- Novel nicotine analogues with potential anti-mycobacterial activity
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Tuberculosis (TB) is the second leading lethal infectious disease in the world after acquired immuno deficiency (AIDs). We have developed a series of twenty-five novel nicotine analogues with de-addiction property and tested them for their activity against Mycobacterium tuberculosis (MTB). In an effort to increase the specificity of action and directing nicotine analogues to target MTB, four promising compounds were further optimized via molecular docking studies against the Dihydrofolate reductase of MTB. After lead optimization, one nicotine analogue [3-(5-(3fluorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one] exhibited minimum inhibitory concentration of 1 μg/mL (2.86 nM) against M. tuberculosis (H37Rv strain), a human pathogenic strain of clinically significant importance. Pharmacokinetic analysis of [3-(5-(3fluorophenyl)nicotinoyl)-1methylpyrrolidin-2-one] with lowest MIC value via oral route in Wistar rats revealed that at a dosage of 5 mg/kg body weight gave a maximum serum drug concentration (Cmax) of 2.86 μg/mL, Tmax of one hour and a half-life (T1/2) of more than 24 h and Volume of distribution (Vd) of 27.36 L. Whereas the parenteral (intra venous) route showed a Cmax of 3.37 μg/mL, Tmax of 0.05 h, T1/2 of 24 h and Vd equivalent to 23.18 L. The acute oral toxicity and repeated oral toxicity studies in female Wistar rats had an LD50 > 2000 mg/kg body weight. Our data suggests that nicotine derivatives developed in the present study has good metabolic stability with tunable pharmacokinetics (PK) with therapeutic potential to combat MTB. However, further in vivo studies for anti-tuberculosis activity and elucidation of mode of action could result in more promising novel drug for treating MTB. To the best of our knowledge this is the first report revealing the anti-mycobacterial potential of nicotine analogue at potential therapeutic concentrations.
- Gandhi, Paresh T.,Athmaram, Thimmasandra Narayanappa,Arunkumar, Gundaiah Ramesh
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Read Online
- Total Syntheses and Antimicrobial Activities of Pyridine Alkaloids from Rubiaceae
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Pyridine alkaloids from Rubiaceae were prepared by palladium-catalyzed cross-coupling reactions of methyl 5-bromonicotinate (6) with various organometallic reagents.Baker's yeast reduction of the ketone 8 gave the levorotatory alcohol (S)-1.On this basis, the naturally occuring alcohol (+)-1 was assigned to be (R)-configurated.The alkaloids 1 and 4 show weak antimicrobial activities. - Keywords: Pyridine alkaloids; Palladium catalyst; Baker's yeast; Antimicrobial activity
- Bracher, F.,Papke, T.
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Read Online
- Novel biphenyl derivative as well as preparation method and medical application thereof
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The invention relates to the field of medicinal chemistry, and discloses biphenyl derivatives with PD-1/PD-L1 inhibitory activity as well as a preparation method and application of the biphenyl derivatives. The invention further discloses a composition containing the biphenyl derivative with the PD-1/PD-L1 inhibitory activity or the pharmaceutically acceptable salt of the biphenyl derivative and a pharmaceutically acceptable carrier of the biphenyl derivative, and application of the biphenyl derivative in preparation of a PD-1/PD-L1 inhibitor. The compound can be used for treating tumors.
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Paragraph 0065; 0085-0087
(2021/07/21)
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- A predictive model for additions to: N -alkyl pyridiniums
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Disclosed in this communication is a thorough study on the dearomative addition of organomagnesium nucleophiles to N-alkyl pyridinium electrophiles. The regiochemical outcomes have observable and predictable trends associated with the substituent patterns on the pyridinium electrophile. Often, the substituent effects can be either additive, giving high selectivities, or ablative, giving competing outcomes. Additionally, the nature of the organometallic nucleophilic component was also investigated for its role in the regioselective outcome. The effects of either reactive component are important to both the overall reactivity and site of nucleophilic addition. The utility of these observed trends is demonstrated in a concise, dearomative synthesis of a tricyclic compound shown to have insecticidal activity. This journal is
- Knight, Brian J.,Tolchin, Zachary A.,Smith, Joel M.
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supporting information
p. 2693 - 2696
(2021/03/18)
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- Nucleophile promoted gold redox catalysis with diazonium salts: C-Br, C-S and C-P bond formation through catalytic Sandmeyer coupling
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Gold-catalyzed C-heteroatom (C-X) coupling reactions are evaluated without using sacrificial oxidants. Vital to the success of this methodology is the nucleophile-assisted activation of aryldiazonium salts, which could be an effective oxidant for converting Au(i) to Au(iii) even without the addition of an assisting ligand or photocatalyst. By accelerating the reaction kinetics to outcompete C-C homo-coupling or diazonium dediazoniation, gold-catalyzed Sandmeyer reactions were achieved with different nucleophiles, forming C-Br, C-S and C-P bonds in high yields and selectivities.
- Peng, Haihui,Cai, Rong,Xu, Chang,Chen, Hao,Shi, Xiaodong
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p. 6190 - 6196
(2016/09/03)
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- Design, Synthesis, and Evaluation of Novel Auxin Mimic Herbicides
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Due to the key roles of auxins as master regulators of plant growth, there is considerable interest in the development of compounds with auxin-like properties for growth management and weed control applications. Herein, we describe the design and multiste
- Do-Thanh, Chi-Linh,Vargas, Jose J.,Thomas, Joseph W.,Armel, Gregory R.,Best, Michael D.
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p. 3533 - 3537
(2016/06/01)
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- Pleuromutilin derivatives such, its pharmaceutical composition and synthetic method and use thereof
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The present invention relates to a class of pleuromytilin compounds represented by the following general formula (I), pharmaceutically acceptable salts and preparation methods thereof, and compositions comprising the compound represented by the general fo
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Paragraph 0089-0091
(2016/11/21)
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- COMPOUNDS AND METHODS for the inhibition of HDAC
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Disclosed are compounds having the formula: wherein X1, X2, X3, R1, R2, R3, R4, Y, A, Z, L and n are as defined herein, and methods of making and using the same.
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Paragraph 0147-0148
(2015/11/24)
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- HETEROCYCLIC COMPOUNDS AND METHODS OF USE THEREOF FOR TREATMENT OF HEPATITIS C
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Compounds of formula (I) that are useful as hepatitis C virus (HCV) NS5B polymerase inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5B polymerase activity, for treating or preventing HCV infections and for i
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Page/Page column 30
(2015/01/16)
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- HETEROCYCLIC COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF HEPATITIS C
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The present invention relates to compounds of formula I that are useful as hepatitis C virus (HCV) NS5B polymerase inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5B polymerase activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.(I)
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Page/Page column 28
(2015/01/16)
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- Novel nicotine derivatives
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Described are novel nicotine derivatives represented by general formulas (I) and (III), and salts thereof, and herbicide and pharmaceutical compositions containing the same as the active ingredient. The compound and salts thereof can control annual or perennial weed growing on the land where various crops such as rice plant, wheat, cotton and corn grow for a wide period ranging from the pre-emergence to growth in a remarkably small dose. The compounds and salts thereof can be useful as an anti-microbial and anti-fungal agents and also for the treatment of blood pressure, skeletal muscle, attention deficit disorder, mental disorders, schizophrenia, Alzheimer disease, Parkinson's disease and depression. Also described is the preparation of the nicotine derivatives having formula (I) and (III).
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Paragraph 0089; 0090
(2013/05/22)
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- ALDOSTERONE SYNTHASE INHIBITORS
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This invention relates to tricyclic triazole analogues of the formula I or their pharmaceutically acceptable salts, wherein the variable are defined herein. The inventive compounds selectively inhibit aldosterone synthetase. This invention also provides for pharmaceutical compositions comprising the compounds of Formula I or their salts as well as to methods for the treatment, amelioration or prevention of conditions that could be treated by inhibiting aldosterone synthetase.
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Page/Page column 48
(2012/11/13)
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- PYRIMIDODIAZEPINONE DERIVATIVE
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The invention provides a pyrimidodiazepinone derivative represented by the general formula (I) [wherein n represents 1 or 2, Z represents a hydrogen atom or the like, R1 and R2 may be the same or different, and each represents a hydrogen atom or the like, A represents a bond, (CH2)m (wherein m represents an integer of 1 to 4), optionally substituted phenylene, optionally substituted pyridinediyl, or C=O, R3 represents a hydrogen atom, optionally substituted lower alkyl, or the like, and R4 represents a hydrogen atom or the like], or a pharmaceutically acceptable salt thereof or the like.
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(2010/04/24)
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- Mild and efficient deoxygenation of amine-N-oxides with BiCl3/Indium system
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The BiCl3/indium system was found to be a new reagent for deoxygenation of various amine-N-oxides to the corresponding amines in good to excellent yields under mild conditions.
- Yoo, Byung Woo,Choi, Jin Woo
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experimental part
p. 3550 - 3554
(2009/12/03)
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- 4-OXO-1,4-DIHYDROQUINOLINE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS
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The present invention is directed to compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.
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Page/Page column 28; 29
(2009/12/05)
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- Mild and efficient deoxygenation of amine-N-oxides with MoCl5/NaI system
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The MoCl5/NaI system was found to be a new reagent for deoxygenation of various amine-N-oxides to the corresponding amines in good to excellent yields under mild conditions. Copyright Taylor & Francis Group, LLC.
- Yoo, Byung Woo,Park, Min Chol
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p. 1646 - 1650
(2008/09/20)
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- Pyridine Derivatives For Inhibiting Human Stearoyl-Coa-Desaturase
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Methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, are disclosed, wherein the methods comprise administering to a mammal in need thereof a compound of formula (I) where x, y, G, J, K, L, M, W, V, R2, R3, R4, R5, R5a,
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Page/Page column 15
(2008/12/06)
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- KINASE INHIBITOR COMPOUNDS
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Pyridine and pyridazine derivatives have unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as cancer.
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Page/Page column 49
(2008/12/07)
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- Fast and efficient access to a family of multifunctional 1,3,5-trisubstituted piperidines
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A collection of new 1,3,5-trisubstituted piperidines has been synthesized starting from the commercially available 5-bromonicotinic acid. A unified, diastereoselective strategy allows the controlled access to both cis and trans stereochemistries. The heterocyclic compounds thus prepared bear multiple functional groups suitable for structural diversification and combichem protocols. Copyright Taylor & Francis Group, LLC.
- Diaz, Jose Luis,Fernandez-Forner, Dolors,Bach, Jordi,Lavilla, Rodolfo
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experimental part
p. 2799 - 2813
(2009/04/11)
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- THERAPEUTICS
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The present invention relates to the use of a compound of formula (I); wherein: R1 comprises a carbonyl group and R2 is a hydrocarbyl group; optionally wherein said ring is further substituted; or a pharmaceutically acceptable salt thereof; in the manufacture of a medicament for use in one or more of: modulating the release of intracellular calcium from a store controlled by nicotinic acid adenine dinucleotide phosphate; modulating calcium spikes in mammalian cells; treating diseases in one or more of brain, heart, pancreatic cells (e.g. pancreatic acinar and pancreatic beta cells), immune cells, T-cells, haemopoietic cells including phagocytes; treating diseases in one or more of brain, heart, pancreatic cells (e.g. pancreatic acinar and pancreatic beta cells), immune cells, T-cells, haemopoietic cells including phagocytes by modulating the release of intracellular calcium from a store controlled by nicotinic acid adenine dinucleotide phosphate; treating diseases in one or more of brain, heart, and T-cells by modulating calcium spikes in mammalian cells.
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Page/Page column 52-53
(2008/06/13)
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- A synthetic entry to 3,5-disubstituted pyridines
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A straightforward entry to 3,5-disubstituted pyridines from 3-substituted pyridines, based on the acylation of N-alkyl-1,4-dihydropyridine derivatives followed by a tandem N-dealkylation-oxidation sequence is reported.
- Bennasar, M.-Llu?sa,Zulaica, Ester,Roca, Tomàs,Alonso, Yolanda,Monerris, Manuel
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p. 4711 - 4714
(2007/10/03)
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- Mild and Efficient Deoxygenation of Amine-N-oxides with Titanium Tetrachloride-Indium System
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TiCl4/In system was found to be a new reagent for deoxygenation of various amine-N-oxides to the corresponding amines in good to excellent yields under mild conditions.
- Yoo, Byung Woo,Choi, Kwang Hyun,Choi, Kyung Il,Kim, Joong Hyup
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p. 4185 - 4189
(2007/10/03)
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- Nicotinyl aspartyl ketones as inhibitors of caspase-3
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Caspase-3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact in the treatment of several degenerative diseases. Since P1 aspartic acid is a required element of recognition for this enzyme, a
- Isabel, Elise,Black, W. Cameron,Bayly, Christopher I.,Grimm, Erich L.,Janes, Marc K.,McKay, Daniel J.,Nicholson, Donald W.,Rasper, Dita M.,Renaud, Johanne,Roy, Sophie,Tam, John,Thornberry, Nancy A.,Vaillancourt, John P.,Xanthoudakis, Steven,Zamboni, Robert
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p. 2137 - 2140
(2007/10/03)
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- Indoles
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A 1,4-substituted cyclic amine derivative represented by the following formula or a pharmacologically acceptable salt thereof: wherein A, B, C, D, T, Y, and Z each represent a methine or a nitrogen linkage; R1, R2, R3, R4, and R5 each represent a substituent; n represents 0 or an integer of 1 to 3; m represents 0 or an integer of 1 to 6; and p represents an integer of 1 to 3. The compounds have serotonin antagonism. They are therefore clinically useful as medicaments, in particular, for treating, ameliorating, and preventing spastic paralysis. They are also useful as central muscle relaxants for ameliorating myotonia.
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- Esterification of carboxylic acids with boron trichloride
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Treatment of carboxylic acids with boron trichloride followed by addition of alcohol provides the carboxylic ester. This esterification, following BCl3 ether or ester O-C cleavage reaction conditions, proceeds cleanly in good yields with most substrates. Cleavage of benzyl esters with boron trichloride then treating with methanol affords the methyl ester.
- Dyke, Christopher A.,Bryson, Thomas A.
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p. 3959 - 3961
(2007/10/03)
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- Synthesis and biological evaluation of some acyclic pyridine C- nucleosides. Part one
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The reaction between 3-bromo-5-chloromethylpyridine hydrochloride (4) with the mono sodium salt of ethylene glycol was investigated. 3-Bromo-5-(2- hydroxyethoxymethyl)-pyridine (5) was synthesized and converted to the 3- carboxy analogue using butyllithiu
- Van Hemel,Esmans,Alderweireldt,Dommisse,De Groot,Balzarini,De Clercq
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p. 2345 - 2366
(2007/10/02)
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- A General Synthesis of 5-Arylnicotinates
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Arylboronic acids have been found to couple efficiently with 5-bromonicotinates to yield 5-arylnicotinates.The reaction is considerably more sensitive to steric inhibition in the arylboronic acid component than in the pyridyl bromide 4.The dianion salt of the boronic acid is implicated as the reactive intermediate responsible for the facile coupling reaction.Pure arylboronic acids are best prepared by using triisopropyl borate as the transmetalating agent.
- Thompson, Wayne J.,Gaudino, John
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p. 5237 - 5243
(2007/10/02)
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