Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
Add more filters










Database
Language
Publication year range
1.
Eur J Med Chem ; 211: 113112, 2021 Feb 05.
Article in English | MEDLINE | ID: mdl-33360800

ABSTRACT

Alzheimer's disease is a progressive brain disorder with characteristic symptoms and several pathological hallmarks. The concept of "one drug, one target" has not generated any new drugs since 2004. The new era of drug development in the field of AD builds upon rationally designed multi-target directed ligands that can better address the complexity of AD. Herewith, we designed ten novel derivatives of 2-propargylamino-naphthoquinone. The biological evaluation of these compounds includes inhibition of monoamine oxidase A/B, inhibition of amyloid-beta aggregation, radical-scavenging, and metal-chelating properties. Some of the compounds possess low cytotoxicity profile with an anti-inflammatory ability in the lipopolysaccharide-stimulated cellular model. All these features warrant their further testing in the field of AD.


Subject(s)
Alzheimer Disease/drug therapy , Naphthoquinones/therapeutic use , Drug Design , Humans , Naphthoquinones/pharmacology , Structure-Activity Relationship
2.
Antioxidants (Basel) ; 9(6)2020 Jun 22.
Article in English | MEDLINE | ID: mdl-32580379

ABSTRACT

Phytoestrogens can have a neuroprotective effect towards ischemia-reperfusion-induced neuronal damage. However, their mechanism of action has not been well described. In this work, we investigate the type of neuronal cell death induced by oxygen and glucose deprivation (OGD) and resupply (OGDR) and pinpoint some of the signaling mechanisms whereby the neuroprotective effects of phytoestrogens occur in these conditions. First, we found that autophagy initiation affords neuronal protection upon neuronal damage induced by OGD and OGDR. The mammalian target of rapamycin/ribosomal S6 kinase (mTOR/S6K) pathway is blocked in these conditions, and we provide evidence that this is mediated by modulation of both the 5' AMP-activated protein kinase (AMPK) and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. These are dampened up or down, respectively, under OGDR-induced neuronal damage. In contrast, the MAPK-Erk kinase/extracellular signal-regulated kinase (MEK/ERK) pathway is increased under these conditions. Regarding the pathways affected by phytoestrogens, we show that their protective properties require autophagy initiation, but at later stages, they decrease mitogen-activated protein kinase (MAPK) and AMPK activation and increase mTOR/S6K activation. Collectively, our results put forward a novel mode of action where phytoestrogens play a dual role in the regulation of autophagy by acting as autophagy initiation enhancers when autophagy is a neuroprotective and pro-survival mechanism, and as autophagy initiation inhibitors when autophagy is a pro-death mechanism. Finally, our results support the therapeutic potential of phytoestrogens in brain ischemia by modulating autophagy.

3.
Curr Med Chem ; 27(26): 4392-4400, 2020.
Article in English | MEDLINE | ID: mdl-29611473

ABSTRACT

Alzheimer's disease (AD) is a complex, neurodegenerative pathology showing, among others, high cholinergic and neurotransmitter deficits, oxidative stress, inflammation, Aß-aggregation resulting in senile plaques formation, and hyperphosphorylation of tau-protein leading to neurofibrillary tangles. Due to its multifactorial and complex nature, multitarget directed small-molecules able to simultaneously inhibit or bind diverse biological targets involved in the progress and development of AD are considered now the best therapeutic strategy to design new compounds for AD therapy. Among them, tacrine is a very well known standard-gold ligand, and natural products have been a traditional source of new agents for diverse therapeutic treatments. In this review, we will update recent developments of multitarget tacrinenatural products hybrids for AD therapy.


Subject(s)
Alzheimer Disease , Acetylcholinesterase , Amyloid beta-Peptides , Biological Products , Cholinesterase Inhibitors , Humans , Tacrine , tau Proteins
4.
Article in English | MEDLINE | ID: mdl-24098252

ABSTRACT

The asymmetric unit of the title mol-ecular salt [systematic name: 1,4,8,11-tetraazacyclotetradecane-1,8-diium bis(3-carboxy-prop-2-enoate)], C10H26N4 (2+)·2C4H3O4 (-), contains two half-cations (both completed by crystallographic inversion symmetry) and two maleate anions. The cyclam macrocycles adopt trans-III conformations, supported by two intra-molecular N-H⋯O hydrogen bonds. The O-bonded H atom of each maleate ion is disordered over two positions with an occupancy ratio of 0.61 (5):0.39 (5): each one generates an intra-molecular O-H⋯O hydrogen bond. In the crystal, the cations are linked to the anions by N-H⋯O hydrogen bonds, generating [001] chains.

5.
J Med Chem ; 50(18): 4539-42, 2007 Sep 06.
Article in English | MEDLINE | ID: mdl-17691761

ABSTRACT

We describe the synthesis of 1,omega-di-1H-imidazoles 2 and 3, derived from l-threitol and d-mannitol, respectively, showing suitable magnetic and toxicological properties, as novel extracellular pH indicators for 1H spectroscopic imaging by magnetic resonance methods.


Subject(s)
Imidazoles/chemical synthesis , Magnetic Resonance Spectroscopy/methods , Neoplasms/chemistry , Animals , Brain Chemistry , Cell Line, Tumor , Extracellular Space/chemistry , Hydrogen-Ion Concentration , Imidazoles/chemistry , Imidazoles/pharmacology , Indicators and Reagents/chemical synthesis , Indicators and Reagents/chemistry , Indicators and Reagents/pharmacology , Rats , Rats, Wistar , Stereoisomerism
6.
J Med Chem ; 48(13): 4276-84, 2005 Jun 30.
Article in English | MEDLINE | ID: mdl-15974581

ABSTRACT

Aza TSAO-T derivatives bearing a dihydroisothiazole dioxide ring instead of an oxathiole dioxide ring at the C-3' position on the sugar moiety were prepared. We have synthesized four families of compounds depending on substitution at both N-3 and N-2' '. Biological evaluation showed that these compounds are HIV-1(III(B))-specific and potent reverse transcriptase inhibitors with EC(50) values between 0.13 and 3.5 microM in cell culture.


Subject(s)
Aza Compounds/pharmacology , HIV-1/physiology , Reverse Transcriptase Inhibitors/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Thymidine/analogs & derivatives , Thymidine/chemical synthesis , Thymidine/pharmacology , Virus Replication/drug effects , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Cell Line , HIV-1/drug effects , HIV-2/drug effects , HIV-2/physiology , Humans , Models, Molecular , Molecular Conformation , Structure-Activity Relationship , Uridine/analogs & derivatives
7.
Article in English | MEDLINE | ID: mdl-14565316

ABSTRACT

TSAO derivatives which were first synthesized in 1992 have shown strong inhibitory effect and selectivity against HIV-1 (Camarasa, M.J.; Pérez-Pérez, M.J.; San-Félix, A.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1992, 35, 2721-2727). The structure-activity relationship of these derivatives has shown strong binding between the amino acids constituting the reverse transcriptase and the different pharmacophore (tert-butyldimethylsilyl group, amino and sulfonate groups of the TSAO derivatives) (Camarasa, M.J.; San-Félix, A.; Pérez-Pérez, M.J.; Velázquez, S., Alvarez, R.; Chamorro, C.; Jimeno, M.L.; Pérez, C.; Gago, F.; De Clercq, E.; Balzarini, J. J. Carbohydr. Chem. 2000, 19, 6403-6406). We described the synthesis of an original TSAO analogue where, basically, the O-1'' atom is replaced by a nitrogen atom.


Subject(s)
Anti-HIV Agents/chemical synthesis , Aza Compounds/chemical synthesis , Spiro Compounds/chemical synthesis , Anti-HIV Agents/chemistry , Aza Compounds/chemistry , Models, Molecular , Molecular Structure , Spiro Compounds/chemistry , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...