- Metabolism of the anthelmintic drug niclosamide by cytochrome P450 enzymes and UDP-glucuronosyltransferases: Metabolite elucidation and main contributions from CYP1A2 and UGT1A1
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1. Niclosamide is an old anthelmintic drug that shows potential in fighting against cancers. Here, we characterized the metabolism of niclosamide by cytochrome P450 enzymes (CYPs) and UDP-glucuronosyltransferases (UGTs) using human liver microsomes (HLM) and expressed enzymes.2. NADPH-supplemented HLM (and liver microsomes from various animal species) generated one hydroxylated metabolite (M1) from niclosamide; and UDPGA-supplemented liver microsomes generated one mono-O-glucuronide (M2). The chemical structures of M1 (3-hydroxy niclosamide) and M2 (niclosamide-2-O-glucuronide) were determined through LC-MS/MS and/or NMR analyses.3. Reaction phenotyping revealed that CYP1A2 was the main enzyme responsible for M1 formation. The important role of CYP1A2 in niclosamide metabolism was further confirmed by activity correlation analyses as well as inhibition experiments using specific inhibitors.4. Although seven UGT enzymes were able to catalyze glucuronidation of niclosamide, UGT1A1 and 1A3 were the enzymes showed the highest metabolic activities. Activity correlation analyses demonstrated that UGT1A1 played a predominant role in hepatic glucuronidation of niclosamide, whereas the role of UGT1A3 was negligible.5. In conclusion, niclosamide was subjected to efficient metabolic reactions hydroxylation and glucuronidation, wherein CYP1A2 and UGT1A1 were the main contributing enzymes, respectively.
- Lu, Danyi,Ma, Zhiguo,Zhang, Tianpeng,Zhang, Xingwang,Wu, Baojian
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- Application of niclosamide and analogs as small molecule inhibitors of Zika virus and SARS-CoV-2 infection
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Zika virus has emerged as a potential threat to human health globally. A previous drug repurposing screen identified the approved anthelminthic drug niclosamide as a small molecule inhibitor of Zika virus infection. However, as antihelminthic drugs are generally designed to have low absorption when dosed orally, the very limited bioavailability of niclosamide will likely hinder its potential direct repurposing as an antiviral medication. Here, we conducted SAR studies focusing on the anilide and salicylic acid regions of niclosamide to improve physicochemical properties such as microsomal metabolic stability, permeability and solubility. We found that the 5-bromo substitution in the salicylic acid region retains potency while providing better drug-like properties. Other modifications in the anilide region with 2′-OMe and 2′-H substitutions were also advantageous. We found that the 4′-NO2 substituent can be replaced with a 4′-CN or 4′-CF3 substituents. Together, these modifications provide a basis for optimizing the structure of niclosamide to improve systemic exposure for application of niclosamide analogs as drug lead candidates for treating Zika and other viral infections. Indeed, key analogs were also able to rescue cells from the cytopathic effect of SARS-CoV-2 infection, indicating relevance for therapeutic strategies targeting the COVID-19 pandemic.
- Shamim, Khalida,Xu, Miao,Hu, Xin,Lee, Emily M,Lu, Xiao,Huang, Ruili,Shah, Pranav,Xu, Xin,Chen, Catherine Z.,Shen, Min,Guo, Hui,Chen, Lu,Itkin, Zina,Eastman, Richard T.,Shinn, Paul,Klumpp-Thomas, Carleen,Michael, Sam,Simeonov, Anton,Lo, Donald C.,Ming, Guo-li,Song, Hongjun,Tang, Hengli,Zheng, Wei,Huang, Wenwei
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supporting information
(2021/03/30)
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- Benzoylaniline compound and application of benzoylaniline compound in preparation of sensitizer of P.aeruginosa inhibitor
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The invention discloses a benzoylaniline compound. The benzoylaniline compound has a structural general formula shown in the specification. The invention also discloses application of the benzoylaniline compound in preparation of a sensitizer of a P.aeruginosa inhibitor or in preparation of a medicine for preventing or treating bacterial infection diseases caused by P.aeruginosa. The invention also discloses an application of niclosamide in preparation of a sensitizer of a P.aeruginosa inhibitor or in preparation of a medicine for preventing or treating bacterial infection diseases caused by P.aeruginosa. The benzoylaniline compound provided by the invention can be used as a medicine for treating and/or preventing bacterial infection diseases caused by P.aeruginosa.
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Paragraph 0085; 0087; 0090-0091; 0206-0209
(2020/08/29)
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- 3-(Ethoxycarbonyl)-1-(5-methyl-5-(nitrosooxy)hexyl)pyridin-1-ium cation: A green alternative to tert-butyl nitrite for synthesis of nitro-group-containing arenes and drugs at room temperature
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Due to their remarkable properties, task-specific ionic liquids have turned out to be progressively popular over the last few years in the field of green organic synthesis. Herein, for the first time, we report that a new task-specific nitrite-based ionic liquid such as 3-(ethoxycarbonyl)-1-(5-methyl-5-(nitrosooxy)hexyl)pyridin-1-ium bis(trifluoromethanesulfonyl)imides (TS-N-IL) derived from biodegradable ethyl nicotinate indeed acted as an efficient and eco-friendly reagent for the synthesis of highly valuable nitroaromatic compounds and drugs including nitroxynil, tolcapone, niclofolan, flutamide, niclosamide and nitrazepam. The bridging of an ionic liquid with nitrite group not only increases the yield and rate of direct C[sbnd]N bond formation reaction but also allows easy product separation and recyclability of a byproduct. Nonvolatile nature, easy synthesis, merely stoichiometric need and mildness are a portion of the extra focal points of TS-N-IL while contrasted with tert-butyl nitrite an outstanding and highly-flammable reagent utilized largely in organic synthesis.
- Chaudhary, Renu,Natarajan, Palani,Rani, Neetu,Sakshi,Venugopalan, Paloth
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supporting information
(2019/12/30)
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- SAR optimization studies on modified salicylamides as a potential treatment for acute myeloid leukemia through inhibition of the CREB pathway
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Disruption of cyclic adenosine monophosphate response element binding protein (CREB) provides a potential new strategy to address acute leukemia, a disease associated with poor prognosis, and for which conventional treatment options often carry a significant risk of morbidity and mortality. We describe the structure-activity relationships (SAR) for a series of XX-650-23 derived from naphthol AS-E phosphate that disrupts binding and activation of CREB by the CREB-binding protein (CBP). Through the development of this series, we identified several salicylamides that are potent inhibitors of acute leukemia cell viability through inhibition of CREB-CBP interaction. Among them, a biphenyl salicylamide, compound 71, was identified as a potent inhibitor of CREB-CBP interaction with improved physicochemical properties relative to previously described derivatives of naphthol AS-E phosphate.
- Chae, Hee-Don,Cox, Nick,Capolicchio, Samanta,Lee, Jae Wook,Horikoshi,Kam, Sharon,Ng, Andrew A.,Edwards, Jeffrey,Butler, Tae-León,Chan, Justin,Lee, Yvonne,Potter, Garrett,Capece, Mark C.,Liu, Corey W.,Wakatsuki, Soichi,Smith, Mark,Sakamoto, Kathleen M.
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supporting information
p. 2307 - 2315
(2019/06/27)
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- Identification and synthesis of low-molecular weight cholecystokinin B receptor (CCKBR) agonists as mediators of long-term synaptic potentiation
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Recently, He et al. reported that CCKB receptors located in the neocortex of the brain when bound to their bound natural ligand, CCK peptides, enhance memory, bringing up the possibility that agonists targeting the CCKB receptor may act as therapeutic agents in diseases in which memory loss is marked as observed in dementia and Alzheimer’s. In this report, we describe the synthesis of novel low-molecular weight benzoamine CCKB receptor agonists. The compounds made in this series were determined to be mostly partial agonists, although some antagonists were identified, as well, capable of triggering calcium release in a cell line that overexpresses the CCKB receptor. Compound 35 demonstrated an EC50 of 0.15 μM in the cell-based assay, but more importantly, several of the compounds, including 35, demonstrated a physiological effect, inducing long-term potentiation in rat brains comparable to the CCK-8 peptide albeit at much higher concentrations. Based on these findings, benzoamines may be the basis for a new series of CCKB receptor agonists in drug-discovery efforts that seek to develop therapeutics to prevent memory loss.
- Zhang, Yanmei,Wang, Yican,Guo, Yiping,Liao, Jinxi,Tu, Zhengchao,Lu, Yongzhi,Ding, Ke,Tortorella, Micky D.,He, Jufang
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p. 387 - 393
(2019/02/01)
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- Preparation method for niclosamide intermediate
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The invention discloses a preparation method for a niclosamide intermediate, and the method belongs to the field of fine chemical production. In the method, the weight ratio of raw materials, for a first reaction, such as o-chloro-p-nitroaniline to xylene to thionyl chloride is (14-15.5%):(14-15.5%):(59.5%):(11%), ethanol is adopted for a second reaction, and the amount of ethanol is equal to the weight of xylene used in the first reaction. The production method has the advantages of simple process, high efficiency, low cost, no pollution, and high yield; compared with a conventional method, the production method has the advantage of low reaction temperature; with the low reaction temperature, firstly, energy is saved, and secondly, the production difficulty of a reactor is reduced; the production method has the other advantage that the yield of the product niclosamide can be increased to more than or equal to 80%, the purity of the product can reach 95.0%, and the product is mainly used for production of niclosamide.
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Paragraph 0013; 0014; 0015
(2017/03/17)
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- Thioctic acid phenol ester derivative as well as preparation method and application thereof
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The invention provides a thioctic acid phenol ester derivative as well as a preparation method and application thereof. The thioctic acid phenol ester derivative has a general molecular formula with a formula (I), the formula (I) is shown in the description, wherein X is halogen and R is substituted phenyl. The thioctic acid phenol ester derivative provided by the invention has a novel structure and relatively high bioactivity and has a relatively good inhibition effect on proliferation and migration of tumor cells; compared with an inhibition effect of cis-platinum on the tumor cells, the inhibition effect of the carbamoyl substituted thioctic acid phenol ester derivative provided by the invention on tumors is better than inhibition strength of the cis-platinum on the tumor cells.
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Paragraph 0054; 0060-0062
(2017/08/31)
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- INHIBITORS OF CREB-CBP INTERACTION FOR TREATMENT OF LEUKEMIA
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Compounds and methods are provided for inhibiting a CREB-CBP protein-protein interaction in a sample. In some cases, the method includes modulating transcription of CREB in a cell that overexpresses CREB. Also provided are methods of inhibiting the proliferation of a cancer cell. The subject CREB transcription inhibitor compounds include a substituted salicylamide or a prodrug thereof. Methods of alleviating symptoms associated with cancer (e.g., Acute Myeloid Leukemia (AML) or Acute Lymphomblastic Leukemia (ALL)) in a subject in need thereof are also provided. Pharmaceutical compositions including the subject compounds find use in treating cancer. The subject compounds may be formulated or provided to a subject in combination with a second agent, e.g. an anticancer agent.
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Page/Page column 40; 41
(2017/10/06)
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- Niclosamide is a Negative Allosteric Modulator of Group I Metabotropic Glutamate Receptors: Implications for Neuropathic Pain
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Purpose: Novel therapeutics are greatly needed that target specific pathological receptors and pathways involved in Neuropathic Pain (NP). Extending our previous work published in this Journal on Group I metabotropic glutamate receptor (mGluR) modulators, we now investigate the therapeutic potential of niclosamide in modulating aberrant glutamate transmission in NP. Method: Calcium mobilization assays and cross-receptor selectivity experiments are conducted to characterize the pharmacological activity of niclosamide. A focused series of niclosamide analogues is then prepared to elucidate key structural determinants that emerged from computational molecular modeling analysis on drug-receptor interactions. Finally, niclosamide and a carbamate derivative are studied to assess their efficacy in an NP-evoked mechanical hyperalgesia model in rats. Results: Niclosamide is a low-nanomolar allosteric antagonist of Group I mGluRs with high selectivity for Group I over homologous Group III mGluRs. The phenolic hydroxyl group of niclosamide forms a crucial hydrogen bond with mGluR1/5. Its bioactive coplanar conformation is further stabilized by the nitro substituent on the B ring and an intramolecular bond. Mechanical hyperalgesia in NP rats is reversed by niclosamide through three different dosing routes. Conclusion: To our knowledge, this is the first report of the salicylanilide class of compounds as potential treatments for NP.
- Ai, Ni,Wood, Richard D.,Yang, Eric,Welsh, William J.
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p. 3044 - 3056
(2016/11/13)
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- Compound, preparation method and application thereof and corresponding targeted drug delivery system and chemotherapy drugs
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The invention relates to a compound, a preparation method and application thereof and a corresponding targeted drug delivery system and chemotherapy drugs. The compound is a novel compound for treating small cell lung cancer or pharmaceutically-acceptable salt of the compound. The formula I of the compound is as shown in the specification, wherein R is acyloxy. The invention further relates to the preparation method of the compound, application of the compound to the preparation of the chemotherapy drugs for treating the small cell lung cancer, the targeted drug delivery system containing the compound, and the chemotherapy drugs containing the compound and used for treating the small cell lung cancer.
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Paragraph 0063; 0064; 0065
(2016/10/24)
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- MULTICOMPARTMENT GRANULATE FORMULATIONS FOR ACTIVE SUBSTANCES
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The invention relates to molded article that contains active substances and comprises at least two compartments that have a different material composition. Each compartment is independently provided with at least one active substance that is contained in a matrix. Each matrix encompasses at least one filler at a concentration of ≧20 percent by weight to ≦100 percent by weight relative to the total weight of the respective matrix. The invention further relates to a method for producing such molded articles as well as the use thereof.
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- Bromonitrothienyldioxanes
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The invention relates to novel 5-bromo-5-nitro-2-thienyl-1,3-dioxanes of the formula (I) in which R1, R2 and R3 are as defined in the description are highly suitable for use as biocides for protecting plants and industrial materials.
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- Dithiazoldioxides and the use thereof as microbicides
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The invention relates to novel dithiazole dioxides, to processes for their preparation and to their use in crop protection and in the protection of materials.
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- N-sulfonyliminodithio compounds useful for in plant and material protection
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N-sulfonyliminodithio compounds have the formula (I), in which R1 and R2 stand for optionally substituted alkyl, alkenyl or alkinyl, and Ar stands for optionally substituted aryl; also disclosed are processes for preparing these compounds and their use for plant and material protection. STR1
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- 1,3,2-benzodithiazol-1-oxides as microbiocides
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A description is given of novel and know 1,3,2-benzodithiazole 1-oxides of the formula (I) STR1 and of their preparation and use for protecting industrial materials against infestation by microorganisms.
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- Mould-resistant emulsion paints
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The application relates to emulsion paints which are protected against fungal infestation by the use of N-alkyl-benzothiophene-2-carboxamide S,S-dioxides.
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- Medicaments containing 1-thiocarbamoyl-5-hydroxy-pyrazoles and their use as agents for combating septic shock
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This application relates to new thiocarbamoyl compounds of the formula (I) STR1 in which R1, R2, R3 and R4 have the meanings given in the description.
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- Palatable solid pesticidal compositions of ethylene and vinyl acetate copolymer
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The invention comprises compositions in solid form of ethylene/vinyl acetate copolymer with an effective amount of bioactive agent, a protein/carbohydrate-lipid source, 0 to 20% of an edible oil and optionally an attractant, dye, preservative, adversive agent and biomarker and the use, thereof, to control pests.
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- 2-Acyl-4-oxo-pyrazino-isoquinoline derivatives and process for the preparation thereof
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2-Acyl-4-oxo-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives of the formula STR1 wherein COR is the acyl radical of an up to 26 carbon atom acid and their physiologically acceptable acid addition and quaternary ammonium salts, are anthelmintics and can be produced by reacting 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline with an acid or a reactive functional derivative thereof.
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