observed. Substitution in the 8-position (amino, dimethylamino, piperidinyl, piperazinyl) or in the 9-position (2-morpholinoethyl) with basic residues or introduction of polar substituents at the 6-amino function (hydroxy, amino, acetyl) represented the best modifications. Functional evaluation of selected adenine derivatives in adenylate cyclase assays at 1321N1 astrocytoma cells stably expressing the rAde1R showed that all compounds investigated were agonists or partial agonists. A subset of compounds was additionally investigated in binding studies at human embryonic kidney (HEK293) cells, which also express a high-affinity adenine binding site. Structure-affinity relationships at the human cell line were similar to those at the rAde1R, but not identical. In particular, N 6-acetyladenine (25, Ki rat: 2.85 μM; Ki human: 0.515 μM) and 8-aminoadenine (33, Ki rat: 6.51 μM; Ki human: 0.0341 μM) were much more potent at the human as compared to the rat binding site. The new AdeR ligands may serve as lead structures and contribute to the elucidation of the functions of the adenine receptor family. 2009 American Chemical Society.
- Borrmann, Thomas,Abdelrahman, Aliaa,Volpini, Rosaria,Lambertucci, Catia,Alksnis, Edgars,Gorzalka, Simone,Knospe, Melanie,Schiedel, Anke C.,Cristalli, Gloria,Müller, Christa E.
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supporting information; scheme or table
p. 5974 - 5989
(2010/03/24)
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- Compounds IV
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The present application relates to new compounds of formula (I), to pharmaceutical compositions comprising the compounds, to processes for their preparation, and to the use of the compounds as leptin receptor modulator mimetics in the preparation of medic
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(2009/08/18)
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