The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Françoise Nepveu - One of the best experts on this subject based on the ideXlab platform.
-
Synthesis and Evaluation of Antiplasmodial Activities of Fluorinated 6-Amino- 2-Aryl-3H-Indolone-N-Oxides
Medicinal Chemistry, 2018Co-Authors: Amani Mejai, Ennaji Najahi, Françoise Nepveu, Pierre Perio, Gneigny Tchani, Laure Vendier, Sandra Bourgeade Delmas, Rym Abidi, Mohamed Haddad, Karine ReybierAbstract:A series of novel 6-amino-2-aryl-3H-Indolone-N-oxides were synthesized at yields of up to 65% and characterized; one was further characterized using X-ray crystallographic analysis. Synthesized compounds were evaluated for their in vitro activity against a chloroquine-resistant (FcB1) strain of Plasmodium falciparum, as well as for the 50% cytotoxic concentration (CC50) on Vero cell lines. The most promising activities were observed for the fluorinated compounds, the most active in vitro being 6-(2-morpholinoacetamido)-2-(4-(trifluoromethoxy) phenyl)-3H-Indolone-N-oxide (IC50: 15.5 nM). In addition, these compounds showed weak cytotoxicity leading to selectivity index values of >170, thus warranting further in vitro and in vivo studies.
-
Antimalarial Activities of Indolones and Derivatives
Current topics in medicinal chemistry, 2014Co-Authors: Françoise Nepveu, Ennaji Najahi, Alexis ValentinAbstract:The search for antimalarial compounds continues to be an area of intensive investigation in medicinal chemistry. This review presents the structural variations around the Indolone-N-oxide core. From these pharmacomodulation studies, new antiplasmodial agents with various structures have emerged. Most of the molecules generated from reduced forms of the Indolone scaffold have led to compounds with antiplasmodial properties. These results confirm the importance of the redox reversibility of the bioreducible N=C bond in these series to obtain antimalarial activities.
-
Albumin-bound nanoparticles of practically water-insoluble antimalarial lead greatly enhance its efficacy
International Journal of Pharmaceutics, 2014Co-Authors: Nehal Ibrahim, Hany Ibrahim, Jerome Dormoi, Sébastien Briolant, Bruno Pradines, Alicia Moreno, Dominique Mazier, Philippe Legrand, Françoise NepveuAbstract:We recently showed that the Indolone-N-oxides can be promising candidates for the treatment of chloroquine-resistant malaria. However, the in vivo assays have been hampered by the very poor aqueous solubility of these compounds resulting in poor and variable activity. Here, we describe the preparation, characterization and in vivo evaluation of biodegradable albumin-bound Indolone-N-oxide nanoparticles. Nanoparticles were prepared by precipitation followed by high-pressure homogenization and characterized by photon correlation spectroscopy, transmission electron microscopy, differential scanning calorimetry and X-ray powder diffraction. The process was optimized to yield nanoparticles of controllable diameter with narrow size distribution suitable for intravenous administration, which guarantees direct drug contact with parasitized erythrocytes. Stable nanoparticles showed greatly enhanced dissolution rate (complete drug release within 30 min compared to 1.5% of pure drug) preserving the rapid antimalarial activity. The formulation achieved complete cure of Plasmodium berghei-infected mice at 25mg/kg with parasitemia inhibition (99.1%) comparable to that of artesunate and chloroquine and was remarkably more effective in prolonging survival time and inhibiting recrudescence. In 'humanized' mice infected with Plasmodium falciparum, the same dose proved to be highly effective: with parasitemia reduced by 97.5% and the mean survival time prolonged. This formulation can help advance the preclinical trials of Indolone-N-oxides. Albumin-bound nanoparticles represent a new strategic approach to use this most abundant plasma protein to target malaria-infected erythrocytes.
-
2-Aryl-3H-indol-3-ones: Synthesis, electrochemical behaviour and antiplasmodial activities
European journal of medicinal chemistry, 2014Co-Authors: Ennaji Najahi, Alexis Valentin, Paul-louis Fabre, Karine Reybier, Françoise NepveuAbstract:Abstract The synthesis of Indolone derivatives and their antiplasmodial activity in vitro against Plasmodium falciparum at the blood stage are described. The 2-aryl-3H-indol-3-ones were synthesized via deoxygenation of Indolone-N-oxides. Electrochemical behaviour, antiplasmodial activity and cytotoxicity on human tumor cell lines were compared to those of Indolone-N-oxides. The antiplasmodial IC50 (concentrations at 50% inhibition) of these compounds ranged between 49 and 1327 nM. Among them, the 2-(4-dimethylaminophenyl)-5-methoxy-indol-3-one, 7, had the best antiplasmodial activity in vitro (IC50 = 49 nM; FcB1 strain) and selectivity index (SI (CC50 MCF7/IC50 FcB1) = 423.4). Thus, the hits identified in this deoxygenated series correspond to their structural homologs in the N-oxide series with comparable electrochemical behaviour at the nitrogen–carbon double bond.
-
Synthesis and biological evaluation of new bis-Indolone-N-oxides
Bioorganic chemistry, 2013Co-Authors: Ennaji Najahi, Alexis Valentin, Nathan Téné, Michel Treilhou, Françoise NepveuAbstract:Abstract A series of bis -Indolone- N -oxides, 1a–f , was prepared from bis (ethynyl)benzenes and o -halonitroaryls and studied for their in vitro antiplasmodial activities against Plasmodium falciparum and representative strains of bacteria and candida as well as for their cytotoxicity against a human tumor cell line (MCF7). They did not cause any haemolysis (300 μg mL −1 ). Of the synthesized bis -Indolones, compound 1a had the most potent antiplasmodial activity (IC 50 = 0.763 μmol L −1 on the FcB1 strain) with a selectivity index (CC 50 MCF7/IC 50 FcB1) of 35.6. No potency against the tested microbial strains was observed.
Hui Gong - One of the best experts on this subject based on the ideXlab platform.
-
Convenient synthesis of functionalized spiro[indoline-3,2′-pyrrolizines] or spiro[indoline-3,3′-pyrrolidines] via multicomponent reactions
Organic and Biomolecular Chemistry, 2015Co-Authors: Liang Chen, Hui GongAbstract:A general and practical route for the in situ generation of a new type of azomethine ylide and its sequential 1,3-dipolar cycloaddition reaction was successfully established. The three-component reaction of secondary α-amino acids including proline, sarcosine, thiazolidine-4-carboxylic acid with dialkyl acetylenedicarboxylate and 3-methyleneoxindoles in refluxing ethanol afforded the functionalized spiro[indoline-3,2′-pyrrolizines], spiro[indoline-3,3′-pyrrolidines] and spiro[indoline-3,6′-pyrrolo[1,2-c]thiazoles] in good yields and with high diastereoselectivity. Furthermore, similar multicomponent reactions using primary α-amino acids such as glycine, alanine and phenylalanine resulted in the corresponding (spiro[indoline-3,3′-pyrrolidine]-1′-yl)maleates.
-
convenient synthesis of functionalized spiro indoline 3 2 pyrrolizines or spiro indoline 3 3 pyrrolidines via multicomponent reactions
Organic and Biomolecular Chemistry, 2015Co-Authors: Jing Sun, Hui Gong, Liang Chen, Chaoguo YanAbstract:A general and practical route for the in situ generation of a new type of azomethine ylide and its sequential 1,3-dipolar cycloaddition reaction was successfully established. The three-component reaction of secondary α-amino acids including proline, sarcosine, thiazolidine-4-carboxylic acid with dialkyl acetylenedicarboxylate and 3-methyleneoxindoles in refluxing ethanol afforded the functionalized spiro[indoline-3,2′-pyrrolizines], spiro[indoline-3,3′-pyrrolidines] and spiro[indoline-3,6′-pyrrolo[1,2-c]thiazoles] in good yields and with high diastereoselectivity. Furthermore, similar multicomponent reactions using primary α-amino acids such as glycine, alanine and phenylalanine resulted in the corresponding (spiro[indoline-3,3′-pyrrolidine]-1′-yl)maleates.
-
Synthesis of spiro[indoline-3,1^\prime -quinolizines] and spiro[indoline-3,4^\prime -pyrido[1,2-a]quinolines] via three-component reactions of azaarenes, acetylenedicarboxylate, and 3-methyleneoxindoles
Molecular Diversity, 2013Co-Authors: Hui GongAbstract:The three-component reactions of substituted pyridines, dimethyl acetylenedicarboxylates, and 3-phenacylideneoxindoles afforded spiro[indoline-3,1 $$^\prime $$ -quinolizines] in high yields and with high diastereoselectivity. The Diels–Alder reactions of spiro[indoline-3,1 $$^\prime $$ -quinolizines] with maleic anhydride and $$N$$ -phenyl maleimides successfully resulted in polyfunctionalized isoquinolinuclidine derivatives. The similar three-component reactions with quinoline resulted in the novel spiro[indoline-3,4 $$^\prime $$ -pyrido[1,2-a]quinolines] in moderate to good yields.
Jia Zhou - One of the best experts on this subject based on the ideXlab platform.
-
design synthesis and biological evaluation of substituted 4 6 dihydrospiro 1 2 3 triazolo 4 5 b pyridine 7 3 indoline 2 5 3h dione analogues as potent ns4b inhibitors for the treatment of dengue virus infection
Journal of Medicinal Chemistry, 2019Co-Authors: Xuping Xie, Haiying Chen, Mark A White, Jing Zou, Pei Yong Shi, Jia ZhouAbstract:A series of substituted 4,6-dihydrospiro[[1,2,3]triazolo[4,5-b]pyridine-7,3'-indoline]-2',5(3H)-dione analogues were synthesized and evaluated as potent dengue virus inhibitors. Throughout a structure-activity relationship exploration on the amide of the Indolone moiety, a wide range of substitutions were found to be well tolerated for chemical optimization at this position. Among these compounds, 15 (JMX0254) displayed the most potent and broad inhibitory activities, effective against DENV-1 to -3 with EC50 values of 0.78, 0.16, and 0.035 μM, respectively, while compounds 16, 21, 27-29, 47, and 70 exhibited relatively moderate to high activities with low micromolar to nanomolar potency against all four serotypes. The biotinylated compound 73 enriched NS4B protein from cell lysates in pull-down studies, and the findings together with the mutation investigations further validated dengue NS4B protein as the target of this class of compounds. More importantly, compound 15 exhibited good in vivo pharmacokinetic properties and efficacy in the A129 mouse model, indicating its therapeutic potential against the dengue virus infection as a drug candidate for further preclinical development.
-
design synthesis and biological evaluation of substituted 4 6 dihydrospiro 1 2 3 triazolo 4 5 b pyridine 7 3 indoline 2 5 3h dione analogues as potent ns4b inhibitors for the treatment of dengue virus infection
Journal of Medicinal Chemistry, 2019Co-Authors: Jimin Xu, Na Ye, Haiying Chen, Mark A White, Jia ZhouAbstract:A series of substituted 4,6-dihydrospiro[[1,2,3]triazolo[4,5-b]pyridine-7,3′-indoline]-2′,5(3H)-dione analogues were synthesized and evaluated as potent dengue virus inhibitors. Throughout a structure–activity relationship exploration on the amide of the Indolone moiety, a wide range of substitutions were found to be well tolerated for chemical optimization at this position. Among these compounds, 15 (JMX0254) displayed the most potent and broad inhibitory activities, effective against DENV-1 to -3 with EC50 values of 0.78, 0.16, and 0.035 μM, respectively, while compounds 16, 21, 27–29, 47, and 70 exhibited relatively moderate to high activities with low micromolar to nanomolar potency against all four serotypes. The biotinylated compound 73 enriched NS4B protein from cell lysates in pull-down studies, and the findings together with the mutation investigations further validated dengue NS4B protein as the target of this class of compounds. More importantly, compound 15 exhibited good in vivo pharmacokinet...
Chaoguo Yan - One of the best experts on this subject based on the ideXlab platform.
-
convenient synthesis of functionalized spiro indoline 3 2 pyrrolizines or spiro indoline 3 3 pyrrolidines via multicomponent reactions
Organic and Biomolecular Chemistry, 2015Co-Authors: Jing Sun, Hui Gong, Liang Chen, Chaoguo YanAbstract:A general and practical route for the in situ generation of a new type of azomethine ylide and its sequential 1,3-dipolar cycloaddition reaction was successfully established. The three-component reaction of secondary α-amino acids including proline, sarcosine, thiazolidine-4-carboxylic acid with dialkyl acetylenedicarboxylate and 3-methyleneoxindoles in refluxing ethanol afforded the functionalized spiro[indoline-3,2′-pyrrolizines], spiro[indoline-3,3′-pyrrolidines] and spiro[indoline-3,6′-pyrrolo[1,2-c]thiazoles] in good yields and with high diastereoselectivity. Furthermore, similar multicomponent reactions using primary α-amino acids such as glycine, alanine and phenylalanine resulted in the corresponding (spiro[indoline-3,3′-pyrrolidine]-1′-yl)maleates.
-
Synthesis of functionalized spiro[indoline-3,4’-pyridines] and spiro[indoline-3,4’-pyridinones] via one-pot four-component reactions
Beilstein-Institut, 2013Co-Authors: Li-juan Zhang, Jing Sun, Chaoguo YanAbstract:In the presence of triethylamine as catalyst, the one-pot four-component reactions of arylamines, methyl propiolate, isatin and malononitrile afforded the functionalized spiro[indoline-3,4’-pyridine] derivatives in good yields. Similar reactions with ethyl cyanoacetate successfully afforded the functionalized spiro[indoline-3,4’-pyridines] and spiro[indoline-3,4’-pyridinones] as the main products according to the structures of the arylamines and other primary amines
-
facile synthesis of spiro indoline 3 3 pyrrolo 1 2 a quinolines and spiro indoline 3 1 pyrrolo 2 1 a isoquinolines via 1 3 dipolar cycloaddition reactions of heteroaromatic ammonium salts with 3 phenacylideneoxindoles
Organic and Biomolecular Chemistry, 2012Co-Authors: Jing Sun, Chaoguo YanAbstract:A series of complex spiro[indoline-3,3′-pyrrolo[1,2-a]quinolines] were efficiently synthesized by 1,3-dipolar cycloaddition reactions of N-phenacylquinolinium bromides with 3-phenacylideneoxindoles in ethanol with triethylamine as base. Under similar conditions the 1,3-cycloadditions of N-phenacylisoquinolinium and N-phenacyl-1,10-phenanthrolinium bromides with 3-phenacylideneoxindoles resulted in the corresponding spiro[indoline-3,1′-pyrrolo[2,1-a]isoquinoline] and spiro[benzo[h]pyrrolo[1,2-a]quinoline-3,3′-indoline] derivatives in good yields. The characterization data of spiro compounds and single crystal determination indicated that this 1,3-cycloaddition reaction is a regioselective and diastereoselective reaction and all prepared spiro compounds exist in the thermodynamically stable trans isomer.
Jing Sun - One of the best experts on this subject based on the ideXlab platform.
-
convenient synthesis of functionalized spiro indoline 3 2 pyrrolizines or spiro indoline 3 3 pyrrolidines via multicomponent reactions
Organic and Biomolecular Chemistry, 2015Co-Authors: Jing Sun, Hui Gong, Liang Chen, Chaoguo YanAbstract:A general and practical route for the in situ generation of a new type of azomethine ylide and its sequential 1,3-dipolar cycloaddition reaction was successfully established. The three-component reaction of secondary α-amino acids including proline, sarcosine, thiazolidine-4-carboxylic acid with dialkyl acetylenedicarboxylate and 3-methyleneoxindoles in refluxing ethanol afforded the functionalized spiro[indoline-3,2′-pyrrolizines], spiro[indoline-3,3′-pyrrolidines] and spiro[indoline-3,6′-pyrrolo[1,2-c]thiazoles] in good yields and with high diastereoselectivity. Furthermore, similar multicomponent reactions using primary α-amino acids such as glycine, alanine and phenylalanine resulted in the corresponding (spiro[indoline-3,3′-pyrrolidine]-1′-yl)maleates.
-
Synthesis of functionalized spiro[indoline-3,4’-pyridines] and spiro[indoline-3,4’-pyridinones] via one-pot four-component reactions
Beilstein-Institut, 2013Co-Authors: Li-juan Zhang, Jing Sun, Chaoguo YanAbstract:In the presence of triethylamine as catalyst, the one-pot four-component reactions of arylamines, methyl propiolate, isatin and malononitrile afforded the functionalized spiro[indoline-3,4’-pyridine] derivatives in good yields. Similar reactions with ethyl cyanoacetate successfully afforded the functionalized spiro[indoline-3,4’-pyridines] and spiro[indoline-3,4’-pyridinones] as the main products according to the structures of the arylamines and other primary amines
-
facile synthesis of spiro indoline 3 3 pyrrolo 1 2 a quinolines and spiro indoline 3 1 pyrrolo 2 1 a isoquinolines via 1 3 dipolar cycloaddition reactions of heteroaromatic ammonium salts with 3 phenacylideneoxindoles
Organic and Biomolecular Chemistry, 2012Co-Authors: Jing Sun, Chaoguo YanAbstract:A series of complex spiro[indoline-3,3′-pyrrolo[1,2-a]quinolines] were efficiently synthesized by 1,3-dipolar cycloaddition reactions of N-phenacylquinolinium bromides with 3-phenacylideneoxindoles in ethanol with triethylamine as base. Under similar conditions the 1,3-cycloadditions of N-phenacylisoquinolinium and N-phenacyl-1,10-phenanthrolinium bromides with 3-phenacylideneoxindoles resulted in the corresponding spiro[indoline-3,1′-pyrrolo[2,1-a]isoquinoline] and spiro[benzo[h]pyrrolo[1,2-a]quinoline-3,3′-indoline] derivatives in good yields. The characterization data of spiro compounds and single crystal determination indicated that this 1,3-cycloaddition reaction is a regioselective and diastereoselective reaction and all prepared spiro compounds exist in the thermodynamically stable trans isomer.