- Ligand-based rational design, synthesis and evaluation of novel potential chemical chaperones for opsin
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Inherited blinding diseases retinitis pigmentosa (RP) and a subset of Leber's congenital amaurosis (LCA) are caused by the misfolding and mistrafficking of rhodopsin molecules, which aggregate and accumulate in the endoplasmic reticulum (ER), leading to photoreceptor cell death. One potential therapeutic strategy to prevent the loss of photoreceptors in these conditions is to identify opsin-binding compounds that act as chemical chaperones for opsin, aiding its proper folding and trafficking to the outer cell membrane. Aiming to identify novel compounds with such effect, a rational ligand-based approach was applied to the structure of the visual pigment chromophore, 11-cis-retinal, and its locked analogue 11-cis-6mr-retinal. Following molecular docking studies on the main chromophore binding site of rhodopsin, 49 novel compounds were synthesized according to optimized one-to seven-step synthetic routes. These agents were evaluated for their ability to compete for the chromophore binding site of opsin, and their capacity to increase the trafficking of the P23H opsin mutant from the ER to the cell membrane. Different new molecules displayed an effect in at least one assay, acting either as chemical chaperones or as stabilizers of the 9-cis-retinal-rhodopsin complex. These compounds could provide the basis to develop novel therapeutics for RP and LCA.
- Bassetto, Marcella,Brancale, Andrea,Pasqualetto, Gaia,Pileggi, Elisa,Rozanowska, Malgorzata,Schepelmann, Martin,Varricchio, Carmine
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supporting information
(2021/09/24)
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- Reductive cyanation of organic chlorides using CO2 and NH3 via Triphos–Ni(I) species
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Cyano-containing compounds constitute important pharmaceuticals, agrochemicals and organic materials. Traditional cyanation methods often rely on the use of toxic metal cyanides which have serious disposal, storage and transportation issues. Therefore, there is an increasing need to develop general and efficient catalytic methods for cyanide-free production of nitriles. Here we report the reductive cyanation of organic chlorides using CO2/NH3 as the electrophilic CN source. The use of tridentate phosphine ligand Triphos allows for the nickel-catalyzed cyanation of a broad array of aryl and aliphatic chlorides to produce the desired nitrile products in good yields, and with excellent functional group tolerance. Cheap and bench-stable urea was also shown as suitable CN source, suggesting promising application potential. Mechanistic studies imply that Triphos-Ni(I) species are responsible for the reductive C-C coupling approach involving isocyanate intermediates. This method expands the application potential of reductive cyanation in the synthesis of functionalized nitrile compounds under cyanide-free conditions, which is valuable for safe synthesis of (isotope-labeled) drugs.
- Dong, Yanan,Li, Yuehui,Yang, Peiju,Zhao, Shizhen
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- Synthesis and antitubercular evaluation of reduced lipophilic imidazo[1,2-a]pyridine-3-carboxamide derivatives
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A series of reduced lipophilic N-benzylic imidazo[1,2-a]pyridine carboxamides (IPAs) with various side chains were designed and synthesized as new anti-TB agents in this work. Five derivatives A2, A3, A4, B1 and B9 exhibit excellent in vitro activity (MIC: 0-∞ and Cmax than Q203 and PBTZ169, suggesting its promising potential to be a lead compound for future antitubercular drug discovery.
- Wang, Hongjian,Wang, Apeng,Gu, Jian,Fu, Lei,Lv, Kai,Ma, Chao,Tao, Zeyu,Wang, Bin,Liu, Mingliang,Guo, Huiyuan,Lu, Yu
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- Development of an SNAr Reaction: A Practical and Scalable Strategy to Sequester and Remove HF
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A simple and operationally practical method to sequester and remove fluoride generated through the SNAr reaction between amines and aryl fluorides is reported. Calcium propionate acts as an inexpensive and environmentally benign in situ scrubbe
- Blacker, A. John,Moran-Malagon, Gabriel,Powell, Lyn,Reynolds, William,Stones, Rebecca,Chapman, Michael R.
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- Development of an SNAr Reaction: A Practical and Scalable Strategy to Sequester and Remove HF
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A simple and operationally practical method to sequester and remove fluoride generated through the SNAr reaction between amines and aryl fluorides is reported. Calcium propionate acts as an inexpensive and environmentally benign in situ scrubbe
- Blacker, A. John,Moran-Malagon, Gabriel,Powell, Lyn,Reynolds, William,Stones, Rebecca,Chapman, Michael R.
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p. 1086 - 1091
(2018/09/29)
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- Biphenyl sulfonic acid ligands for catalytic C-N cross coupling of aryl halides with anilines and secondary amines
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The use of two biphenyl sulfonic acid ligands for the catalytic C-N cross coupling of aryl halides with anilines, 3-aminopyridine, and secondary amines is reported. Our results represent a significant improvement compared to state of the art methods especially with regards to the removal of palladium.
- Wittel, B?rbel,Vogel, Till,Scharl, Heiko,Nerdinger, Sven,Lehnemann, Bernd,Meudt, Andreas,Snieckus, Victor
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p. 4583 - 4593
(2018/07/31)
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- USE OF DISUBSTITUTED BENZENES TO CONTROL INSECTICIDE-RESISTANT PESTS
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The invention is in the technical field of insect control and relates to the use of a disubstituted benzenes for controlling insecticide-resistant pests such as mosquitoes and cockroaches.
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Page/Page column 44
(2018/11/26)
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- FATTY ACID SYNTHASE INHIBITORS
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Disclosed are compounds having Formula (I), wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Y, m, and n are defined herein and methods of using the same.
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Page/Page column 53; 54; 57
(2014/01/07)
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- Synthesis and antileishmanial activity of novel 5-(5-nitrofuran-2-y1)-1,3, 4-thiadiazoles with piperazinyl-linked benzamidine substituents
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In order to optimize the antileishmanial activity of piperazinyl-linked 5-(5-nitrofuran-2-yl)-1,3,4-thiadiazoles, we synthesized a series of 5-(5-nitrofuran-2-y1)-1,3,4-thiadiazoles with piperazinyl-linked benzamidine substituent as scaffold found in pentamidine related antiprotozoals. The structure of target compounds was confirmed by IR, 1H NMR, 13C NMR and Mass spectral data. All compounds were tested for in vitro activity against the promastigote and amastigote forms of Leishmania major. From the results, we found that the substitution on amidine nitrogen has profound role in the biological activity of these compounds. The 5-nitrofuran-2-yl-1,3,4-thiadiazoles having n-propyl, n-butyl and benzyl side chain on benzamidine (as in compounds 2d, 2e and 2g, respectively) showed very good activity in both forms of promastigote and amastigote. The most active compound was N-propyl-4-(4-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl) piperazin-1-yl) benzamidine hydrochloride (2d) with IC50 value of 0.08 μM in promastigote model. This compound showed a very low level of toxicity against macrophages (CC50 = 785 μM), with the highest selectivity index (SI = 78.5) among the tested compounds.
- Tahghighi, Azar,Marznaki, Farzane Rezazade,Kobarfard, Farzad,Dastmalchi, Siavoush,Mojarrad, Javid Shahbazi,Razmi, Sepideh,Ardestani, Sussan Kabudanian,Emami, Saeed,Shafiee, Abbas,Foroumadi, Alireza
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experimental part
p. 2602 - 2608
(2011/06/21)
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- Novel benzo[ b ]thiophene derivatives as new potential antidepressants with rapid onset of action
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We report benzo[b]thiophene derivatives synthesized according to a dual strategy. 8j, 9c, and 9e with affinity values toward 5-HT7R and 5-HTT were selected to probe their antidepressant activity in vivo using the forced swimming text (FST). The results showed significant antidepressant activity after chronic treatment. 9c was effective in reducing the immobility time in FST even after acute treatment. These findings identify these compounds as a new class of antidepressants with a rapid onset of action.
- Berrade, Luis,Aisa, Bárbara,Ramirez, María J.,Galiano, Silvia,Guccione, Salvatore,Moltzau, Lise Román,Levy, Finn Olav,Nicoletti, Ferdinando,Battaglia, Giuseppe,Molinaro, Gemma,Aldana, Ignacio,Monge, Antonio,Perez-Silanes, Silvia
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supporting information; experimental part
p. 3086 - 3090
(2011/07/07)
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- Synthesis and antibacterial activity of new 1,4-disubstituted piperazine derivatives
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In search of antibacterial agents new 4-phenylpiperazine derivatives were obtained. Their structures include some heterocyclic (thiazole, oxadiazole, piperazine, and benzimidazole) systems, as well as functional (thioamide and amidoxime) groups, frequentl
- Pancechowska-Ksepko, Danuta,Spalinska, Katarzyna,Foks, Henryk,Kedzia, Anna,Wierzbowska, Maria,Kwapisz, Ewa,Janowiec, Mieczyslaw,Zwolska, Zofia,Augustynowicz-Kopec, Ewa
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experimental part
p. 1252 - 1263
(2009/04/07)
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- Therapeutic quinazoline derivatives
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A compound of formula (I) or a salt, ester, amide or prodrug thereof; where X is O, or S, S(O), S(O)2 or NR6 where R6 is hydrogen of C1-6alkyl; R5 is an optionally substituted 6-membered aromatic ring containing at least one nitrogen atom, and R1, R2, R3, R4 are independently selected from halogeno, cyano, nitro, C1-3alkylsulphanyl, —N(OH)R7— (wherein R7 is hydrogen, or C1-3alkyl), or R9X1— (wherein X1 represents a direct bond, —O—, —CH2—, —OC(O), —C(O)—, —S—, —SO—, —SO2—, —NR10C(O)—, —C(O)NR11—, —SO2NR12—, —NR13SO2— or NR14— (wherein R10, R11, R12, R13 and R14 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl), and R9 is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl or optionally substituted alkoxy; provided that at least one of R2 or R3 is other than hydrogen. These compounds inhibit aurora 2 kinase and are useful in the preparation of medicaments for the treatment of proliferative disease such as cancer.
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- Potent, selective, and orally active adenosine A2A receptor antagonists: Arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines
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Antagonism of the adenosine A2A receptor offers great promise in the treatment of Parkinson's disease. Employing the known pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A2A antagonist SCH 58261 as a starting point, we identified the potent and selective (vs. A1) antagonist 11 h, orally active in the rat haloperidol-induced catalepsy model. We further optimized this lead to the methoxyethoxyethyl ether 12a (SCH 420814), which shows broad selectivity, good pharmacokinetic properties, and excellent in vivo activity.
- Neustadt, Bernard R.,Hao, Jinsong,Lindo, Neil,Greenlee, William J.,Stamford, Andrew W.,Tulshian, Deen,Ongini, Ennio,Hunter, John,Monopoli, Angela,Bertorelli, Rosalia,Foster, Carolyn,Arik, Leyla,Lachowicz, Jean,Ng, Kwokei,Feng, Kung-I
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p. 1376 - 1380
(2008/02/05)
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- Process for preparing monoarylpiperazines
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The invention provides a process for preparing arylpiperazines from the corresponding aryl chlorides or bromides and piperazine using a base and a catalyst consisting of a palladium salt and a bisaryldialkylphosphine.
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Page/Page column 5
(2008/06/13)
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- Synthesis and pharmacological evaluation of potent and highly selective D3 receptor ligands: Inhibition of cocaine-seeking behavior and the role of dopamine D3/D2 receptors
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The synthesis, pharmacological evaluation, and structure - activity relationships (SARs) of a series of novel arylalkylpiperazines structurally related to BP897 (3) are described. In binding studies, the new derivatives were tested against a panel of dopamine, serotonin, and noradrenaline receptor subtypes. Focusing mainly on dopamine D3 receptors, SAR studies brought to light a number of structural features required for high receptor affinity and selectivity. Several heteroaromatic systems were explored for their dopamine receptor affinities, and combinations of synthesis, biology, and molecular modeling, were used to identify novel structural leads for the development of potent and selective D3 receptor ligands. Introduction of an indole ring linked to a dichlorophenylpiperazine system provided two of the most potent and selective ligands known to date (D 3 receptor affinity in the picomolar range). The intrinsic pharmacological properties of a subset of potent D3 receptor ligands were also assessed in [35S]-GTPγS binding assays. Evidence from animal studies, in particular, has highlighted the dopaminergic system's role in how environmental stimuli induce drug-seeking behavior. We therefore tested two novel D3 receptor partial agonists and a potent D 3-selective antagonist in vivo for their effect in the cocaine-seeking behavior induced by reintroduction of cocaine-associated stimuli after a long period of abstinence, and without any further cocaine. Compound 5g, a nonselective partial D3 receptor agonist with a pharmacological profile similar to 3, and 5p, a potent and selective D 3 antagonist, reduced the number of active lever presses induced by reintroduction of cocaine-associated stimuli. However, 5q, a highly potent and selective D3 partial agonist, did not have any effect on cocaine-seeking behavior. Although brain uptake studies are needed to establish whether the compounds achieve brain concentrations comparable to those active in vitro on the D3 receptor, our experiments suggest that antagonism at D2 receptors might significantly contribute to the reduction of cocaine craving by partial D3 agonists.
- Campiani, Giuseppe,Butini, Stefania,Trotta, Francesco,Fattorusso, Caterina,Catalanotti, Bruno,Aiello, Francesca,Gemma, Sandra,Nacci, Vito,Novellino, Ettore,Stark, Jennifer Ann,Cagnotto, Alfredo,Fumagalli, Elena,Carnovali, Francesco,Cervo, Luigi,Mennini, Tiziana
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p. 3822 - 3839
(2007/10/03)
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- 1,4-Disubstituted benzenes as insecticides
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Compounds of formula I: wherein A, B, D, and R are as defined herein and their agriculturally acceptable salts are disclosed as effective insecticides. In addition, compositions comprising an insecticidally effective amount of a compound of Formula I in admixture with at least one agriculturally acceptable extender or adjuvant and methods of controlling insects comprising applying said compositions to locus on crops where control is desired are disclosed. It is emphasized that his abstract is provided to comply with the rules requiring an abstract that will allow a searcher or other reader to quickly ascertain the subject matter of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims (see 37 C.F.R. 1.72(b)).
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- Sequential mono-N-arylation of piperazine nitrogens. Part 1: A simplified method and its application to the preparation of a key N,N'-biaryl piperazine antifungal intermediate
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A simple sequential N-arylation of piperazine without the use of a protecting group, catalyst, specialized equipment or a large excess of piperazine, and its application towards the preparation of the key differentially N,N'-biarylated piperazine antifungal intermediate N-(4-hydroxyphenyl)-N'-(4-aminophenyl)piperazine, 6, is described.
- Hepperle, Michael,Eckert, Jeffrey,Gala, Dinesh
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p. 5655 - 5659
(2007/10/03)
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- Sequential mono-N-arylation of piperazine nitrogens. Part 2: The role of hydrogen bonding
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A mechanistic study of the simple sequential N-arylation of piperazine suggests that in an electron-withdrawing group (EWG) containing N-arylated piperazines, hydrogen bonding of the secondary amine hydrogen is important for its non-metal catalyzed conversion to N,N'-diaryl piperazines. A combination of synthetic experiments, molecular modeling, and NMR studies were carried out to test this hypothesis.
- Eckert, Jeffrey,Chan, Tze-Ming,Osterman, Rebecca M.,Lambert, Joseph B.,Gala, Dinesh
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p. 5661 - 5665
(2007/10/03)
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- Design and synthesis of an orally active GPIIb/IIIa antagonist based on a phenylpiperazine scaffold
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The design and synthesis of an orally active LMW non-peptide GPIIb/IIIa antagonist, based on a N,N'-bisphenylpiperazine scaffold, is described. The optimal compound showed a high in vitro binding potency (pIC50=8.7) in combination with potent oral antithrombotic activity (30-40% inhibition of thrombus growth at 0.3-3 mg/kg) with a duration of action of >90 min. in a hamster cheek pouch model.
- Van Maarseveen, Jan H.,Den Hartog, Jack A.J.,Tipker, Koos,Reinders, Jan-Hendrik,Brakkee, Joost,Schoen, Uwe,Kehrbach, Wolfgang,Kruse, Chris G.
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p. 1531 - 1536
(2007/10/03)
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- Carboxylic acid derivatives, pharmaceutical compositions containing these compounds and processes for preparing them
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The invention relates to carboxylic acid derivatives of general formula wherein A to G are defined as in claim 1, the tautomers thereof, the stereoisomers thereof including the mixtures thereof and the addition salts thereof, particularly the physiologically acceptable salts with inorganic or organic acids or bases, which have valuable pharmacological properties, preferably inhibitory effects on aggregation, and to pharmaceutical compositions containing the compounds and processes for preparing them.
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- Diaminopyrimidines
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Substituted-phenyl derivatives of 5-(1,4-piperazinyl)-2,4-pyrimidinediamine are effective as antibacterial and antitumor agents. Methods of preparing such compounds, pharmaceutical compositions based thereon, and a method of treating bacterial infections in a mammal in need of such treatment are disclosed.
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