- Synthesis of isoquinuclidine analogs of chloroquine: Antimalarial and antileishmanial activity
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The isoquinuclidine (2-azabicyclo[2.2.2]octane) ring system may be viewed as a semi-rigid boat form of the piperidine ring and, when properly substituted, a scaffold for rigid analogs of biologically active ethanolamines and propanolamines. It is present in natural products (such as ibogaine and dioscorine) that display interesting pharmacological properties. In this study, we have expanded our continuing efforts to incorporate this ring system in numerous pharmacophores, by designing and synthesizing semirigid analogs of the antimalarial drug chloroquine. The analogs were tested in vitro against Plasmodium falciparum strains and Leishmania donovani promastigote cultures. Compounds 6 and 13 displayed potent antimalarial activity against both chloroquine-susceptible D6 and the -resistant W2 strains of P. falciparum. All analogs also demonstrated significant antileishmanial activity with compounds 6 and 13 again being the most potent. The fact that these compounds are active against both chloroquine-resistant and chloroquine-sensitive strains as well as leishmanial cells makes them promising candidates for drug development.
- Faruk Khan,Levi, Mark S.,Tekwani, Babu L.,Wilson, Norman H.,Borne, Ronald F.
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- A non-hallucinogenic psychedelic analogue with therapeutic potential
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The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to v
- Cameron, Lindsay P.,Tombari, Robert J.,Lu, Ju,Pell, Alexander J.,Hurley, Zefan Q.,Ehinger, Yann,Vargas, Maxemiliano V.,McCarroll, Matthew N.,Taylor, Jack C.,Myers-Turnbull, Douglas,Liu, Taohui,Yaghoobi, Bianca,Laskowski, Lauren J.,Anderson, Emilie I.,Zhang, Guoliang,Viswanathan, Jayashri,Brown, Brandon M.,Tjia, Michelle,Dunlap, Lee E.,Rabow, Zachary T.,Fiehn, Oliver,Wulff, Heike,McCorvy, John D.,Lein, Pamela J.,Kokel, David,Ron, Dorit,Peters, Jamie,Zuo, Yi,Olson, David E.
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p. 474 - 479
(2020/12/13)
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- Enantioselective Formal Total Synthesis of (-)-Quinagolide
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The enantioselective formal total synthesis of (-)-quinagolide has been accomplished in a linear sequence of 8 purification steps from pyridine. The key steps are (a) organocatalyzed Diels-Alder reaction for fixing all three stereocenters on piperidine ri
- Chavan, Subhash P.,Kadam, Appasaheb L.,Gonnade, Rajesh G.
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supporting information
p. 9089 - 9093
(2019/11/14)
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- Clathrodin, hymenidin and oroidin, and their synthetic analogues as inhibitors of the voltage-gated potassium channels
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We have prepared three alkaloids from the Agelas sponges, clathrodin, hymenidin and oroidin, and a series of their synthetic analogues, and evaluated their inhibitory effect against six isoforms of the Kv1 subfamily of voltage-gated potassium channels, Kv1.1-Kv1.6, expressed in Chinese Hamster ovary (CHO) cells using automated patch clamp electrophysiology assay. The most potent inhibitor was the (E)-N-(3-(2-amino-1H-imidazol-4-yl)allyl)-4,5-dichloro-1H-pyrrole-2-carboxamide (6g) with IC50 values between 1.4 and 6.1 μM against Kv1.3, Kv1.4, Kv1.5 and Kv1.6 channels. All compounds tested displayed selectivity against Kv1.1 and Kv1.2 channels. For confirmation of their activity and selectivity, compounds were additionally evaluated in the second independent system against Kv1.1-Kv1.6 and Kv10.1 channels expressed in Xenopus laevis oocytes under voltage clamp conditions where IC50 values against Kv1.3-Kv1.6 channels for the most active analogues (e.g. 6g) were lower than 1 μM. Because of the observed low sub-micromolar IC50 values and fairly low molecular weights, the prepared compounds represent good starting points for further optimisation towards more potent and selective voltage-gated potassium channel inhibitors.
- Zidar, Nace,?ula, Ale?,Toma?i?, Tihomir,Rogers, Marc,Kirby, Robert W.,Tytgat, Jan,Peigneur, Steve,Kikelj, Danijel,Ila?, Janez,Ma?i?, Lucija Peterlin
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p. 232 - 241
(2017/08/14)
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- Diels-Alder Reactions of α-Amido Acrylates with N-Cbz-1,2-dihydropyridine and Cyclopentadiene
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Thermal Diels-Alder reactions of α-amido acrylates with N-Cbz-1,2-dihydropyridine and cyclopentadiene have been explored to investigate the factors influencing the endo/exo selectivity. For the dihydropyridine, steric factors allowed the diastereoselectivity to be modulated to favor either endo- or exo-ester adducts. For cyclopentadiene, the endo-ester adducts were favored regardless of steric perturbation, although catalysis by bulky Lewis acids increased the proportion of exo-ester adducts in some cases. These Lewis acids were incompatible with the dihydropyridine diene as they induced its decomposition.
- Abas, Hossay,Frampton, Christopher S.,Spivey, Alan C.
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p. 9947 - 9956
(2016/11/02)
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- Pathogen detection
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Pathogens are detected through the use of mutation-resistant ligands.
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Page/Page column 119
(2016/02/29)
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- Enantioselective Synthesis of Chiral Piperidines via the Stepwise Dearomatization/Borylation of Pyridines
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We have developed a novel approach for the synthesis of enantioenriched 3-boryl-tetrahydropyridines via the Cu(I)-catalyzed regio-, diastereo-, and enantioselective protoborylation of 1,2-dihydropyridines, which were obtained by the partial reduction of the pyridine derivatives. This dearomatization/enantioselective borylation stepwise strategy provides facile access to chiral piperidines together with the stereospecific transformation of a stereogenic C-B bond from readily available starting materials. Furthermore, the utility of this method is demonstrated for the concise synthesis of the antidepressant drug (-)-paroxetine. A theoretical study of the reaction mechanism is also described.
- Kubota, Koji,Watanabe, Yuta,Hayama, Keiichi,Ito, Hajime
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supporting information
p. 4338 - 4341
(2016/05/09)
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- A convenient strategy for synthesizing the Agelas alkaloids clathrodin, oroidin, and hymenidin and their (un)saturated linker analogs
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A convenient strategy for the scalable synthesis of the 2-aminoimidazole alkaloids, clathrodin, oroidin, and hymenidin derived from marine Agelas species and their analogs possessing a saturated or unsaturated linker moiety is described. The key intermediates, 4-(3-aminopropyl)-1H-imidazol-2-amine and (E)-4-(3-aminoprop-1-en-1-yl)-1H-imidazol-2-amine were obtained through two different synthetic pathways starting from l-ornithine and benzyl 1,2-dihydropyridine-1-carboxylate respectively, using (i) an innovative combination of Weinreb amide strategy with di-Boc protection, and (ii) a modified pyridine-1(2H)-carboxylate based strategy. Convenient access to these 2-aminoimidazole amines is crucial for the synthesis of libraries of clathrodin, oroidin, and hymenidin analogs.
- ?ula, Ale?,Kikelj, Danijel,Ila?, Janez
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supporting information
p. 3999 - 4001
(2014/07/08)
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- Highly enantioselective synthesis of isoquinuclidine by diels-alder reaction of 1,2-dihydropyridine utilizing chiral bisoxazoline-Cu(II) complex
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The enantioselective Diels-Alder (D-A) reaction between N-phenoxycarbonyl- or N-benzyloxycarbonyl-1,2-dihydropyridine (1a or 1b) and N(2)-acryloyl-N(1)-(1- naphthylmethyl)-5,5-dimethylpyrazolidin-3-one (2b) using (S,S)-bisoxazoline- Cu(II) catalyst (A, B, C or D) has been investigated. Utilizing (S,S)-t-Bu-bisoxazoline-Cu(II) catalyst C, the D-A reaction of 1a and 2 afforded the endo-(7S)-isoquinuclidines (3, 4 or 5) in good chemical yields with high enantioselectivity (up to 99% e.e.).
- Hutabarat, N.D.M. Romauli,Seki, Chigusa,Shimizu, Takashi,Hirama, Masafumi,Kohari, Yoshihito,Nakano, Hiroto,Uwai, Koji,Takano, Nobuhiro,Kwon, Eunsang,Matsuyama, Haruo
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p. 203 - 217
(2013/08/23)
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- Reductive Heck coupling: An efficient approach toward the iboga alkaloids. Synthesis of ibogamine, epiibogamine and iboga analogs
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A mild and efficient synthetic route to the iboga scaffold by employing reductive-Heck type annulation is described. The utility of this process is demonstrated by the direct access to the ibogamine, epiibogamine and iboga-analogs. The cyclization precursors were readily obtained from 2-iodoaniline by heteroannulation reaction with suitable alkynes followed by iodination.
- Jana, Goutam Kumar,Sinha, Surajit
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supporting information; experimental part
p. 1671 - 1674
(2012/04/11)
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- Asymmetric total synthesis of (+)-luciduline: Toward a general approach to related lycopodium alkaloids
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As part of a research program directed toward the synthesis of Lycopodium alkaloids, a multigram scale asymmetric synthesis of intermediate 11 was achieved in 11 steps from pyridine (17). In addition to our alkene metathesis strategy, a key feature of thi
- Barbe, Guillaume,Fiset, Dominic,Charette, Andre B.
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experimental part
p. 5354 - 5362
(2011/08/06)
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- Synthesis of new series of iboga analogues
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Synthesis of new iboga-analogues, replacing the indole ring with a benzofuran moiety has been described. Starting materials are the suitably substituted benzofuran derivatives and have been synthesized by Pd-catalyzed reactions. The conversion of endo-6-m
- Paul, Sibasish,Pattanayak, Sankha,Sinha, Surajit
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supporting information; experimental part
p. 6166 - 6169
(2011/12/01)
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- ISOQUINUCLIDINE DERIVATIVE AND METHOD FOR PRODUCING 1-CYCLOHEXENE-1-CARBOXYLIC ACID DERIVATIVE BY USING THE SAME
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The present invention provides an isoquinuclidine derivative which can be used to easily synthesize oseltamivir or an analog thereof. In particular, the present invention provides an isoquinuclidine derivative represented by the following formula (1) or an enantiomer thereof: wherein in the formula (1), A represents a protective group for the nitrogen atom; R1 to R1 each independently represent an alkyl group which may have a substituent, an aryl group which may have a substituent, or a hydrogen atom; and X represents a halogen atom.
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Page/Page column 10-12
(2009/05/29)
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- FUSED HETEROCYCLIC COMPOUNDS USEFUL AS MODULATORS OF NUCLEAR HORMONE RECEPTOR FUNCTION
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Disclosed are fused heterocyclic compounds of Formula (I) or pharmaceutically-acceptable salts or stereoisomers thereof. Also disclosed are methods of using such compounds in the treatment of at least one androgen receptor-associated condition, such as, f
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Page/Page column 71
(2009/06/27)
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- A practical synthesis of (-)-oseltamivir
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Oseltamivir phosphate (Tamiflu) is a potent inhibitor of neuraminidase, and is used worldwide as a drug for type A or B influenza. The industrial synthesis of oseltamivir uses shikimic acid as a starting material, but the price fluctuates, depending on the supply of star anise. We have developed a practical synthesis of oseltamivir from pyridine, which features an asymmetric Diels-Alder reaction of dihydropyridine using MacMillan's catalyst, a bromolactonization, Hofmann rearrangement with PhI(OAc)2, and a domino transformation of the bicyclo[2.2.2] system into an aziridine compound.
- Satoh, Nobuhiro,Akiba, Takahiro,Yokoshima, Satoshi,Fukuyama, Tohru
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experimental part
p. 3239 - 3245
(2009/08/15)
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- A practical synthesis of (-)-oseltamivir
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(Chemical Equation Presented) Keep it simple: Still in hot demand, the influenza drug (-)-oseltamivir phosphate (tamiflu; see scheme) has now been synthesized from pyridine by using inexpensive reagents. A strict minimum of purification steps are required in a synthetic route which features an asymmetric Diels-Alder reaction, a bromolactonization, a Hofmann rearrangement, and a domino transformation of a bicyclo[2.2.2] system into an aziridine intermediate.
- Satoh, Nobuhiro,Akiba, Takahiro,Yokoshima, Satoshi,Fukuyama, Tohru
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p. 5734 - 5736
(2008/04/12)
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- Discovery and activity of (1R,4S,6R)-N-[(1R)-2-[4-cyclohexyl-4-[[(1,1- dimethylethyl)amino]carbonyl]-1-piperidinyl]-1-[(4-fluorophenyl)methyl] -2-oxoethyl]-2-methyl-2-azabicyclo[2.2.2]octane-6-carboxamide (3, RY764), a potent and selective melanocortin su
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A novel isoquinuclidine containing selective melanocortin subtype-4 receptor small molecule agonist, 3 (RY764), is reported. Its in vivo characterization revealed mechanism-based food intake reduction and erectile activity augmentation in rodents.
- Ye, Zhixiong,Guo, Liangqin,Barakat, Khaled J.,Pollard, Patrick G.,Palucki, Brenda L.,Sebhat, Iyassu K.,Bakshi, Raman K.,Tang, Rui,Kalyani, Rubana N.,Vongs, Aurawan,Chen, Airu S.,Chen, Howard Y.,Rosenblum, Charles I.,MacNeil, Tanya,Weinberg, David H.,Peng, Qianping,Tamvakopoulos, Constantin,Miller, Randy R.,Stearns, Ralph A.,Cashen, Doreen E.,Martin, William J.,Metzger, Joseph M.,Strack, Alison M.,MacIntyre, D. Euan,Van Der Ploeg, Lex H. T.,Patchett, Arthur A.,Wyvratt, Matthew J.,Nargund, Ravi P.
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p. 3501 - 3505
(2007/10/03)
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- Thermal and induced decompositions of N′-alkoxycarbonyldihydropyridines: End product analysis and EPR spectra of azacyclohexadienyl radicals
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Hydrogen abstraction from N-alkoxycarbonyldihydropyridines generated azacyclohexadienyl radicals (pyridinyl radicals) which are characterised by EPR spectroscopy. In the presence of peroxide initiators, N-alkoxycarbonyl-1,2-dihydropyridines decomposed with production of pyridine, the corresponding alkyl formate, alkyl benzoate and alkanol being formed as the major products. Absence of cyclised products in experiments with substrates containing hex-5-enyl, pent-4-enyloxy etc. units demonstrates that radical production must be minor and that N-alkoxycarbonylazacyclohexadienyl radicals do not readily undergo ss-scission of the exocyclic N-C bond. The most probable mechanism is a direct 1,2-elimination of formate. The alcohols which accompanied the other products are probably formed by hydrolysis of the formates and benzoates. Analogous chemistry is displayed by N-alkoxycarbonyl-1,4-dihydropyridines at higher temperatures where 1,4-elimination of formate is too rapid for homolytic radical production to compete.
- Baguley, Paul A.,Walton, John C.
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p. 1423 - 1429
(2007/10/03)
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- Azetidine derivatives to treat memory and learning disorders
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This invention relates to novel azetidines and derivatives thereof, as well as to pharmaceutical compositions and methods of treating memory and learning disorders. Another aspect of the invention relates to a method of utilizing the compounds and composi
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- Synthesis and biological activity of 1,2,4-oxadiazole derivatives: Highly potent and efficacious agonists for cortical muscarinic receptors
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The synthesis and biochemical evaluation of novel 1,2,4-oxadiazole-based muscarinic agonists which can readily penetrate into the CNS is reported. Efficacy and binding of these compounds are markedly influenced by the structure and physicochemical properties of the cationic head group. In a series of azabicyclic ligands efficacy and affinity are influenced by the size of the surface area presented to the receptor, at the active site, and the degree of conformational flexibility. The exo-1-azanorbornane 16a represents the optimum arrangement, and this compound is one of the most efficacious and potent muscarinic agonists known. In a series of isoquinuclidine based muscarinic agonists efficacy and are influenced by the geometry between the cationic head group and hydrogen bond acceptor pharmacophore and steric bulk in the vicinity of the base. The anti configuration represented by 22a is optimal for muscarinic activity. Ligands with pK(a) below 6.5 show poor binding to the muscarinic receptor as exemplified by the diazabicyclic derivative 42.
- Street,Baker,Book,Kneen,MacLeod,Merchant,Showell,Saunders,Herbert,Freedman,Harley
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p. 2690 - 2697
(2007/10/02)
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- Azetidine derivatives, compositions and methods of treating
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This invention relates to novel azetidines and derivative thereof, as well as to pharmaceutical compositions and methods of treating memory and learning disorders. Another aspect of the invention relates to a method of utilizing the compounds and compositions as biological tools and materials for characterizing excitatory amino acid receptor systems. A further aspect of the invention relates to a method of treating PCP toxicity and abuse.
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- Indolo[2,3-a]quinolizine and indolo[2,3-g]cyclopent[a]indolizine derivatives, compositions and methods employing them for treating ulcers
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The invention relates to new indolo[2,3-g]cyclopent[a]indolizine derivatives of the formulae (II) STR1 and/or (III) STR2 wherein W is alkoxycarbonyl having from one to four carbon atoms in the alkoxy moiety or cyano, R1 is hydrogen or alkyl hav
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- 2-Azabicyclo(2.2.2)octane derivatives and their use as immunosuppressive agents
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The invention relates to new 2-azabicyclo[2.2.2]octane derivatives of the formula (I), STR1 wherein A is hydrogen, alkoxycarbonyl having from one to 4 carbon atoms in the alkoxy group, phenylalkoxycarbonyl having from one to 4 carbon atoms in the alkoxy moiety, alkyl having from one to 6 carbon atoms, aralkyl containing from one to 4 carbon atoms in the alkyl moiety or substituted acyl, R1 is hydrogen or alkyl having from one to 4 carbon atoms, Z is hydrogen or halogen, X is hydrogen or halogen, Y is hydrogen, or X and Y together represent a C--C bond, W is alkoxycarbonyl having from one to 4 carbon atoms in the alkoxy moiety, cyano, carboxamido or haloformyl, or if X stands for halogen, X and Y together represent a STR2 group. According to another aspect of the invention there is provided a process for the preparation of the above compounds, which are pharmaceutically active, in particular, possess valuable anticonvulsive, vasodilating or gastric acid secretion inhibiting properties. Pharmaceutical compositions containing compounds of the formula (I) are also within the scope of the invention.
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- Diels-Alder Adducts of 1-Benzenesulfonylindole-2-acrylates and 1-(Alkoxycarbonyl)-1,2-dihydropyridines. Intermediates for Synthesis of Iboga Alkaloid Analogues
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Diels-Alder reactions between methyl 1-benzenesulfonylindole-2-acrylate and several 1-(alkoxycarbonyl)-1,2-dihydropyridines give protected methyl 7-(2-indolyl)-2-azabicyclooctene-7-carboxylates which serve as intermediates for the synthesis of analogues of the iboga alkaloids.Methods for deprotection of both the carbamate nitrogen and indole nitrogen are reported.The 7-(2-indolyl)-2-azabicyclooctene-7-carboxylates show a tendency to undergo fragmentation of the C-1,C-7 bond of the 2-azabicyclooctene ring, probably by retro-Mannich reactions.Several 6-nor-20-deethyl analogues of catharanthine have been prepared from intermediates derived from the deprotected Diels-Alder adducts.
- Sundberg, Richard J.,Bloom, Jonathan D.
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p. 4836 - 4842
(2007/10/02)
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