- Overcoming chloroquine resistance in malaria: Design, synthesis, and structure-activity relationships of novel hybrid compounds
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Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria.
- Boudhar, Aicha,Ng, Xiao Wei,Loh, Chiew Yee,Chia, Wan Ni,Tan, Zhi Ming,Nosten, Francois,Dymock, Brian W.,Tan, Kevin S. W.
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- Phosphine-Catalyzed Synthesis of Chiral N-Heterocycles through (Asymmetric) P(III)/P(V) Redox Cycling
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Phosphine-catalyzed tandem Michael addition/intramolecular Wittig reactions have been developed for the synthesis of chiral 2,5-dihydro-1H-pyrrole and tetrahydropyridine derivatives. These processes have been rendered catalytic in phosphine, thanks to the in situ reduction of phosphine oxide by phenylsilane. Furthermore, catalytic and asymmetric P(III)/P(V) processes were implemented using enantiopure chiral phosphines.
- Lorton, Charlotte,Saleh, Nidal,Voituriez, Arnaud
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supporting information
p. 3340 - 3344
(2021/06/26)
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- Probing the ligand preferences of the three types of bacterial pantothenate kinase
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Pantothenate kinase (PanK) catalyzes the transformation of pantothenate to 4′-phosphopantothenate, the first committed step in coenzyme A biosynthesis. While numerous pantothenate antimetabolites and PanK inhibitors have been reported for bacterial type I and type II PanKs, only a few weak inhibitors are known for bacterial type III PanK enzymes. Here, a series of pantothenate analogues were synthesized using convenient synthetic methodology. The compounds were exploited as small organic probes to compare the ligand preferences of the three different types of bacterial PanK. Overall, several new inhibitors and substrates were identified for each type of PanK.
- Guan, Jinming,Barnard, Leanne,Cresson, Jeanne,Hoegl, Annabelle,Chang, Justin H.,Strauss, Erick,Auclair, Karine
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supporting information
p. 5896 - 5902
(2018/11/23)
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- Multifunctional chemical crosslinking agent, preparation method and application thereof
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The invention relates to a multifunctional chemical crosslinking agent. The multifunctional chemical crosslinking agent is a three-arm type structure consisting of two reaction functional group arms and an arm containing an affine functional group and a c
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Paragraph 0118; 0119; 0120; 0121
(2017/09/13)
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- SERINE/THREONINE KINASE INHIBITORS
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Compounds having the formula I wherein R1, R2, R3, R4, R5, Ra, Rb, Rc, Rd, Re, n, r, s and t are as defined herein and which compounds are inhibitors of PAK1. Also disclosed are compositions and methods for treating cancer and hyperproliferative disorders.
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Paragraph 42.1
(2015/02/19)
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- SERINE/THREONINE KINASE INHIBITORS
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Compounds having the formula I, or a pharmaceutically acceptable salt thereof, wherein R1, R2, X1, X2, and Ar are as defined herein, are inhibitors of PAK1. Also disclosed are compositions and methods for treating cancer and hyperproliferative disorders using such compounds.
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Paragraph 0184-0186
(2014/11/11)
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- SERINE/THREONINE KINASE INHIBITORS
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Compounds having the formula I, or a pharmaceutically acceptable salt thereof, wherein R1, R2, X1, X2, and Ar are as defined herein, are inhibitors of PAK1. Also disclosed are compositions and methods for treating cancer and hyperproliferative disorders.
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Paragraph 0167; 0168
(2014/11/11)
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- A facile synthesis of ω-aminoalkyl ammonium hydrogen phosphates
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A series of ω-aminoalkyl ammonium hydrogen phosphates were synthesized through a simple and efficient three-step method. The starting materials, ω-aminoalkyl alcohols (AC-n, with carbon number n = 3, 4, 5, 6), were amino-protected with 9-fluorenylmethyl chloroformate (Fmoc-Cl), followed by phosphorylation with POCl3 and deprotection in piperidine/DMF. The structures of each intermediate and final product were confirmed by 1H NMR, FTIR and mass spectrum. The yield of each step was about 77-92%, with a total yield higher than 56%. This new method was superior in low-cost raw materials, mild reaction temperatures (0-25°C) and easy purification methods.
- Kong, Wei Bo,Zhou, Xiao Yong,Yang, Yang,Xie, Xing Yi
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experimental part
p. 923 - 926
(2012/09/21)
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- Efficient loading of primary alcohols onto a solid phase using a trityl bromide linker
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The Letter describes an improved, rapid and mild strategy for the loading of primary alcohols onto a polystyrene trityl resin via a highly reactive trityl bromide linker. This protocol facilitates an efficient resin loading even of acid-sensitive or heat-
- Crestey, Fran?ois,Ottesen, Lars K.,Jaroszewski, Jerzy W.,Franzyk, Henrik
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body text
p. 5890 - 5893
(2009/04/05)
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- Convenient method for the preparation of carbamates, carbonates, and thiocarbonates
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(Chemical Equation Presented) A convenient, rapid, and efficient method for the preparation of carbamates from amines with 1-alkoxycarbonyl-3-nitro-1,2,4- triazole transfer reagents is reported. Reactions of newly synthesized stable crystalline reagents with alkyl amines were completed in a few minutes without any additional base, and highly pure carbamates were obtained without chromatographic purification. These highly active reagents are also useful for the selective protection of nucleobases and preparation of carbonates and thiocarbonates.
- Shimizu, Mamoru,Sodeoka, Mikiko
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p. 5231 - 5234
(2008/09/17)
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- A versatile annulation protocol toward novel constrained phosphinic peptidomimetics
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(Chemical Equation Presented) The development of a novel 3-center 2-component annulation reaction between α,ω-carbamoylaldehydes and suitably monoalkylated phosphinic acids is reported. Depending on the starting α,ω-carbamoylaldehyde, diverse phosphinic scaffolds varying in the size of their rigidity element, the nature and stereochemistry of substituents, and the participation of heteroatoms in the azacyclic ring system can be obtained in one synthetic step and in high yield. In addition, this methodology allows the synthesis of Fmoc-protected constrained aminophosphinic acids that can be easily converted to suitable pseudodipeptide building blocks compatible with the requirements of peptide synthesis on the solid phase. Finally, the careful choice of both substituents and protecting groups can provide functionally diverse, orthogonally protected constrained scaffolds for extended derivatization of the target phosphinic peptidomimetic structrures.
- Nasopoulou, Magdalini,Georgiadis, Dimitris,Matziari, Magdalini,Dive, Vincent,Yiotakis, Athanasios
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p. 7222 - 7228
(2008/02/12)
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- Influence of N-amino protecting group on aldolase-catalyzed aldol additions of dihydroxyacetone phosphate to amino aldehydes
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This work examines the influence of N-protecting groups on the conversion and stereoselectivity of dihydroxyacetone phosphate (DHAP) dependent aldolase-catalyzed aldol additions of DHAP to N-protected-3-aminopropanal. Phenylacetyl-(PhAc-), tert-butyloxycarbonyl- (tBoc-) and fluoren-9-ylmethoxycarbonyl- (Fmoc-)-3-aminopropanal were evaluated as substrates for d-fructose 1,6-bisphosphate aldolase from rabbit muscle (RAMA), and l-rhamnulose-1-phosphate aldolase (RhuA) and l-fuculose-1-phosphate aldolase (FucA), both from Escherichia coli. Using PhAc and tBoc ca. 70% conversions to the aldol adduct were achieved, whereas Fmoc gave maximum conversions of ca. 25%. The stereoselectivity of the DHAP-aldolases did not depend on the N-protected-3-aminopropanal derivative. Moreover, inversion of FucA stereoselectivity relative to that obtained with the natural l-lactaldehyde was observed. Both N-PhAc and tBoc adduct product derivatives were successfully deprotected by penicillin G acylase (PGA)-catalyzed hydrolysis at pH 7 and by treatment with aqueous TFA (6% v/v), respectively. However, the corresponding cyclic imine sugars could not be isolated, presumable due to the presence of a highly reactive primary amine and a keto group in the molecule, which lead to a number of unexpected reactions.
- Calveras, Jordi,Bujons, Jordi,Parella, Teodor,Crehuet, Ramon,Espelt, Laia,Joglar, Jesús,Clapés, Pere
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p. 2648 - 2656
(2007/10/03)
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- The study of the reaction of terminated oligomerization in the synthesis of oligo-(β1-6)-glucosamines
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The applicability of terminated oligomerization to the synthesis of oligo-(β1-6)-glucosamines, fragments of the intercellular polysaccharide adhesin of staphylococci, was studied. The reactions of terminated oligomerization were carried out with mono-, di-, and trisaccharide monomers and N-protected aminopropanol; and spacered mono-and disaccharides as terminating molecules were also attempted. The primary formation of cyclic products of monomer intramolecular glycosylation was observed in almost all the reactions. Only the experiments with the monomer based on the disaccharide bromide under the conditions of the Helferich reaction led to reduced yields (30%) of the cyclic products. However, even in this case, the desired terminated oligosaccharides were generated in approximately 10% yield and mainly were the products of single glycosylation of the terminator by the monomer. These experiments allow the conclusion that, under the examined conditions, the reaction of terminated oligomerization could not result in the synthesis of oligoglucosamines with a high molecular mass. Pleiades Publishing, Inc., 2006.
- Gening,Tsvetkov,Pier,Nifantiev
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p. 389 - 399
(2008/02/09)
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- Asymmetric synthesis of highly substituted azapolycyclic compounds via 2-alkenyl sulfoximines: Potential scaffolds for peptide mimetics
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The application of metalated, enantiomerically pure acyclic and cyclic 2-alkenyl sulfoximines for the synthesis of highly substituted aza(poly)cyclic ring systems is described. The method relies on a one-pot combination of a reagent-controlled allyl transfer reaction to α- or β-amino aldehydes, followed by a Michael-type cyclization of the intermediate vinyl sulfoximines generated in the first step. The sulfur-free target compounds are preferentially obtained by samarium iodide treatment of the sulfonimidoyl substituted heterocycles. In addition to this methodological work, initial results on the biological activity of selected examples are reported. Furthermore, a concept for the transformation of peptidic lead structures into non-peptide mimetics is described, and the relevance of the new approach to highly substituted azaheterocycles in this context is discussed.
- Reggelin, Michael,Junker, Bernd,Heinrich, Timo,Slavik, Stefan,Buehle, Philipp
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p. 4023 - 4034
(2007/10/03)
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- New nonnucleoside substrates for terminal deoxynucleotidyl transferase: Synthesis and dependence of substrate properties on structure
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N-(9-Fluorenylmethoxycarbonyl)-ω-aminoalkyl-, N-(9- fluorenylmethoxycarbonyl)-8-amino-3,6-dioxaoctyl, and N-[(9- fluorenylmethoxycarbonyl)-6-aminohexanoyl]-2-aminoethyl triphosphates were synthesized. All of them were shown to be the substrates of the cal
- Khandazhinskaya,Kukhanova,Jasko
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p. 352 - 356
(2008/02/03)
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- Repetitive solid-phase synthesis of polyamines
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A repetitive solid-phase method for the synthesis of polyamines is described. Primary amino groups attached to a crosslinked polystyrene resin are monoalkylated by acid labile, benzhydryl-based alkyl chlorides. Reductive alkylation of the resulting secondary amino group by Fmoc-protected aminoaldehydes gives a N-benzhydryl polyamine backbone. Treatment of the resin with trifluoroacetic acid cleaves both the benzhydryl protective group and the polyamine derivative from the resin. By using benzhydryl protective groups with different acid stability, unbranched, branched and partly branched polyamines are synthesized.
- J?nsson, Daniel,Undén, Anders
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p. 3125 - 3128
(2007/10/03)
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- Oligonucleotide labeling: Synthesis of a new spin-labeled 2'-deoxyguanosine analogue
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In order to achieve an EPR sensitive probe for DNA, 3-carboxy-Proxyl free radical was linked to O-6 of dG through a five-atoms-tether. The modified base was incorporated into a 30-mer ODN, then annealed to its complementary DNA strand. Hydrodinamic parame
- Giordano, Cesare,Pedone, Francesco,Fattibene, Paola,Cellai, Luciano
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p. 1301 - 1310
(2007/10/03)
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- The Synthesis of Oxa-Analogues and Homologues of Naturally Occuring Polyamines
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A number of polyamine oxa-analogues 14a-d, 19 have been synthesized.Spermidine oxa-analogues and homologues 14 were made from N-(aminooxypropyl)phthalimide 8a which was obtained either from the Fmoc-deprotection of N-phthalimide 4a or from the reaction between 3-bromopropylamine and N-hydroxyphthalimide, both reactions involving an unusual rearrangement mechanism.Sulphonated derivatives 9, 16, upon Mitsunobu condensation with N-protected 3-aminopropanol or N-alkylation with N-(bromoalkyl)phthalimides, afforded the fully protected spermidine and spermine oxa-analogues.Subsequent sequential deprotection gave spermidine analogues 14.Using the same strategy, spermine oxa-analogues 19 was synthesised. - Keywords: polyamines; oxa-analogues of polyamines; polyamine homologues; rearrangement; synthesis
- Lin, P. Kong Thoo,Kuksa, V. A.,Maguire, N. M.
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p. 859 - 866
(2007/10/03)
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- Convenient protection of amines as carbamates using polymer-bound HOBT as catalyst
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A method for the facile protection of primary and secondary amines as carbamate (Cbz, Fmoc and t-Boc) derivatives using polymer bound 1-hydroxybenzotriazole (HOBT) is reported.
- Dendrinos, Kleanthis G.,Kalivretenos, Aristotle G.
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p. 1463 - 1464
(2007/10/03)
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