83 research outputs found
Hydrogen sulfide: A worthwhile tool in the design of new multitarget drugs
No full textH2S is a gaseous molecule able to trigger a plethora of central physiological and pharmacological effects as antioxidant, pro- and anti-inflammatory, pro- and anti-nociceptive, neuromodulator, and cytoprotective. The polypharmacology of H2S depends on the wide variety of targets implicated, but, despite the efforts, the mechanisms of action that should clarify its activity are still not completely unrevealed. Nevertheless, many attempts to exploit the multifaceted profile of this molecule have already been accomplished and many chemical entities containing an H2S-releasing pharmacophore have been synthetized. Here we discuss recent investigations on multitarget molecules able to release H2S, with a particular focus on the combinations of "native drug" with moieties structurally able to release H2S and their applications as therapeutic tools in bone disease, gastrointestinal system and neurodegenerative disorders
A review on the hybrids of hydroxycinnamic acid as multi-target-directed ligands against Alzheimer's disease
No full textAlzheimer's disease (AD), a complex chronic progressive central nervous system degenerative disease and a public health problem of the world, often characters cognitive dysfunction accompaning aggression and depression, and may lead to death. More attentions should be paid on it because there is no modified strategy against AD till now. AD is featured with the loss of cholinergic neurons, the amyloid-beta peptide (AÎ2) plaques and the neurofibrillary tangles and several hypotheses were established to explain the pathogenesis of AD. Hydroxycinnamic acids, including caffeic acid (CA) and ferulic acid (FA) are widely distributed in natural plants and fruits. CA and FA exert various pharmacological activities, including anti-inflammatory, antioxidant, neuroprotection, anti-amyloid aggregation and so on. All these pharmacological activities are associated with the treatment of AD. Here we summarized the pharmacological activities of CA and FA, and their hybrids as multi-target-directed ligands (MTDLs) against AD. The future application of CA and FA was also discussed, hoping to provide beneficial information for the development of CA- and FA-based MTDLs against AD
Symbiotic approach applied to the synthesis of new agents for the treatment of Alzheimer’s disease
No full textAlzheimer disease (AD) is a progressive age-dependent neurodegenerative pathology. The number of people with AD is steadily increasing and has a severe impact on individuals, families, and society. Although the etiology of AD is not yet completely explored, it is now commonly established that it is a multifactorial neurodegenerative pathology.
Nowadays, many agents have been synthesized for the treatment of memory and cognition impairments able to interact with different targets. Unfortunately, AD therapy still lack in effectiveness therefore, the search for new potential drugs is heavily pursued. Consistently, the search for new multitarget agents has led us to design and
synthesize a series of tacrine–hydroxycinnamic acid (caffeic or ferulic acid) hybrids that showed acetylcholinesterase (AChE) inhibitory activity and antioxidants properties1
. Recently, with the aim of increasing the affinity for the butyrylcholinesterase (BuChE) we reported the synthesis and in vitro activities of novel rivastigmine-hydroxycinnamic
acid hybrids as inhibitors of AChE and BuChE, ROS scavengers and inhibitors of Aβ aggregation 2.. In order to expand the SAR study for this new class of compounds, herein we describe the design and synthesis of analogs 1-6 obtained by the symbiotic combination of rivastigmine skeleton with natural antioxidant agents such as gallic acid and 2-chromonecarboxylic acid. The new ligands were evaluated in different systems for neuroprotective, antioxidant, ChE inhibitory and inhibitory of Aβ aggregation properties
Symbiotic approach applied to the synthesis of new agents for the treatment of Alzheimer’s disease
No full textAlzheimer disease (AD) is a progressive age-dependent neurodegenerative pathology. The number of people with AD is steadily increasing and has a severe impact on individuals, families, and society. Although the etiology of AD is not yet completely explored, it is now commonly established that it is a multifactorial neurodegenerative pathology.
Nowadays, many agents have been synthesized for the treatment of memory and cognition impairments able to interact with different targets. Unfortunately, AD therapy still lack in effectiveness therefore, the search for new potential drugs is heavily pursued. Consistently, the search for new multitarget agents has led us to design and
synthesize a series of tacrine–hydroxycinnamic acid (caffeic or ferulic acid) hybrids that showed acetylcholinesterase (AChE) inhibitory activity and antioxidants properties1
. Recently, with the aim of increasing the affinity for the butyrylcholinesterase (BuChE) we reported the synthesis and in vitro activities of novel rivastigmine-hydroxycinnamic
acid hybrids as inhibitors of AChE and BuChE, ROS scavengers and inhibitors of Aβ aggregation 2.. In order to expand the SAR study for this new class of compounds, herein we describe the design and synthesis of analogs 1-6 obtained by the symbiotic combination of rivastigmine skeleton with natural antioxidant agents such as gallic acid and 2-chromonecarboxylic acid. The new ligands were evaluated in different systems for neuroprotective, antioxidant, ChE inhibitory and inhibitory of Aβ aggregation properties
Dimer of rivastigmine and caffeic acid or ferulic acid, preparation method and drug composition thereof
No full textThe present invention relates to synthesis of a series of rivastigmine derivatives, wherein the structural formula is represented by a formula (I). According to the present invention, with the substituent changing, the inhibition of acetylcholine/butyrylcholine esterase by adjusting the rivastigmine derivatives, the inhibition of glutamic acid-induced oxidative stress, the reduction of damage of H2O2 and other ROS on HT22 cells, the inhibition of beta-amyloid protein self-aggregation, and the clearing of DPPH free radicals, the rivastigmine derivatives can simultaneously act on multiple targets. The rivastigmine derivatives can be made into the suitable pharmaceutical dosage form for Alzheimer's disease treatment
Multi-targeted ChEI-copper chelating molecules as neuroprotective agents
No full textThe identification of a valid therapeutic treatment for Alzheimer's disease (AD)represents nowadays an urgent and still unmet medical need, since currently available anti-AD drugs only relieve symptoms and show a modest efficacy. Recent evidence indicates that multi-target-directed ligands (MTDLs)can potentially provide an effective strategy to develop innovative therapies directed towards the onset and progression of this multifactorial neurodegenerative disorder. In this work we designed, synthesized and evaluated a new series of MTDLs bearing the rivastigmine skeleton (ChE-inhibitor)linked to known metal-chelating moieties with linkers of different length. For all the novel derivatives, AChE/BuChE inhibitory activity, ROS scavenging activity and potential cytotoxicity have been assessed. For the best compound (4), copper chelating properties and neuroprotective effects were also evaluated. Our data demonstrated that hybrid derivative 4 is able to effectively inhibit AChE and BuChE and to chelate copper, showing a protective action on neurons. These results, although preliminary, indicate that compound 4 can be considered as a possible hit molecule for the development of new anti-AD MTDLs
Synthesis and pharmacological evaluation of multifunctional tacrine derivatives against several disease pathways of AD
No full textA novel series of tacrine derivatives were designed and synthesized by combining caffeic acid (CA), ferulic
acid (FA) and lipoic acid (LA) with tacrine. The antioxidant study revealed that all the hybrids have much
more antioxidant capacities compared to CA. Among these compounds, 1b possessed a good ability to
inhibit the b-amyloid protein (Ab) self-aggregation, sub-micromole acetylcholinesterase (AChE)/butyrylcholinesterase
(BuChE) inhibitory, modest BACE1 inhibitory. Moreover, compound 1b also was a DPPH
radical scavenger and copper chelatory as well as had potent neuroprotective effects against glutamateinduced
cell death with low toxicity in HT22 cells. Our findings suggest that the compound 1b might be a
promising lead multi-targeted ligand and worthy of further developing for the therapy of Alzheimer’s
disease
Synthesis and anti-glioblastoma effects of artemisinin-isothiocyanate derivatives
No full textA series of novel artemisinin (ART) derivatives containing an isothiocyanate (ITC) group were synthesized. All the compounds showed more potent anti-tumor effects than those of parent dihydroartemisinin (DHA) towards glioblastoma multiforme U87 in vitro. Among them, 5b had the strongest cytotoxic activity which exerted its effects in a concentration-dependent but not time-dependent manner (IC50 7.41 mM for 24 h, 7.35 mM for 72 h). Pyknosis was observed in 5b-treated U87 cells. Multiple intrinsic apoptotic pathways were induced by 5b including the upregulation of caspase 9, the release of cytochrome c, an increase of the proapoptotic protein Bax, a decrease of the anti-apoptotic protein Bcl 2, and the activation of execution pathways by the upregulation of caspase 3. In addition to apoptosis, an autophagic mechanism was also involved in 5b-induced cytotoxicity to human GBM U87 cells by upregulating the expression of LC3-II and downregulating p62. Furthermore, 5b also significantly attenuated the migration of U87 cells. Therefore, our results suggest that 5b may be a promising molecule for the further development of a novel drug for the treatment of glioblastoma
Discovery of novel rivastigmine-hydroxycinnamic acid hybrids as multi-targeted agents for Alzheimer's disease
No full textA series of rivastigmine-caffeic acid and rivastigmine-ferulic acid hybrids were designed, synthesized, and evaluated as multifunctional agents for Alzheimer’s disease (AD) in vitro. The new compounds exerted antioxidant neuroprotective properties and good cholinesterases (ChE) inhibitory activities. Some of them also inhibited amyloid protein (Aβ) aggregation. In particular, compound 5 emerged as promising drug candidates endowed with neuroprotective potential, ChE inhibitory, Aβ self-aggregation inhibitory and copper chelation properties. These data suggest that compound 5 offers an attractive starting point for further lead optimization in the drug-discovery process against AD
Secreted Phospholipase A2s Protect Neurons from Apoptosis Independent of Enzymatic Activity
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