Naamidine A reveals a promising zinc-binding strategy for topical antifungal therapy.

Fungal disease affects over a billion people worldwide. Naamidine A inhibits the growth of diverse fungal pathogens through an unknown mechanism. Here, we show that the supplementation of medium with excess zinc abolishes the antifungal activity of naamidine A. Furthermore, we highlight that naamidine A has in vitro activity against terbinafine-resistant Trichophyton spp. and in vivo efficacy in a mouse model of dermatomycosis caused by T. mentagrophytes, highlighting its therapeutic potential as a topical treatment.

Charge Transfer Copper Chelating Complex and Biogenically Synthesized Copper Oxide Nanoparticles Using Salvia officinalis Laves Extract in Comparative Spectrofluorimetric Estimation of Anticancer Dabrafenib.

Cancer is a broad category of disease that can affect virtually any organ or tissue in the body when abnormal cells grow uncontrollably, invade surrounding tissue, and/or spread to other organs. Dabrafenib is indicated for the treatment of adult patients with advanced non-small cell lung cancer. In the present study, two newly developed spectrofluorimetric probes for the detection of the anticancer drug Dabrafenib (DRF) in its authentic and pharmaceutical products using an ecologically synthesized copper oxide nanoparticle (CuONPs) from Salvia officinalis leaf extract and a copper chelate complex are presented. The first system is based on the influence of the particular optical properties of CuONPs on the enhancement of fluorescence detection. The second system, on the other hand, acts through the formation of a copper charge transfer complex. Various spectroscopic and microscopic studies were performed to confirm the environmentally synthesized CuONPs. The fluorescence detections in the two systems were measured at λex 350 and λem of 432 nm. The results showed the linear concentration ranges for the DRF-CuONPs-SDS and DRF-Cu-SDS complexes were determined to be 1.0-500 ng mL- 1 and 1.0-200 ng mL- 1, respectively. FI = 1.8088x + 21.418 (r = 0.9997) and FI = 2.7536x + 163.37 (r = 0.9989) were the regression equations. The lower detection and quantification limits for the aforementioned fluorescent systems were determined to be 0.4 and 0.8 ng mL- 1 and 1.0 ng mL- 1, respectively. The results also showed that intra-day DRF assays using DRF-CuONPs-SDS and DRF-Cu(NO3)2-SDS systems yielded 0.17% and 0.54%, respectively. However, the inter-day assay results for the above systems were 0.27% and 0.65%, respectively. The aforementioned two systems were effectively used in the study of DRF with excellent percent recoveries of 99.66 ± 0.42% and 99.42 ± 0.56%, respectively. Excipients such as magnesium stearate, titanium dioxide, red iron oxide, and silicon dioxide used in pharmaceutical formulations, as well as various common cations, amino acids, and sugars, had no effect on the detection of compound.

Unveiling piperazine-quinoline hybrids as potential multi-target directed anti-Alzheimer's agents: design, synthesis and biological evaluation.

Multi-target directed ligands (MTDLs) have recently been popularized due to their outstanding efficacy in combating the complicated features of Alzheimer's disease. This study details the synthesis of piperazine-quinoline-based MTDLs through a multicomponent Petasis reaction, targeting multiple factors such as AChE, BuChE, metal chelation to restore metal dyshomeostasis, and antioxidant activity. Some of the synthesized compounds exhibited notable inhibitory activity against AChE and BuChE enzymes at specific concentrations. Among the synthesized compounds compound (95) containing a 4-chloroaniline moiety and a 4-methoxybenzyl group displayed the most promising inhibitory activities against AChE (IC50 3.013 µM) and BuChE (IC50 = 3.144 µM). Compound (83) featuring 2-methoxyaniline and 4-fluorobenzyl substituents, exhibited the highest BuChE inhibition (IC50 1.888 µM). Notably, compound (79) demonstrated 93-times higher selectivity for BuChE over AChE. Molecular docking and molecular dynamics simulations were also performed to explore the binding modes and stability of these compounds with the AChE amd BuChE proteins. Further, kinetics study was performed against AChE for comounds (83 and 95) which indicated mixed inhibition of the enzyme by these compounds, Amongs the synthesized compounds, nine compounds were assessed for their antioxidant activity, displaying significant antioxidant properties with IC50 values ranging from 156 µM to 310 µM. Moreover, all the compounds demonstrated metal chelating tendency with Cu+2, Zn+2, Fe+2, Fe+3 and Al+3. This study provides insights into the design of novel MTDLs, highlighting compound (95) as a potential candidate for combating Alzheimer's disease.

Study of multifunctional anti-AD ligands: design, synthesis, X-ray crystal structure and biological evaluation of diosmetin derivatives.

The development of anti-AD drugs has attracted much attention as the number of AD patients is increasing year by year. Five diosmetin derivatives (1-5) were designed and synthesized by introducing carbamate groups. The crystal structure of 1 was analyzed by X-ray diffraction, which showed a large conjugated coplanar structure and might be favorable for the insertion into the Aß folding. Meanwhile, in vitro experiments were carried out to investigate the anticholinesterase activity, metal chelating property, antioxidant activity, and anti-Aß aggregation ability of 1-5. The results showed that 1-5 had good cholinesterase inhibitory activities. Compound 4 showed the highest inhibitory activities against butyrylcholinesterase (IC50 = 0.0760 µM). Further kinetic experiments and molecular docking studies showed that 4 could bind well to butyrylcholinesterase. The molecular dynamics simulations also signified that compared with diosmetin, 4 could reduce the flexibility of the butyrylcholinesterase protein skeleton to a greater extent, and thus had a better inhibitory effect. In addition, 1-5 could selectively chelate copper ions and all of them had good antioxidant activity as well as anti-Aß aggregation ability. Among them, 4 had the strongest activity to inhibit Cu2+-induced Aß aggregation (51.09%) and had low cytotoxicity. In addition, in vivo ROS activity assay (Caenorhabditis elegans) showed that 4 had the ability to scavenge ROS. Besides, the in vivo Aß aggregation assay showed that 4 could reduce Aß aggregation. In conclusion, 4 has the potential to be developed into a multifunctional anti-AD drug.

Fishing antioxidant 4-hydroxycoumarin derivatives: synthesis, characterization, and in vitro assessments.

Coumarins represent a diverse class of natural compounds whose importance in pharmaceutical and agri-food sectors has motivated multiple novel synthetic derivatives with broad applicability. The phenolic moiety in 4-hydroxycoumarins underscores their potential to modulate the equilibrium between free radicals and antioxidant species within biological systems. The aim of this work was to assess the antioxidant activity of 18 4-hydroxycoumarin coumarin derivatives, six of which are commercially available and the other 12 were synthesized and chemically characterized and described herein. The 4-hydroxycoumarins were prepared by a two steps synthetic strategy with satisfactory yields. Their antioxidant potential was evaluated through three in vitro methods, two free radical-scavenging assays (DPPH• and ABTS•+) and a metal chelating activity assay. Six synthetic coumarins (4a, 4g, 4h, 4i, 4k, 4l) had a scavenging capacity of DPPH• higher than butylated hydroxytoluene (BHT) (IC50 = 0.58 mmol/L) and compound 4a (4-hydroxy-6-methoxy-2 H-chromen-2-one) with an IC50 = 0.05 mmol/L outperformed both BHT and ascorbic acid (IC50 = 0.06 mmol/L). Nine hydroxycoumarins had a scavenging capacity against ABTS•+ greater (C3, 4a, 4c) or comparable (C1, C2, C4, C6, 4g, 4l) to Trolox (IC50 = 34.34 µmol/L). Meanwhile, the set had a modest ferrous chelation capacity, but most of them (C2, C5, C6, 4a, 4b, 4h, 4i, 4j, 4k, 4l) reached up to more than 20% chelating ability percentage. Collectively, this research work provides valuable structural insights that may determine the scavenging and metal chelating activity of 4-hydroxycoumarins. Notably, substitutions at the C6 position appeared to enhance scavenging potential, while the introduction of electron-withdrawing groups showed promise in augmenting chelation efficiency.

Synthesis and investigation of the cholinesterase inhibitory and antioxidant capacities of some novel N'-(quinolin-4-ylmethylene)propanehydrazides against Alzheimer's disease.

One of the worst long-term health issues of the past few decades is Alzheimer's disease (AD). Unfortunately, there are currently insufficient choices for treating and caring for AD, which makes it a popular subject for drug development research. Studies on the development of drugs for AD have primarily concentrated on the use of multitarget directed ligands. Following this strategy, we designed new ChE inhibitors with additional antioxidant and metal chelator effects. In this research, eight novel N'-(quinolin-4-ylmethylene)propanehydrazide derivatives were synthesized and characterized. We then evaluated the inhibition potency of all the final compounds for cholinesterase enzymes. Among them, 4e (IC50 acetylcholinesterase [AChE] = 0.69 µM and butyrylcholinesterase [BChE]= 26.00 µM) and 4h (IC50's AChE= 7.04 µM and BChE= 16.06 µM) were found to be the most potent AChE and BChE inhibitors, respectively.

Streptomycetes as Microbial Cell Factories for the Biotechnological Production of Melanin.

Melanins are complex, polymeric pigments with interesting properties like UV-light absorbance ability, metal ion chelation capacity, antimicrobial action, redox behaviors, and scavenging properties. Based on these characteristics, melanins might be applied in different industrial fields like food packaging, environmental bioremediation, and bioelectronic fields. The actual melanin manufacturing process is not environmentally friendly as it is based on extraction and purification from cuttlefish. Synthetic melanin is available on the market, but it is more expensive than animal-sourced pigment and it requires long chemical procedures. The biotechnological production of microbial melanin, instead, might be a valid alternative. Streptomycetes synthesize melanins as pigments and as extracellular products. In this review, the melanin biotechnological production processes by different Streptomyces strains have been revised according to papers in the literature. The different fermentation strategies to increase melanin production such as the optimization of growth conditions and medium composition or the use of raw sources as growth substrates are here described. Diverse downstream purification processes are also reported as well as all the different analytical methods used to characterize the melanin produced by Streptomyces strains before its application in different fields.

A Metal Chelation Therapy to Effectively Eliminate Breast Cancer and Intratumor Bacteria While Suppressing Tumor Metastasis by Copper Depletion and Zinc Ions Surge.

The intratumor microbiota results in the immunosuppressive microenvironment and facilitates tumor growth and metastasis. However, developing a synergistic therapy with antitumor, antibacterial, and antimetastatic effects faces enormous challenges. Here, we propose an metal chelation therapy to effectively eliminate tumor and intratumor bacteria and suppress tumor metastasis. Different from traditional chelation therapy that only consumes metal elements, this therapy not only eliminates the crucial metal elements for tumor metabolism but also releases new metal ions with antitumor and antibacterial properties. Based on the high demand for copper in breast cancer, we prepare a fibrous therapeutic nanoagent (Zn-PEN) by chelating D-Penicillamine (D-PEN) with Zn2+. Firstly, Zn-PEN achieves dual inhibition of oxidative phosphorylation and glycolysis metabolism  through copper depletion and Zn2+ activated cGAS-STING pathway, thus inducing tumor cell death. Secondly, Zn-PEN has the capability to eradicate Fusobacterium nucleatum in breast cancer, thereby mitigating its immunosuppressive impact on the tumor microenvironment. Finally, Zn-PEN effectively inhibits tumor metastasis through multiple routes, including the inhibition of epithelial-mesenchymal transition process, activation of cGAS-STING pathway, and elimination with F. nucleatum. Therefore, we verify the feasibility of Zn-PEN mediated metal chelation therapy in a 4T1 model infected with F. nucleatum, providing a new therapeutic strategy for inhibiting tumor metastasis.

Rivastigmine-Benzimidazole Hybrids as Promising Multitarget Metal-Modulating Compounds for Potential Treatment of Neurodegenerative Diseases.

With the goal of combating the multi-faceted Alzheimer's disease (AD), a series of Rivastigmine-Benzimidazole (RIV-BIM) hybrids was recently reported by us as multitarget-directed ligands, thanks to their capacity to tackle important hallmarks of AD. In particular, they exhibited antioxidant activity, acted as cholinesterase inhibitors, and inhibited amyloid-ß (Aß) aggregation. Herein, we moved forward in this project, studying their ability to chelate redox-active biometal ions, Cu(II) and Fe(III), with widely recognized roles in the generation of oxidative reactive species and in protein misfolding and aggregation in both AD and Parkinson's disease (PD). Although Cu(II) chelation showed higher efficiency for the positional isomers of series 5 than those of series 4 of the hybrids, the Aß-aggregation inhibition appears more dependent on their capacity for fibril intercalation than on copper chelation. Since monoamine oxidases (MAOs) are also important targets for the treatment of AD and PD, the capacity of these hybrids to inhibit MAO-A and MAO-B was evaluated, and they showed higher activity and selectivity for MAO-A. The rationalization of the experimental evaluations (metal chelation and MAO inhibition) was supported by computational molecular modeling studies. Finally, some compounds showed also neuroprotective effects in human neuroblastoma (SH-SY5Y cells) upon treatment with 1-methyl-4-phenylpyridinium (MPP+), a neurotoxic metabolite of a Parkinsonian-inducing agent.

Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer's Disease.

A series of previously synthesized conjugates of tacrine and salicylamide was extended by varying the structure of the salicylamide fragment and using salicylic aldehyde to synthesize salicylimine derivatives. The hybrids exhibited broad-spectrum biological activity. All new conjugates were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The structure of the salicylamide moiety exerted little effect on anticholinesterase activity, but AChE inhibition increased with spacer elongation. The most active conjugates were salicylimine derivatives: IC50 values of the lead compound 10c were 0.0826 µM (AChE) and 0.0156 µM (BChE), with weak inhibition of the off-target carboxylesterase. The hybrids were mixed-type reversible inhibitors of both cholinesterases and displayed dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking, which, along with experimental results on propidium iodide displacement, suggested their potential to block AChE-induced ß-amyloid aggregation. All conjugates inhibited Aß42 self-aggregation in the thioflavin test, and inhibition increased with spacer elongation. Salicylimine 10c and salicylamide 5c with (CH2)8 spacers were the lead compounds for inhibiting Aß42 self-aggregation, which was corroborated by molecular docking to Aß42. ABTS•+-scavenging activity was highest for salicylamides 5a-c, intermediate for salicylimines 10a-c, low for F-containing salicylamides 7, and non-existent for methoxybenzoylamides 6 and difluoromethoxybenzoylamides 8. In the FRAP antioxidant (AO) assay, the test compounds displayed little or no activity. Quantum chemical analysis and molecular dynamics (MD) simulations with QM/MM potentials explained the AO structure-activity relationships. All conjugates were effective chelators of Cu2+, Fe2+, and Zn2+, with molar compound/metal (Cu2+) ratios of 2:1 (5b) and ~1:1 (10b). Conjugates exerted comparable or lower cytotoxicity than tacrine on mouse hepatocytes and had favorable predicted intestinal absorption and blood-brain barrier permeability. The overall results indicate that the synthesized conjugates are promising new multifunctional agents for the potential treatment of AD.

Comparative Study for Spectrofluorimetric Determination of Ambroxol Hydrochloride Using Aluminum Metal Transfer Chelation Complex and Biogenic Synthesis of Aluminum Oxide Nanoparticles Using Lavandula spica Flowers Extract.

The existing study pronounces two newly developed spectrofluorimetric probes for the assay of ambroxol hydrochloride in its authentic and commercial formulations using an aluminum chelating complex and a biogenically mediated and synthesized aluminum oxide nanoparticles (Al2O3NPs) from Lavandula spica flower extract. The first probe is based on the formation of an aluminum charge transfer complex. However, the second probe is based on the effect of the unique optical characteristics of Al2O3NPs in the enhancement of fluorescence detection. The biogenically synthesized Al2O3NPs were confirmed using various spectroscopic and microscopic investigations. The fluorescence detections in the two probes were measured at a λex of 260 and 244 and a λem of 460 and 369 nm for the two suggested probes, respectively. The findings showed that the fluorescence intensity (FI) covered linear concentration ranges of 0.1-200 ng mL-1 and 1.0-100 ng mL-1 with a regression of ˃0.999 for AMH-Al2O3NPs-SDS and AMH-Al(NO3)3-SDS, respectively. The lower detection and quantification limits were evaluated and found to be 0.04 and 0.1 ng mL-1 and 0.7 and 0.1 ng/mL-1 for the abovementioned fluorescence probes, respectively. The two suggested probes were successfully applied for the assay of ambroxol hydrochloride (AMH) with excellent percentage recoveries of 99.65% and 99.85%, respectively. Excipients such as glycerol and benzoic acid used as additives in pharmaceutical preparations, several common cations, and amino acids, as well as sugars, were all found to have no interference with the approach.

A Practical Approach to Bicyclic Carbamoyl Pyridones with Application to the Synthesis of HIV-1 Integrase Strand Transfer Inhibitors.

An efficient one-pot synthetic method has been developed for the preparation of bicyclic carbamoyl pyridones from the known common intermediate methyl 5-((2,4-difluorobenzyl)carbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (8). The scalable protocol is facile and employs readily available reagents, needing only a single purification as the final step. The utility of the approach was demonstrated by preparing a library of HIV-1 integrase strand transfer inhibitors (INSTIs) that differ by the presence or absence of a double bond in the B-ring of the bicyclic carbamoyl pyridines 6 and 7. Several of the analogs show good antiviral potencies in single-round HIV-1 replication antiviral assays and show no cytotoxicity in cell culture assays. In general, the compounds with a B-ring double bond have higher antiviral potencies than their saturated congeners. Our methodology should be applicable to the synthesis of a range of new metal-chelating analogs.

Design, synthesis, spectroscopic characterization, in vitro tyrosinase inhibition, antioxidant evaluation, in silico and kinetic studies of substituted indole-carbohydrazides.

In the current study, twenty-five indole-carbohydrazide derivatives linked to different aryl substitutions were rationally designed and synthesized. The structures of all derivatives were confirmed using different spectroscopic techniques including 1H NMR, 13C NMR, Mass spectrometry, and elemental analysis. The tyrosinase inhibitory activities of all synthetic compounds exhibited IC50 values in the range of 0.070 to > 100 µM. Structure-activity relationships showed that compounds 4f (R = 4-OH, IC50 = 0.070 µM), 8f (R = 4-OH, IC50 = 0.072 µM), and 19e (IC50 = 0.19 µM) with para-OH substituent at the R position was found to be the most active members of all three tested series. Kinetic studies exhibited that compounds 4f, 8f, and 19e are mixed-type inhibitors. Furthermore, toxicity and cell-based anti-melanogenesis assessments were performed on the most potent derivatives and it was shown that 4f, 8f, and 19e had no toxicity at 8 µM and reduced the percent of melanin content to 68.43, 72.61, 73.47 at 8 µM, respectively. In silico analyses of absorption, distribution, metabolism, and excretion (ADME) profile of synthesized compounds showed that these molecules followed drug-likeness rules and acceptable predictive ADMET features. Results of the docking study were almost in line with biological results with ChemPLP values of 53.56 to 79.33. Also, the docking study showed the critical interactions of potent inhibitors with the active site of the enzyme which affects the potency of the synthesized hybrids. Based on molecular dynamic simulations, compound 4f exhibited pronounced interaction with the critical residues of the tyrosinase active site so that the indole ring participated in H-bond interaction with Gly281 and 4-hydroxy benzylidene recorded another H-bond interaction with Asp289 plus hydrophobic interactions with Phe292. Hydrazide linker also exhibited three H-bond interactions with His263 and Gly281.

Synthesis of a New Glycoconjugate with Di-á´ -Psicose Anhydride Structure.

Demand for healthy diets has led researchers to explore new saccharide as sucrose alternatives. ᴅ-Psicose, the C-3 epimer of ᴅ-fructose, has a similar sweetness intensity to sucrose but contributes fewer calories. This study proposes a disaccharide with a stable structure derived from ᴅ-psicose. The compound with a spiro-tricyclic core was generated at 32% conversion via caramelization of ᴅ-psicose under acidic anhydrous conditions. The compound was identified by high-resolution mass spectrometry and multi-dimensional nuclear magnetic resonance (NMR). The molecular formula was established as C12H20O10 from the molecular weight of m/z 324.1055. Twelve signals were observed by the 13C NMR spectrum. This compound, denoted di-ᴅ-psicose anhydride (DPA), exhibited a lower water solubility (40 g/L) and higher thermal stability (peak temperature = 194.7 °C) than that of ᴅ-psicose (peak temperature = 126.5 °C). The quantitatively evaluated metal ion scavenging ability of DPA was the best in magnesium (average 98.6 ± 1.1%). This synthesis methodology can provide disaccharides with high stability-reducing heavy metals.

Thymosin ß4 Is an Endogenous Iron Chelator and Molecular Switcher of Ferroptosis.

Thymosin ß4 (Tß4) was extracted forty years agofrom calf thymus. Since then, it has been identified as a G-actin binding protein involved in blood clotting, tissue regeneration, angiogenesis, and anti-inflammatory processes. Tß4 has also been implicated in tumor metastasis and neurodegeneration. However, the precise roles and mechanism(s) of action of Tß4 in these processes remain largely unknown, with the binding of the G-actin protein being insufficient to explain these multi-actions. Here we identify for the first time the important role of Tß4 mechanism in ferroptosis, an iron-dependent form of cell death, which leads to neurodegeneration and somehow protects cancer cells against cell death. Specifically, we demonstrate four iron2+ and iron3+ binding regions along the peptide and show that the presence of Tß4 in cell growing medium inhibits erastin and glutamate-induced ferroptosis in the macrophage cell line. Moreover, Tß4 increases the expression of oxidative stress-related genes, namely BAX, hem oxygenase-1, heat shock protein 70 and thioredoxin reductase 1, which are downregulated during ferroptosis. We state the hypothesis that Tß4 is an endogenous iron chelator and take part in iron homeostasis in the ferroptosis process. We discuss the literature data of parallel involvement of Tß4 and ferroptosis in different human pathologies, mainly cancer and neurodegeneration. Our findings confronted with literature data show that controlled Tß4 release could command on/off switching of ferroptosis and may provide novel therapeutic opportunities in cancer and tissue degeneration pathologies.

Design, synthesis and biological evaluation of a series of iron and copper chelating deferiprone derivatives as new agents active against Candida albicans.

Candida albicans, in specific conditions, is responsible of severe invasive systemic candidiasis that are related to its ability to produce biofilm on biological and artificial surfaces. Many studies reported the role of iron in fungal growth and virulence and the ability of metal chelating agents to interfere with C. albicans metabolism, virulence and biofilm formation. Here we report the activity of 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone (deferiprone) derivatives against C. albicans planktonic cells and biofilm. Some of the studied compounds (2b and 3b) were able to chelate Fe(III) and Cu(II), and showed an interesting activity on planktonic cells (MIC50 of 32 µg/mL and 16 µg/mL respectively) and on biofilm formation (BMIC50 of 32 µg/mL and 16 µg/mL respectively) in cultured ATCC 10,231C. albicans; this activity was reduced, in a concentration dependent way, by the addition of Fe(III) and Cu(II) to the culture media. Furthermore, the most active compound 3b showed a low toxicity on Galleria mellonella larvae.

Design, synthesis and in-vitro evaluation of fluorinated triazoles as multi-target directed ligands for Alzheimer disease.

Alzheimer disease is multi-factorial and inflammation plays a major role in the disease progression and severity. Metals and reactive oxygen species (ROS) are the key mediators for inflammatory conditions associated with Alzheimer's. Along multi-factorial nature, major challenge for developing new drug is the ability of the molecule to cross blood brain barrier (BBB). We have designed and synthesized multi-target directed hexafluorocarbinol containing triazoles to inhibit Amyloid ß aggregation and simultaneously chelate the excess metals present in the extracellular space and scavenge the ROS thus reduce the inflammatory condition. From the screened compound library, compound 1c found to be potent and safe. It has demonstrated inhibition of Amyloid ß aggregation (IC50 of 4.6 µM) through selective binding with Amyloid ß at the nucleation site (evidenced from the molecular docking). It also chelate metals (Cu+2, Zn+2 and Fe+3) and scavenges ROS significantly. Due to the presence of hexafluorocarbinol moiety in the molecule it may assist to permeate BBB and improve the pharmacokinetic properties. The in-vitro results of compound 1c indicate the promiscuity for the development of hexafluorocarbinol containing triazoles amide scaffold as multi-target directed therapy against Alzheimer disease.

Design, synthesis and biological evaluation of 2-styryl-5-hydroxy-4-pyrone derivatives and analogues as multiple functional agents with the potential for the treatment of Alzheimer's disease.

A novel series of 2-styryl-5-hydroxy-4-pyrone derivatives and analogues were designed and synthesized as H3 receptor antagonism based multitarget-directed ligands (MTDLs) for AD therapy using pharmacophore-combine strategy. The 2-styryl-5-hydroxy-4-pyrone pharmacophore with metal ion chelation, antioxidation, and Aß aggregation inhibition activities was employed as the "eastern part", and a typical phenoxyalkylamine moiety was used as "central ring + western part" of the H3 receptor antagonist. The biological evaluation revealed that the majority of the target compounds demonstrated desirable multiple functions. The two most promising compounds 8a and 8b exhibited nanomolar IC50 values on H3 receptor antagonism, excellent metal ion chelating capability, more potent ABTS+ scavenging activity than Trolox, efficient Aß self-aggregation and Cu2+-induced aggregation inhibitory activities, as well as disaggregation activities against Aß self/Cu2+-induced aggregation.

Role of metals in Alzheimer's disease.

Metal homeostasis in the central nervous system (CNS) is a crucial component of healthy brain function, because metals serve as enzymatic cofactors and are key components of intra- and inter-neuronal signaling. Metal dysregulation wreaks havoc on neural networks via induction and proliferation of pathological pathways that cause oxidative stress, synaptic impairment, and ultimately, cognitive deficits. Thus, exploration of metal biology in relation to neurodegenerative pathology is essential in pursuing novel therapies for Alzheimer's Disease and other neurodegenerative disorders. This review covers mechanisms of action of aluminum, iron, copper, and zinc ions with respect to the progressive, toxic accumulation of extracellular ß-amyloid plaques and intracellular hyperphosphorylated neurofibrillary tau tangles that characterizes Alzheimer's Disease, with the goal of evaluating the therapeutic potential of metal ion interference in neurodegenerative disease prevention and treatment. As neuroscientific interest in the role of metals in neurodegeneration escalates-in large part due to emerging evidence substantiating the interplay between metal imbalances and neuropathology-it becomes clear that the use of metal chelating agents may be a viable method for ameliorating Alzheimer's Disease pathology, as its etiology remains obscure. We conclude that, although metal therapies can potentially deter neurodegenerative processes, the most promising treatments will remain elusive until further understanding of neurodegenerative etiology is achieved. New research directions may best be guided by animal models of neurodegeneration, which reveal specific insights into biological mechanisms underlying dementia.

Multifunctional Small Molecules as Potential Anti-Alzheimer's Disease Agents.

Alzheimer's disease (AD) is a severe multifactorial neurodegenerative disorder characterized by a progressive loss of neurons in the brain. Despite research efforts, the pathogenesis and mechanism of AD progression are not yet completely understood. There are only a few symptomatic drugs approved for the treatment of AD. The multifactorial character of AD suggests that it is important to develop molecules able to target the numerous pathological mechanisms associated with the disease. Thus, in the context of the worldwide recognized interest of multifunctional ligand therapy, we report herein the synthesis, characterization, physicochemical and biological evaluation of a set of five (1a-e) new ferulic acid-based hybrid compounds, namely feroyl-benzyloxyamidic derivatives enclosing different substituent groups, as potential anti-Alzheimer's disease agents. These hybrids can keep both the radical scavenging activity and metal chelation capacity of the naturally occurring ferulic acid scaffold, presenting also good/mild capacity for inhibition of self-Aß aggregation and fairly good inhibition of Cu-induced Aß aggregation. The predicted pharmacokinetic properties point towards good absorption, comparable to known oral drugs.