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1.
Pharmaceuticals (Basel) ; 15(11)2022 Nov 14.
Article in English | MEDLINE | ID: mdl-36422534

ABSTRACT

Since its introduction in 1981, the chemistry of self-immolative systems has received increasing attention in different application areas, such as analytical chemistry, medicinal chemistry, and materials science. This strategy is based on a stimulation that triggers a cascade of disassembling reactions leading to the release of smaller molecules. The particular reactivity of the nitro group, due to its powerful electron-withdrawing nature, has been exploited in the field of self-immolative chemistry. In this context, the present review describes the major role of the nitro group in self-immolative processes depending on its position.

2.
J Org Chem ; 87(6): 4483-4488, 2022 Mar 18.
Article in English | MEDLINE | ID: mdl-35258309

ABSTRACT

We describe herein the intermolecular addition reaction of benzyl halides to aldehydes and imines using photoactivated tetrakis(dimethylamino)ethylene (TDAE) as superphotoreductant. 3,4-Dihydroisocoumarins, 1,2-diarylethanols, and 1,2-diarylcarbamates were obtained with good functional group tolerance using simple, mild, and metal-free conditions.

3.
Molecules ; 25(24)2020 Dec 14.
Article in English | MEDLINE | ID: mdl-33327601

ABSTRACT

Anthracycline antibiotics play an important role in cancer chemotherapy. The need to improve their therapeutic index has stimulated an ongoing search for anthracycline analogs with enhanced properties. This review aims to summarize the common synthetic approaches to benzo[g]quinoxaline-5,10-diones and their uses in heterocyclic chemistry. Because of the valuable biological activities of the 1,4-diazaanthraquinone compounds, a summary of the most promising heterocyclic quinones is provided together with their antitumor properties.


Subject(s)
Anthraquinones/chemical synthesis , Antineoplastic Agents/chemical synthesis , Chemistry Techniques, Synthetic , Quinoxalines/chemical synthesis , Topoisomerase Inhibitors/chemical synthesis , Anthraquinones/pharmacology , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Humans , Inhibitory Concentration 50 , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/pathology , Quinoxalines/pharmacology , Structure-Activity Relationship , Topoisomerase Inhibitors/pharmacology , Tumor Suppressor Protein p53/agonists , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
4.
J Org Chem ; 85(23): 15736-15742, 2020 Dec 04.
Article in English | MEDLINE | ID: mdl-33226220

ABSTRACT

We report here the intermolecular metal-free addition reaction of functionalized benzyl halides to aldehydes using a super electron donor (SED). The metal-free and mild conditions allowed the formation of 3,4-dihydroisocoumarins and 1,2-diarylethanols with unprecedented functional group tolerance.

5.
J Med Chem ; 61(18): 8402-8416, 2018 09 27.
Article in English | MEDLINE | ID: mdl-30153009

ABSTRACT

Rhinoviruses (RVs) have been linked to exacerbations of many pulmonary diseases, thus increasing morbidity and/or mortality in subjects at risk. Unfortunately, the wide variety of RV genotypes constitutes a major hindrance for the development of Rhinovirus replication inhibitors. In the current investigation, we have developed a novel series of pyrazole derivatives that potently inhibit the Rhinovirus replication. Compounds 10e and 10h behave as early stage inhibitors of Rhinovirus infection with a broad-spectrum activity against RV-A and RV-B species (EC50 < 0.1 µM). We also evaluate the dynamics of the emerging resistance of these promising compounds and their in vitro genotoxicity. Molecular docking experiments shed light on the pharmacophoric elements interacting with residues of the drug-binding pocket.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Drug Design , Enterovirus Infections/drug therapy , Pyrazoles/chemistry , Rhinovirus/drug effects , Virus Replication/drug effects , Animals , Enterovirus Infections/virology , HeLa Cells , Humans , Male , Micronucleus Tests , Models, Molecular , Molecular Structure , Protein Conformation , Rats , Rats, Sprague-Dawley , Rhinovirus/genetics , Structure-Activity Relationship
6.
Eur J Med Chem ; 140: 528-541, 2017 Nov 10.
Article in English | MEDLINE | ID: mdl-28987610

ABSTRACT

Rhinovirus (RV), member of the Enterovirus genus, is known to be involved in more than half of the common colds. Through advances in molecular biology, rhinoviruses have also been associated with exacerbations of chronic pulmonary diseases (e.g. asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis). In the current investigation, we develop a novel series of 4,5-dimethoxybenzyl derivatives that potently inhibits rhinovirus replication. Compound (S)-7f blocks RV-B14 replication with an EC50 value of 0.25 µM and shows a low toxicity in HeLa cells (CC50 > 271 µM). Enantioseparation followed by an absolute configuration determination by a Mosher's method revealed the interest of enantiopure compounds. Molecular docking studies permitted the identification of key biological interactions within the drug-binding pocket and an in silico drug-like study revealed a good potential for the development of these derivatives.


Subject(s)
Antiviral Agents/pharmacology , Heterocyclic Compounds/pharmacology , Antiviral Agents/chemistry , Circular Dichroism , HeLa Cells , Heterocyclic Compounds/chemistry , Humans , Magnetic Resonance Spectroscopy , Molecular Docking Simulation , Rhinovirus/drug effects , Spectrometry, Mass, Electrospray Ionization , Stereoisomerism , Structure-Activity Relationship
7.
Molecules ; 22(7)2017 Jul 14.
Article in English | MEDLINE | ID: mdl-28708088

ABSTRACT

A mild and metal-free regiodivergent addition of carbon nucleophiles to α,ß-unsaturated electrophiles was developed. Total 1,2-regioselectivity was observed in the addition of nitrobenzyl chloride derivative 1 to α,ß-unsaturated aldehydes 2 in the presence of TDAE. Moreover, the reaction between p-nitrobenzyl chloride 1a and α,ß-unsaturated iminium salts 4 led to the formation of the 1,4-adduct with total regioselectivity.


Subject(s)
Aldehydes/chemistry , Carbon/chemistry , Chemistry Techniques, Synthetic/methods , Metals/chemistry , Nitrobenzenes/chemistry , Magnetic Resonance Spectroscopy/methods , Mass Spectrometry/methods , Molecular Structure , Salts/chemistry , Stereoisomerism
8.
Eur J Med Chem ; 124: 959-966, 2016 Nov 29.
Article in English | MEDLINE | ID: mdl-27770736

ABSTRACT

We report a novel series of quinoxaline derivatives from which agents with antiproliferative activity have been identified. Two ethyl 3-(arylethynyl)quinoxaline-2-carboxylates demonstrated substantial antiproliferative activity against both human non-small cell lung carcinoma (A549) and glioblastoma (U87-MG) cell lines. Pyrido[4,3-b]quinoxalin-1(2H)-ones demonstrated poor activity against A549 and U87-MG cell lines. Three of the derivatives in ethyl 3-(arylethynyl)quinoxaline-2-carboxylate series demonstrated substantial antiproliferative activity. The arylethynyl derivative 2a and 2d proved to be the most cytotoxic with an IC50 value of 3.3 µM for both A549 and U87-MG cell lines.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Carboxylic Acids/chemistry , Drug Design , Quinoxalines/chemical synthesis , Quinoxalines/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Humans , Quinoxalines/chemistry
9.
Molecules ; 21(11)2016 Nov 04.
Article in English | MEDLINE | ID: mdl-27827934

ABSTRACT

We report here a practical and metal-free synthesis of novel enantiopure amides containing the drug-like 5-nitroimidazole scaffold. The first step was a metal-free diastereoselective addition of 4-(4-(chloromethyl)phenyl)-1,2-dimethyl-5-nitro-1H-imidazole to enantiomerically pure N-tert-butanesulfinimine. Then, the N-tert-butanesulfinyl-protected amine was easily deprotected under acidic conditions. Finally, the primary amine was coupled with different acid chlorides or acids to give the corresponding amides. The mild reaction conditions and high tolerance for various substitutions make this approach attractive for constructing pharmacologically interesting 5-nitroimidazoles.


Subject(s)
Amides/chemical synthesis , Nitroimidazoles/chemistry , Amides/chemistry , Molecular Structure , Stereoisomerism
10.
Molecules ; 21(10)2016 Oct 24.
Article in English | MEDLINE | ID: mdl-27783046

ABSTRACT

We report here a novel and easy-to-handle reductive dehalogenation of 9-bromofluorene in the presence of arylaldehydes and dicarbonyl derivatives to give the corresponding fluorenyl alcohol derivatives and Darzens epoxides as by-products in tetrakis(dimethylamino)ethylene (TDAE) reaction conditions. The reaction is believed to proceed via two successive single electron transfers to generate the fluorenyl anion which was able to react with different electrophiles. A mechanistic study was conducted to understand the formation of the epoxide derivatives.


Subject(s)
Alcohols/chemical synthesis , Dimethylamines/chemistry , Ethanolamines/chemical synthesis , Ethylenes/chemistry , Fluorenes/chemical synthesis , Alcohols/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Fluorenes/chemistry , Lumefantrine , Propionates/chemistry
11.
Angew Chem Int Ed Engl ; 55(20): 5994-9, 2016 05 10.
Article in English | MEDLINE | ID: mdl-27061743

ABSTRACT

Polymerization reactions with organic electron donors (OED) as initiators are presented herein. The metal-free polymerization of various activated alkene and cyclic ester monomers was performed in short reaction times, under mild conditions, with small amounts of organic reducing agents, and without the need for co-initiators or activation by photochemical, electrochemical, or other methods. Hence, OED initiators enabled the development of an efficient, rapid, room-temperature process that meets the technical standards expected for industrial processes, such as energy savings, cost-effectiveness and safety. Mechanistic investigations support an electron-transfer initiation pathway that leads to the reduction of the monomer.

12.
Eur J Med Chem ; 115: 453-62, 2016 Jun 10.
Article in English | MEDLINE | ID: mdl-27049678

ABSTRACT

Human rhinoviruses (HRV) are the predominant cause of common colds and flu-like illnesses, but are also responsible for virus-induced exacerbations of asthma and chronic obstructive pulmonary disease. However, to date, no drug has been approved yet for clinical use. In this study, we present the results of the structure-based lead optimization of a class of new small-molecule inhibitors that we previously reported to bind into the pocket beneath the canyon of the VP1 protein. A small series of analogues that we designed based on the available structure and interaction data were synthesized and evaluated for their potency to inhibit the replication of HRV serotype 14. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-(4-(pyridin-4-yl)phenyl)ethanol (3v) was found to be a potent inhibitor exhibiting micromolar activity (EC50 = 3.4 ± 1.0 µM) with a toxicity for HeLa cells that was significantly lower than that of our previous hit (LPCRW_0005, CC50 = 104.0 ± 22.2 µM; 3v, CC50 > 263 µM).


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Benzene Derivatives/chemistry , Benzene Derivatives/pharmacology , Rhinovirus/chemistry , HeLa Cells , Humans , Models, Molecular
13.
Tetrahedron ; 72(16): 1969-1977, 2016 Apr 21.
Article in English | MEDLINE | ID: mdl-27019535

ABSTRACT

Studies directed toward the oxidative and reductive desulfurization of readily available 2'-S-aryl-2'-thiouridine derivatives were investigated with the prospect to functionalize the C2'-position of nucleosides. The oxidative desulfurization-difluorination strategy was successful on 2-(arylthio)alkanoate surrogates, while extension of the combination of oxidants and fluoride sources was not an efficient fluorination protocol when applied to 2'-S-aryl-2'-thiouridine derivatives, resulting mainly in C5-halogenation of the pyrimidine ring and C2'-monofluorination without desulfurization. Cyclic voltammetry of 2'-arylsulfonyl-2'-deoxyuridines and their 2'-fluorinated analogues showed that cleavage of the arylsulfone moiety could occur, although at relatively high cathodic potentials. While reductive-desulfonylation of 2'-arylsulfonyl-2'-deoxyuridines with organic electron donors (OEDs) gave predominantly base-induced furan type products, chemical (OED) and electrochemical reductive-desulfonylation of the α-fluorosulfone derivatives yielded the 2'-deoxy-2'-fluorouridine and 2',3'-didehydro-2',3'-dideoxy-2'-fluorouridine derivatives. These results provided good evidence of the generation of a C2'-anion through carbon-sulfur bond cleavage, opening new horizons for the reductive-functionalization approaches in nucleosides.

14.
Molecules ; 20(1): 1262-76, 2015 Jan 14.
Article in English | MEDLINE | ID: mdl-25594341

ABSTRACT

We describe an original pathway to produce new 5-substituted 3-methyl-6-nitro-benzoxazolones by the reaction of aromatic carbonyl and α-carbonyl ester derivatives with a benzoxazolinonic anion formed exclusively via the TDAE strategy.


Subject(s)
Benzoxazoles/chemical synthesis , Dimethylamines/chemistry , Ethylenes/chemistry , Anions/chemistry , Benzoxazoles/chemistry , Carbon-13 Magnetic Resonance Spectroscopy , Proton Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray Ionization
15.
Sci Pharm ; 83(2): 221-31, 2015.
Article in English | MEDLINE | ID: mdl-26839819

ABSTRACT

Thiosulfonate derivatives based on quinones were synthesized for studying "structure-activity relationship" compounds with an acylated and a free amino-group. Anti-platelet activity of the synthesized compounds was determined and the influence of substituents on the activity of the derivatives was assessed.

16.
Eur J Med Chem ; 87: 440-53, 2014 Nov 24.
Article in English | MEDLINE | ID: mdl-25282267

ABSTRACT

Following the promising antileishmanial results previously obtained in monoamidoxime series, a new series of derivatives was synthesized using manganese(III) acetate, Wittig reactions and Suzuki-Miyaura cross coupling reactions. Pharmacomodulation in R(1), R(2) or R(3) substituents on the amidoxime structure is shown to influence antiprotozoan activity in vitro: a monosubstituted phenyl group in R1 (32-35) led to an activity against Leishmania donovani promastigotes (32, IC50 = 9.16 µM), whereas a polysubstituted group (36-37) led to an activity against Plasmodium falciparum (36, IC50 = 2.76 µM). Modulating chemical substituents in R(2) and R(3) only influenced the antiplasmodial activity in vitro. This suggests that the amidoxime scaffold has properties that could make it a promising new antiparasitic pharmacophore.


Subject(s)
Antiparasitic Agents/chemistry , Antiparasitic Agents/pharmacology , Oximes/chemistry , Oximes/pharmacology , Carbon-13 Magnetic Resonance Spectroscopy , Inhibitory Concentration 50 , Spectrometry, Mass, Electrospray Ionization
17.
Molecules ; 19(9): 14987-98, 2014 Sep 18.
Article in English | MEDLINE | ID: mdl-25237753

ABSTRACT

Neuroblastoma is an aggressive pediatric malignancy with significant chemotherapeutic resistance. In order to obtain new compounds active on neuroblastoma cell lines, we investigated the reactivity of carbanion formed via TDAE in quinoxaline series. The new synthesized compounds were tested for their anti-proliferative activity on two neuroblastoma cell lines, and seven oxirane derivatives obtained interesting activities.


Subject(s)
Neuroblastoma/pathology , Quinoxalines/chemical synthesis , Cell Line, Tumor , Humans , In Vitro Techniques , Magnetic Resonance Spectroscopy , Quinoxalines/pharmacology
18.
J Antimicrob Chemother ; 69(10): 2723-32, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24948704

ABSTRACT

OBJECTIVES: To study the characteristics and the mode of action of the anti-rhinovirus compound 4-[1-hydroxy-2-(4,5-dimethoxy-2-nitrophenyl)ethyl]benzonitrile (LPCRW_0005). METHODS: The antiviral activity of LPCRW_0005 was evaluated in a cytopathic effect reduction assay against a panel of human rhinovirus (HRV) strains. To unravel its precise molecular mechanism of action, a time-of-drug-addition study, resistance selection and thermostability assays were performed. The crystal structure of the HRV14/LPCRW_0005 complex was elucidated as well. RESULTS: LPCRW_0005 proved to be a selective inhibitor of the replication of HRV14 (EC(50) of 2 ±â€Š1 µM). Time-of-drug-addition studies revealed that LPCRW_0005 interferes with the earliest stages of virus replication. Phenotypic drug-resistant virus variants were obtained (≥30-fold decrease in susceptibility to the inhibitory effect of LPCRW_0005), which carried either an A150T or A150V amino acid substitution in the VP1 capsid protein. The link between the mutant genotype and drug-resistant phenotype was confirmed by reverse genetics. Cross-resistance studies and thermostability assays revealed that LPCRW_0005 has a similar mechanism of action to the capsid binder pleconaril. Elucidation of the crystal structure of the HRV14/LPCRW_0005 complex revealed the existence of multiple hydrophobic and polar interactions between the VP1 pocket and LPCRW_0005. CONCLUSIONS: LPCRW_0005 is a novel inhibitor of HRV14 replication that acts as a capsid binder. The compound has a chemical structure that is markedly smaller than that of other capsid binders. Structural studies show that LPCRW_0005, in contrast to pleconaril, leaves the toe end of the pocket in VP1 empty. This suggests that extended analogues of LPCRW_0005 that fill the full cavity could be more potent inhibitors of rhinovirus replication.


Subject(s)
Antiviral Agents/pharmacology , Nitriles/pharmacology , Rhinovirus/drug effects , Virus Replication/drug effects , Animals , Antiviral Agents/chemistry , Binding Sites , Cell Line , Cytopathogenic Effect, Viral/drug effects , Drug Resistance, Viral/genetics , Genotype , Humans , Hydrophobic and Hydrophilic Interactions , Models, Molecular , Molecular Conformation , Mutation , Nitriles/chemistry , Protein Binding , RNA, Viral , Rhinovirus/genetics , Viral Proteins/chemistry , Viral Proteins/metabolism
19.
Molecules ; 19(3): 3068-83, 2014 Mar 11.
Article in English | MEDLINE | ID: mdl-24619352

ABSTRACT

We present herein the synthesis in good yields of two series of highly functionalized thiazolidinone derivatives from the reactions of various 4-phenyl-3-thio-semicarbazones with ethyl 2-bromoacetate and diethyl acetylenedicarboxylate, respectively.


Subject(s)
Heterocyclic Compounds/chemical synthesis , Thiosemicarbazones/chemistry , Chemistry Techniques, Synthetic
20.
Eur J Med Chem ; 76: 445-59, 2014 Apr 09.
Article in English | MEDLINE | ID: mdl-24602790

ABSTRACT

Human rhinoviruses are a common cause of respiratory infections, and thus constitute an important target for medicinal chemistry. Still, no drug has been approved for clinical use. We report herein the discovery of dibenzenic derivatives with potent and specific in vitro anti-rhinoviral 14 activity. A total of 99 structural analogues were synthesized by an original synthesis method, i.e. through one organic agent Tetrakis(DimethylAmino)Ethylene (TDAE) and a structure-activity relationship was established. It was shown that 4,5-dimethoxy scaffold and the presence of a C-4 substituted aromatic moiety were necessary to the in vitro activity of these original agents. However, modifications on liker were not convincing. The benzonitrile derivative 23 was identified as the most potent and selective inhibitor of rhinovirus replication in these series (EC50 of 2 ± 0.5 µM, CC50 of 184 µM, selectivity index of 92).


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/therapeutic use , Nitriles/chemical synthesis , Nitriles/therapeutic use , Phenylethyl Alcohol/analogs & derivatives , Picornaviridae Infections/drug therapy , Rhinovirus/drug effects , Antiviral Agents/chemistry , HeLa Cells , Humans , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Nitriles/chemistry , Phenylethyl Alcohol/chemical synthesis , Phenylethyl Alcohol/chemistry , Phenylethyl Alcohol/therapeutic use , Structure-Activity Relationship
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