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The copper-catalysed azide-alkyne cycloaddition was applied to prepare three enantiomeric pairs of heterodimers containing a tacrine residue and a 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) or 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) moiety held together via linkers of variable lengths containing a 1,2,3-triazole ring and 3, 4, or 7 CH2 groups. The heterodimers were tested as inhibitors of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE). The enantiomeric heterodimers with the longest linkers exhibited the highest inhibition potencies for AChE (IC50 = 9.7 nM and 11 nM) and BuChE (IC50 = 8.1 nM and 9.1 nM). AChE exhibited the highest enantioselectivity (ca. 4-fold). The enantiomeric pairs of the heterodimers were found to be inactive (GI50 > 100 µM), or to have weak antiproliferative properties (GI50 = 84–97 µM) against a panel of human cancer cells.

Alzheimer's disease (AD) constitutes one of the most devastating diseases, with an extraordinarily high increase expected for the next few years. Despite the numerous efforts so far, there is still no cure but just palliative treatments.The main topic covered herein has been the development of butyrylcholinesterase (BuChE) inhibitors with the aim of increasing the levels of the neurotransmitter acetylcholine (ACh). Two main groups of compounds have been considered: multitarget and non-multitarget ligands, depending on whether the structural design is focused or not on other key targets and pathogenic factors of the disease. Seventeen patents regarding multitarget-directed ligands (MTDLs), twelve for non-multitarget derivatives, and three for miscellaneous use have been covered in the period 2018-2021.BuChE is an attractive target in the treatment of AD. It is the most prevalent cholinesterase within more advanced stages of the disease, so drugs inhibiting it would be suitable for the treatment of mid- to severe Alzheimer's patients. Moreover, BuChE has been proved to be connected with some other key hallmarks of the disease, like amyloidogenesis; hybridization of a BuChE-targeting pharmacophore with other scaffolds designed for other therapeutic targets is quite a promising design for potential anti-Alzheimer's drugs.

The synthesis of four tetra-tacrine clusters where the tacrine binding units are attached to a central scaffold via linkers of variable lengths is described. The multivalent inhibition potencies for the tacrine clusters were investigated for the inhibition of acetylcholinesterase. Two of the tacrine clusters displayed a small but significant multivalent inhibition potency in which the binding affinity of each of the tacrine binding units increased up to 3.2 times when they are connected to the central scaffold. Junta de Andalucía. FQM134 Ministerio de Ciencia e Innovación de España (MICINN) y fondos FEDER de la Unión Europea. CTQ2016-78703-P

We have designed unprecedented cholinesterase inhibitors based on 1-deoxynojirimycin as potential anti-Alzheimer’s agents. Compounds are comprised of three key structural motifs: the iminosugar, for interaction with cholinesterase catalytic anionic site (CAS); a hydrocarbon tether with variable lengths, and a fragment derived from 2-phenylethanol for promoting interactions with peripheral anionic site (PAS). Title compounds exhibited good selectivity towards BuChE, strongly depending on the substitution pattern and the length of the tether. The lead compounds were found to be strong mixed inhibitors of BuChE (IC50 = 1.8 and 1.9 µM). The presumptive binding mode of the lead compound was analysed using molecular docking simulations, revealing H-bond interactions with the catalytic subsite (His438) and CAS (Trp82 and Glu197) and van der Waals interactions with PAS (Thr284, Pro285, Asn289). They also lacked significant antiproliferative activity against tumour and non-tumour cells at 100 µM, making them promising new agents for tackling Alzheimer’s disease through the cholinergic approach. Dirección General de Investigación de España. CTQ2016-78703-P Junta de Andalucía. FQM134 Fondo Europeo de Desarrollo Regional (FEDER) y Consejo Nacional de Ciencia y Tecnología de México (CONACYT). CB-2015/257465 Ministerio de Ciencia, Innovación y Universidades y Agencia Estatal de Investigación de España y Fondos FEDER de la Unión Europea (MCIU/AEI/FEDER). PGC2018-094503-B-C22

Cancer, one of the most devastating degenerative diseases nowadays, is one of the main targets in Medicinal Chemistry and Pharmaceutical industry. Due to the significant increase in the incidence of cancer within world population, together with the complexity of such disease, featured with a multifactorial nature, access to new drugs targeting different biological targets connected to cancer is highly necessary.:Among the vast arsenal of compounds exhibiting antitumor activities, this review will cover the use of carbohydrate derivatives as privileged scaffolds. Their hydrophilic nature, together with their capacity of establishing selective interactions with biological receptors located on cell surface, involved in cell-to-cell communication processes, has allowed the development of an ample number of new templates useful in cancer treatment.:Their intrinsic water solubility has allowed their use as of pro-drug carriers for accessing more efficiently the pharmaceutical targets. The preparation of glycoconjugates in which the carbohydrate is tethered to a pharmacophore has also allowed a better permeation of the drug through cellular membranes, in which selective interactions with the carbohydrate motifs are involved. In this context, the design of multivalent structures (e.g. gold nanoparticles) has been demonstrated to enhance crucial interactions with biological receptors like lectins, glycoproteins that can be involved in cancer progression.:Moreover, the modification of the carbohydrate structural motif, by incorporation of metal complexes, or by replacing their endocyclic oxygen, or carbon atoms with heteroatoms has led to new antitumor agents.:Such diversity of sugar-based templates with relevant antitumor activity will be covered in this review.

The chromane ring system is widely distributed in nature and has proven to be a highly potent pharmacophore in medicinal chemistry, which includes the area of Alzheimer's and Parkinson's diseases. We report on the development of a gem-dimethylchroman-4-ol family that was shown to give good inhibition of equine serum butyrylcholinesterase (eqBuChE) (in the range 2.9 - 7.3 μM) and in the same range of currently used drugs. We also synthesized a small library of gem-dimethylchroman-4-amine compounds, via a simple reductive amination of the corresponding chromanone precursor, that were also selective for eqBuChE presenting inhibitions in the range 7.6 - 67 μM. Kinetic studies revealed that they were mixed inhibitors. Insights into their mechanism of action were obtained through molecular docking and STD-NMR experiments, and the most active examples showed excellent drug-likeness and pharmacological properties predicted using Swiss-ADME. We also prepared a set of propargyl gem-dimethylchromanamines, for monoamine oxidase (MAO) inhibition but they were only moderately active (the best being 28% inhibition at 1 µM on MAO-B). Overall, our compounds were found to be best suited as inhibitors for BuChE.

[EN] The necessity for developing novel cytostatic agents with improved activities and reduced side-effects to tackle cancer prompted us to investigate mitochondria-targeted compounds, an approach that is gaining attention for the selective transportation of cytotoxic agents. We envisioned the possibility of conjugating a phenethyl alcohol motif, decorated with a series of phenol-based substituents on the aryl moiety, with a triphenyl phosphonium scaffold (a mitochondriadirected vector), through a hydrocarbon chain of different lengths. Thus, such compounds that incorporate the phenethyl skeleton can be considered as masked phenolic compounds derived from relevant natural counterparts found in olive tree (e.g. tyrosol, hydroxytyrosol). Title compounds exhibited very strong in vitro antiproliferative activities against the panel of six human tumor cell lines tested, with GI50 values ranging from the nanomolar (0.026 ± 0.010 mM for 36) to the submicromolar range in most of the cases; this represents an improvement of up to 350-fold compared to classical chemotherapeutic agents, like 5-fluorouracil or cisplatin. Interestingly, decrease in the linker length led to an increase of GI50 values against non-tumor cells, thus allowing a remarkable improvement of selectivity (SI up to 269). The very promising antiproliferative activities prompted us to further investigate their behaviour against multidrug resistant cell lines (MDR). The results indicated a reduced sensitivity of the multidrug resistant cells to compounds, probably due to P-gp-mediated efflux of these antiproliferative agents. Interestingly, activities were completely restored to the same levels by co-administration of tariquidar, a well-known inhibitor of P-gp. Flow cytometry analysis on sensitive cell lines revealed a decrease in the percentage of cells in G1 phase accompanied by increase in S and G2/M phases. In addition, a significant increase in subG1 area, was observed. These results are compatible with the necrotic and apoptotic cell death detected in the Annexin V assay, and with the depolarization of the mitochondria membrane. Thus, the new mitochondriotropic agents reported herein can be considered as promising antiproliferative agents, endowed with remarkable potency and selectivity, including MDR cells, upon coadministration with a pump-efflux inhibitor., We thank Grant PID2020-116460RB-I00 funded by MCIN/AEI/10.13039/501100011033, and Junta de Andalucia (FQM134) for financial support. A.P. and J.M.P. thank the Spanish Government (PGC2018-094503-B-C22, MCIU/AEI/FEDER, UE) and the Canary Islands Government (ProID2020010101, ACIISI/FEDER, UE) for financial support. A.P. thanks the EU Social Fund (FSE) and the Canary Islands ACIISI for a predoctoral grant TESIS2020010055. J.D. and M.P thank the Ministry of Education, Science and Technological Development of the Republic of Serbia for financial support (451-03-9/2021e14/200007). This work was performed within the framework of COST Action CA17104 STRATAGEM -"New diagnostic and therapeutic tools against multidrug resistant tumors". We would also like to thank the Servicio de Resonancia Magn~etica Nuclear, CITIUS (University of Seville) for the performance of NMR experiments.

Herein, we report the preparation of a panel of Schiff bases analogues as antiprotozoal agents by modification of the stereoelectronic effects of the substituents on N-1 and N-4 and the nature of the chalcogen atom (S, Se). These compounds were evaluated towards Trypanosoma cruzi and Trichomonas vaginalis. Thiosemicarbazide 31 showed the best trypanocidal profile (epimastigotes), similar to benznidazole (BZ): IC50 (31)=28.72 μM (CL-B5 strain) and 33.65 μM (Y strain), IC50 (BZ)=25.31 μM (CL-B5) and 22.73 μM (Y); it lacked toxicity over mammalian cells (CC50 > 256 µM). Thiosemicarbazones 49, 51 and 63 showed remarkable trichomonacidal effects (IC50 =16.39, 14.84 and 14.89 µM) and no unspecific cytotoxicity towards Vero cells (CC50 ≥ 275 µM). Selenoisosters 74 and 75 presented a slightly enhanced activity (IC50=11.10 and 11.02 µM, respectively). Hydrogenosome membrane potential and structural changes were analysed to get more insight into the trichomonacidal mechanism.

The synthesis of four heterodimers in which the copper(I)-catalysed azide-alkyne cycloaddition was employed to connect a 1-deoxynojirimycin moiety with a benzotriazole scaffold is reported. The heterodimers were investigated as inhibitors against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The heterodimers displayed preferential inhibition (> 9) of BuChE over AChE in the micromolar concentration range (IC50 = 7–50 µM). For the most potent inhibitor of BuChE, Cornish-Bowden plots were used, which demonstrated that it behaves as a mixed inhibitor. Modelling studies of the same inhibitor demonstrated that the benzotriazole and 1-deoxynojirimycin moiety is accommodated in the peripheral anionic site and catalytic anionic site, respectively, of AChE. The binding mode to BuChE was different as the benzotriazole moiety is accommodated in the catalytic anionic site.

Concerned by the urgent need to explore new approaches for the treatment of Alzheimer's disease, we herein describe the synthesis and evaluation of new multitarget molecules. In particular, we have focused our attention on modulating the activity of cholinesterases (AChE, BuChE) in order to restore the levels of the neurotransmitter acetylcholine, and of O-GlcNAcase (OGA), which is associated with hyperphosphorylation of tau protein, in turn related to the formation of neurofibrillary tangles in the brain. Specifically, we considered the possibility of using carbohydrate-fused 1,3-selenazolines, decorated with a 2-alkylamino or 2-alkoxy moieties. On the one hand, the presence of a selenium atom might be useful in modulating the intrinsic oxidative stress in AD. On the other hand, such bicyclic structure might behave as a transition state analogue of OGA hydrolysis. Moreover, upon protonation, it could mimic the ammonium cation of acetylcholine. The lead compound, bearing a propylamino moiety on C-2 position of the selenazoline motif, proved to be a good candidate against AD; it turned out to be a strong inhibitor of BuChE (IC

[Image: see text] Molecular hybridization is a valuable approach in drug discovery. Combining it with multicomponent reactions is highly desirable, since structurally diverse libraries can be attained efficiently in an eco-friendly manner. In this work, isatin is used as the key building block for the Ugi 4-center 3-component reaction synthesis of oxindole–lactam hybrids, under catalyst-free conditions. The resulting oxindole−β-lactam and oxindole−γ-lactam hybrids were evaluated for their potential to inhibit relevant central nervous system targets, namely cholinesterases and monoamine oxidases. Druglikeness evaluation was also performed, and compounds 4eca and 5dab exhibited great potential as selective butyrylcholinesterase inhibitors, at the low micromolar range, with an interesting predictive pharmacokinetic profile. Our findings herein reported suggest oxindole–lactam hybrids as new potential agents for the treatment of Alzheimer’s disease.

Cancer accounts for one of the most complex diseases nowadays due to its multifactorial nature. Despite the vast number of cytotoxic agents developed so far, good therapeutic approaches are not always reached. In recent years, multitarget drugs are gaining great attention against multifactorial diseases in contraposition to polypharmacy. Herein we have accomplished the conjugation of phenolic derivatives with an ample number of organochalcogen motifs with the aim of developing novel antiproliferative agents. Their antioxidant, and antiproliferative properties (against six tumour and one non-tumour cell lines) were analysed. Moreover, in order to predict P-gp-mediated chemoresistance, the P-glycoprotein assay was also conducted in order to determine whether compounds prepared herein could behave as substrates of that glycoprotein. Selenium derivatives were found to be significantly stronger antiproliferative agents than their sulfur isosters. Moreover, the length and the nature of the tether, together with the nature of the organoselenium scaffold were also found to be crucial features in the observed bioactivities. The lead compound, bearing a methylenedioxyphenyl moiety, and a diselenide functionality, showed a good activity (GI50 = 0.88‒2.0 &micro, M) and selectivity towards tumour cell lines (selectivity index: 14‒32), moreover, compounds considered herein were not substrates for the P-gp efflux pump, thus avoiding the development of chemoresistance coming from such mechanism, commonly found for widely-used chemotherapeutic agents.

Despite the rapidly increasing number of patients suffering from type 2 diabetes, Alzheimer's disease, and diabetes-induced dementia, there are no disease-modifying therapies that are able to prevent or block disease progress. In this work, we investigate the potential of nature-inspired glucosylpolyphenols against relevant targets, including islet amyloid polypeptide, glucosidases, and cholinesterases. Moreover, with the premise of Fyn kinase as a paradigm-shifting target in Alzheimer's drug discovery, we explore glucosylpolyphenols as blockers of Aβ-induced Fyn kinase activation while looking into downstream effects leading to Tau hyperphosphorylation. Several compounds inhibit Aβ-induced Fyn kinase activation and decrease pTau levels at 10 μM concentration, particularly the per-O-methylated glucosylacetophloroglucinol and the 4-glucosylcatechol dibenzoate, the latter inhibiting also butyrylcholinesterase and β-glucosidase. Both compounds are nontoxic with ideal pharmacokinetic properties for further development. This work ultimately highlights the multitarget nature, fine structural tuning capacity, and valuable therapeutic significance of glucosylpolyphenols in the context of these metabolic and neurodegenerative disorders.

Our goal was the evaluation of a series of N-1,2,3-triazole-isatin derivatives for multi-target activity which included cholinesterase (ChE) inhibition and β-amyloid (Aβ) peptide anti-aggregation. The compounds have shown considerable promise as butyrylcholinesterase (BuChE) inhibitors. Although the inhibition of eel acetylcholinesterase (eeAChE) was weak, the inhibitions against equine BuChE (eqBuChE) and human BuChE (hBuChE) were more significant with a best inhibition against eqBuChE of 0.46 μM. In some cases, these molecules gave better inhibitions for hBuChE than eqBuChE. For greater insights into their mode of action, molecular docking studies were carried out, followed by STD-NMR validation. In addition, some of these compounds showed weak Aβ anti-aggregation activity. Hepatotoxicity studies showed that they were non-hepatoxic and neurotoxicity studies using neurite outgrowth experiments led to the conclusion that these compounds are only weakly neurotoxic.

Being aware of the enormous biological potential of organoselenium and polyphenolic compounds, we have accomplished the preparation of novel hybrids, combining both pharma-cophores in order to obtain new antioxidant and antiproliferative agents. Three different families have been accessed in a straightforward and chemoselective fashion: carbohydrate-containing N-acylisoselenoureas, N-arylisoselenocarbamates and N-arylselenocarbamates. The nature of the organoselenium framework, number and position of phenolic hydroxyl groups and substituents on the aromatic scaffolds afforded valuable structure–activity relationships for the biological as-says accomplished: antioxidant properties (antiradical activity, DNA-protective effects, Glutathione peroxidase (GPx) mimicry) and antiproliferative activity. Regarding the antioxidant activity, selenocar-bamates 24–27 behaved as excellent mimetics of GPx in the substoichiometric elimination of H2O2 as a Reactive Oxygen Species (ROS) model. Isoselenocarbamates and particularly their selenocarbamate isomers exhibited potent antiproliferative activity against non-small lung cell lines (A549, SW1573) in the low micromolar range, with similar potency to that shown by the chemotherapeutic agent cisplatin (cis-diaminodichloroplatin, CDDP) and occasionally with more potency than etoposide (VP-16). Ministerio de Ciencia e Innovación PID2020-116460RB-I00 Junta de Andalucía FQM134 Gobierno de las Islas Canarias ProID2020010101

Aim: The increasing number of cancer cases has stimulated researchers to seek for novel approaches. We have combined two bioactive moieties: a polyphenolic scaffold and an organoselenium motif. Four different families (isothiocyanates/thioureas, and their selenium isosters) derived from dopamine, (±)-norepinephrine and R-epinephrine were accessed. Results: Heterocumulenes derived from dopamine and β-O-methylnoradrenaline were strong antiproliferative agents (GI502, -Ph) on the phenyl ring, were also strong antiproliferative agents, besides exhibiting good antiradical and glutathione peroxidase-like activities. Up to a 14-fold increased activity was achieved compared with classical chemotherapeutic agents, exhibiting also different mechanisms of action (cell cycle assays). Redox analysis on HeLa cells suggested an increase of ROS levels after the incubation period. Conclusion: the combination of organoselenium and phenolic moieties might provide valuable lead compounds with relevant antiproliferative properties.

From a screening study of various potential inhibitors for cholinesterases (ChEs), compound (rac)-1 (4-((3-hydroxy-2-oxo-3-phenylindolin-1-yl) methyl) piperidin-1-ium chloride) showed an IC50 of 18 μM for butyrylcholinesterase (BuChE). Herein we present a toxicological and pharmacological evaluation of (rac)-1 to determine its potential for use as an alternative ChE inhibitor for the treatment of Alzheimer’s disease. The strategy adopted included in vivo and ex vivo studies with mouse models, Molecular Modelling and Saturation Transfer Difference (STD) NMR studies. Preliminary molecular docking studies were conducted with both (R) and (S)-1 with acetylcholinesterase (AChE) and BuChE, prior to advancing to the mouse model, and indeed favorable interactions were observed, with (R)-1 showing the best binding with AChE and (S)-1 with BuChE. STD-NMR studies were used to successfully validate these results. Toxicological studies were also conducted using the Artemia salina model, with donepezil as reference. It was found that in the in vivo mouse studies that (rac)-1 presented a slightly better inhibition of AChE (0.096 µmol.min−1.mg−1) than donepezil (0.112 µmol.min−1.mg−1) and the same level of inhibition for BuChE as donepezil (0.014 µmol.min−1.mg−1).

Concerned by the devastating effects of Alzheimer's disease, and the lack of effective drugs, we have carried out the design of a series of tacrine-phenolic heterodimers in order to tackle the multifactorial nature of the disease. Hybridization of both pharmacophores involved the modification of the nature (imino, amino, ether) and the length of the tether, together with the type (hydroxy, methoxy, benzyloxy), number and position of the substituents on the aromatic residue. Title compounds were found to be strong and selective inhibitors of human BuChE (from low nanomolar to subnanomolar range), an enzyme that becomes crucial in the more advanced stages of the disease. The lead compound, bearing an ether-type tether, had an IC50 value of 0.52 nM against human BuChE, and a selectivity index of 323, with an 85-fold increase of activity compared to parent tacrine; key interactions were analysed using molecular modelling. Moreover, it also inhibited the self-aggregation of Aβ42, lacking neurotoxicity up to 5 μM concentration, and showed neuroprotective activity in primary rat neurons in a serum and K+ deprivation model, widely employed for reproducing neuronal injury and senescence. Moreover, low hepatoxicity effects and complete stability under physiological conditions were found for that compound. So, overall, our lead compound can be considered as a promising multitarget-directed ligand against Alzheimer's disease, and a good candidate for developing new drugs.

Herein we report the synthesis of N-alkylated deoxynojirimycin derivatives decorated with a selenoureido motif at the hydrocarbon tether as an example of unprecedented multitarget agents. Title compounds were designed as dual drugs for tackling simultaneously the Gaucher disease (by selective inhibition of β-glucosidase, Ki = 1.6-5.5 μM, with improved potency and selectivity compared to deoxynojirimycin) and its neurological complications (by inhibiting AChE, Ki up to 5.8 μM). Moreover, an excellent mimicry of the selenoenzyme glutathione peroxidase was also found for the catalytic scavenging of H2O2 (Kcat/Kuncat up to 640) using PhSH as a cofactor, with improved activity compared to known positive controls, like (PhSe)2 and ebselen; therefore, such compounds are also excellent scavengers of peroxides, an example of reactive oxygen species present at high concentrations in patients of Gaucher disease and neurological disorders.

Herein we report a straightforward preparation of new antiproliferative agents based on the hybridization of a coumarin skeleton and an organoselenium motif. Three families were obtained: isoselenocyanate, selenocarbamates and selenoureas. The main purpose of these hybrid structures is the development of new antiproliferative agents with a multitarget mode of action. A strong correlation between the nature of the organosenium scaffold and the antiproliferative activity was observed. Thus, whereas selenocarbamates proved to be inactive, or moderate antiproliferative agents, isoselenocyanate and most of the selenoureas behaved as strong antiproliferative agents, with GI50 values within the low micromolar range. Interestingly, a good selectivity toward tumor cell lines was found for some of the compounds. Moreover, an increase in the ROS level was observed for tumor cells, and accordingly, these pro-oxidant species might be involved in their mode of action. Overall, title compounds were found not to be substrates for P-glycoprotein, which is overexpressed in many cancer cells as a way of detoxification, and thus, to develop drug resistance. In silico calculations revealed that the selenoderivatives prepared herein might undergo a strong interaction with the active site of HDAC8, and therefore, be potential inhibitors of histone deacetylase 8. In vitro assessment against HDAC8 revealed a strong inhibition of such enzyme exerted by selenoureas, particularly by symmetrical coumarin-containing selenourea. Two compounds showed good antiproliferative data and appear as plausible leads for further testings. The symmetrical coumarin 6 displays the best in vitro inhibition of HDAC8, but is affected by P-gp. In contrast, the N-butyl selenourea coumarin derivative 5a escapes P-gp resistance but has lower HDAC8 inhibition activity.

Herein we report the straightforward preparation of novel conformationally-restricted steroids from trans-androsterone and estrone, decorated with spiranic oxazolidin-2-one or 2-aminooxazoline motifs at C-17 as potential antiproliferative agents. Such unprecedented pharmacophores were accessed using an aminomethylalcohol derivative at C-17 as the key intermediate; reaction of such functionality with triphosgene, or conversion into N-substituted thioureas, followed by an intramolecular cyclodesulfurization reaction promoted by yellow HgO, furnished such spirocycles in excellent yields. Title compounds were tested in vitro against a panel of six human tumor cell lines, named A549 (non-small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon), and the results were compared with steroidal chemotherapeutic agents (abiraterone and galeterone); the A-ring of the steroidal backbone, the nature of the heterocycle and the N-substituents proved to be essential motifs for establishing structure-activity relationships concerning not only the potency but also the selectivity against tumor cell lines. Estrone derivatives, particularly those bearing a spiranic 2-aminooxazoline scaffold were found to be the most active compounds, with GI50 values ranging from the low micromolar to the submicromolar level (0.34–1.5 μM). Noteworthy, the lead compounds showed a remarkable increase in activity against the resistant cancer cell lines (T-47D and WiDr) compared to the anticancer reference drugs (up to 120-fold).

We have designed a series of tacrine-based homo- and heterodimers that incorporate an antioxidant tether (selenoureido, chalcogenide) as new dual compounds: for the treatment of Alzheimer's disease and as antiproliferative agents. Symmetrical homodimers bearing a dichalcogenide or selenide-based tether, the best compounds in the series, were found to be strong and highly selective electric eel AChE inhibitors, with inhibition constants within the low nanomolar range. This high inhibitory activity was confirmed on recombinant human AChE for the most interesting derivatives. The three most promising homodimers also showed a good inhibitory activity towards amyloid-β self aggregation. The symmetric disulfide derivative bis[5-(1′,2′,3′,4’-tetrahydroacridin-9′-ylamino)pentyl]disulfide (19) showed the best multipotent profile and was not neurotoxic on immortalized mouse cortical neurons even at 50 μM concentration. These results represent an improvement in activity and selectivity compared to parent tacrine, the first marketed drug against Alzheimer's disease. Title compounds also exhibited excellent in vitro antiproliferative activities against a panel of 6 human tumor cell lines, with GI50 values within the submicromolar range for the most potent derivatives (0.12–0.95 μM); such values represent a spectacular increase compared to currently-used chemotherapeutic agents, such as 5-FU (up to 306−fold) and cisplatin (up to 162−fold). Cell cycle experiments indicated the accumulation of cells in the G1 phase of the cycle, a different mechanism than the reported for cisplatin. The breast cancer cell lines turned out to be the most sensitive one of the panel tested. Dirección General de Investigación CTQ2016-78703-P, CTQ2011-28417-C02-01, CEI10/00018 Junta de Andalucía FQM134 Fondo Europeo de Desarrollo Regional 501100008530 EU Research Potential FP7-REGPOT-2012-CT2012-31637-IMBRAIN

Background Recently, the study of marine natural products has gained interest due to their relevant biological activities. Specially, seaweeds produce bioactive compounds that could act as modulators of cell signaling pathways involved in a plethora of diseases. Thereby, the description of the molecular mechanisms by which seaweeds elicit its biological functions will certainly pave the way to the pharmacological development of drugs. Aim This review describes the molecular mechanisms by which seaweeds act and its possible utilization in the design of new drugs. Methods This review was conducted according to the PRISMA-P guidelines for systematic reviews. Two independent authors searched into four different databases using combinations of keywords. Two more authors selected the articles following the eligibility criteria. Information extraction was conducted by two separated authors and entered into spreadsheets. Methodological quality and risk of bias were determined applying a 12-question Risk of Bias criteria tool. Results and discussion We found 2360 articles (SCOPUS: 998; PubMed: 678; Wiley: 645 and EBSCO: 39) using the established keywords, of which 113 articles fit the inclusion criteria and were included in the review. This work comprises studies in cell lines, and animal models, any clinical trial was excluded. The articles were published from 2005 up to March 31st 2018. The biggest amount of articles was published in 2017. Furthermore, the seaweeds tested in the studies were collected in 15 countries, mainly in Eastern countries. We found that the main modulated signaling pathways by seaweeds-derivate extracts and compounds were: L-Arginine/NO, TNF-α, MAPKs, PI3K/AKT/GSK, mTOR, NF-κB, extrinsic and intrinsic apoptosis, cell cycle, MMPs and Nrf2. Finally, the articles we analyzed showed moderate risk of bias in almost all the parameters evaluated. However, the studies fail to describe the place and characteristics of sample collection, the sample size, and the blindness of the experimental design. Conclusion In this review we identified and summarized relevant information related to seaweed-isolated compounds and extracts having biological activity; their role in different signal pathways to better understand their potential to further development of cures for cancer, diabetes, and inflammation-related diseases.

Imino- and azasugar glycosidase inhibitors display pH dependant inhibition reflecting that both the inhibitor and the enzyme active site have groups that change protonation state with pH. With the enzyme having two acidic groups and the inhibitor one basic group, enzyme-inhibitor complexes with three (EH3I), two (EH2I), one (EHI), or no protons (EI), are possible. In the present work an analysis method is presented that from pH-inhibition data allows one to distinguish between the different complexes and determine which protonation state is preferred. It is also possible to determine the pH-independent binding constants of the inhibitor. Analysis of pH data for imino- and azasugar inhibition of β-glucosidases revealed that basic glycosidase inhibitors bind as the monoprotonated (EHI) complex. Three neutral inhibitors were also studied and two of these were also bound exclusively as the EHI complex while a third bound both as a EHI and a EH2I complex.

Aim: Numerous chronic diseases exhibit multifactorial etiologies, so focusing on a single therapeutic target is usually an inadequate treatment; instead, multi-target drugs are preferred. Herein, a panel of phenolic thioureas and selenoureas were designed as new prototypes against multifactorial diseases concerning antioxidation and cytotoxicity, as a pro-oxidant environment is usually found in such diseases. Results: Selenoureas were excellent antiradical agents and biomimetic catalysts of glutathione peroxidase for the scavenging of H2O2. They were also potent and selective cytotoxic agents against cancer cells, in particular HeLa (IC50 2.77–6.13 μM), apoptosis being involved. Selenoureas also reduced oxidative stress in HeLa cells (IC50= 3.76 μM). Conclusion: Phenolic selenoureas are promising lead structures for the development of drugs targeting multifactorial diseases like cancer.

We have explored the rich structural diversity provided by an α-azido ester derived from d -arabinose as the source of sugar templates with reduced conformational flexibility. Using transient α-thioureido(selenoureido) esters we have prepared spiranic thio(seleno)hydantoins at the C-3 position of the sugar moiety. In this context, the first example of a stable spiranic α-lactam (or aziridinone) was isolated as a by-product in the hydrogenolysis of the starting α-azido ester. Furthermore, using copper(I)-catalyzed azido–alkyne cycloaddition (click chemistry), we have accessed bicyclic cis-fused α-triazolyl lactones fixed in the furanose form. Spiranic thiohydantoins turned out to be moderate, though selective, inhibitors of glycosidases, whereas their selenium isosters behaved as good free radical scavengers.

The synthesis of a series of l-fuco-configured selenosugars, isosters of the potent glycosidase inhibitor isofucofagomine has been accomplished by a double nucleophilic displacement of a dimesylated derivative with selenide anion generated in situ. Se-Alkylation and oxidation of the corresponding selenane afforded a selenonium and a selenoxide, respectively. The biological activities of such compounds have been evaluated, finding a dual activity caused by the presence of the selenium atom: the selenane exerted a good glutathione peroxidase mimicry by efficiently scavenging H2O2 in the presence of thiols, whereas the stable selenoxide derivative was found to be the first example of a selenosugar acting as a good α-l-fucosidase inhibitor.

We have explored the preparation of conformationally-restricted pseudonucleosides bearing a spiranic thiohydantoin scaffold on C-3 of the sugar moiety by coupling partially protected 3-amino-3-methoxycarbonyl and 3-isothiocyanato-3-methoxycarbonyl glucofuranose derivatives with alkyl(aryl)isothiocyanates or with alkyl(aryl)amines; the key step is a spontaneous or thermal-induced intramolecular nucleophilic substitution of transient thioureas. Upon deprotection, final spiranic thiohydantoins were evaluated as glycosidase and glycogen phosphorylase inhibitors.

The complexation of the potent olive oil antioxidant hydroxytyrosol (HT) with commercial β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) in aqueous solutions has been studied for the first time. The 1:1 stoichiometries of the complexes were evidenced by Job’s plot and the association constants were determined by linear regressions from Scott’s method. The geometry of the HT/β-CD complex was elucidated by 2D-ROESY experiments, suggesting insertion of the catechol moiety with the hydroxyalkyl chain directed to the primary rim. The antioxidant activity of encapsulated HT was also evaluated by scavenging of the stable DPPH radical, observing an improvement of the scavenging activity upon increase of the cyclodextrin concentration. Complexation of HT with β-CD also provided a strong photoprotection of the polyphenolic compound upon irradiation with UV (λ=254 nm).

In our ongoing program aimed at the design, synthesis and biological evaluation of novel gem-difluoromethylenated glycosidase inhibitors, the gem-difluoromethylenated polyhydroxylated pyrrolidines as analogues of 2,5-dideoxy-2,5-imino-D-mannitol (DMDP) were designed and prepared. The crystal structure of gem-difluoromethylenated polyhydroxylated pyrrolidine 17 contains an N-H…F intermolecular hydrogen bond. The biological assessment of gem-difluoromethylenated polyhydroxylated pyrrolidines showed that the modification by the gem-difluoromethylene group decreased the inhibitory activities of DMDP.

Aryl, alkyl, and sugar-derived isoselenocyanates were prepared by a one-pot procedure starting from the corresponding formamides, using triphosgene as a dehydrating agent, triethylamine, and black selenium powder. The preparation of sugar selenoureas by coupling of O-protected sugar-derived isoselenocyanates with different amines, and by coupling of unprotected glycopyranosyl amines with phenyl isoselenocyanate was also accomplished. The synthesis of a glucopyranos-2-yl-selenazole starting from O-protected 2-amino-2-deoxy-d-glucose by coupling with benzoyl isoselenocyanate, Se-alkylation with phenacyl bromide, and acid-catalyzed dehydration is also reported. Unprotected N-(β-d-glucopyranosyl)-N′-phenylselenourea was transformed into a 1,2-trans-fused bicyclic isourea upon treatment with aqueous hydrogen peroxide; the same isourea was prepared by a one-pot three-step procedure from β-d-glycopyranosylamine by thiophosgenation, coupling with aniline, and HgO-mediated desulfurization.

1,2-cis-Fused bicyclic sugar thiocarbamates of gluco and manno configurations have been prepared by treatment of the corresponding O-unprotected amino sugars and glycopyranosyl amines with thiophosgene. The reactivity of these compounds towards amines has been studied in order to determine whether these compounds could act as latent isothiocyanates; it is shown that 1,2-cis-fused bicyclic sugar thiocarbamates are more stable than their trans analogues, and are not transformed into thioureas upon treatment with amines. An unprecedented isomerization of a peracetylated glucopyranoso[2,1-d]oxazolidine-2-thione into a glucopyranoso[2,1-d]thiazolidin-2-one in DMF is also reported. The structure of this thiazolidin-2-one was confirmed by X-ray crystallography.

We report the selective preparation of α- and β-cyclodextrins bearing one and two phosphate moieties on the primary rim. These compounds were prepared by selective O-debenzylation of fully protected derivatives, followed by phosphorylation and deprotection. The synthesis of an α-cyclodextrin with both, a carboxylic group and a phosphate moiety on primary positions is also described. Title compounds are examples of negatively charged cyclodextrins that might be of interest in studying the complexation of cationic guests.

A versatile and expeditious synthesis of taurine-derived thioureas, ureas, and guanidines using taurine isothiocyanate as the key intermediate is reported. Thioureas were obtained by a one-pot two-step procedure starting from taurine by the isothiocyanation reaction with thiophosgene in aqueous THF, followed by coupling with aliphatic and aromatic amines. Desulfurization of thiourea derivatives with yellow mercury(II) oxide gave access to either taurine-containing ureas or guanidines in a one-pot three-step fashion. This methodology was successfully applied to the preparation of a cyclodextrin-derived thiourea and guanidine with a taurine residue in their structures.

A series of new α-cyclodextrin derivatives with a substituted propylene bridge attached to the 6-O's of the A,D-glucose units are reported. The compounds were prepared from the known 6 A ,6 D -di- O -(prop-2-methylidene-1,3-dienyl)-hexadeca- O -benzyl-α-cyclodextrin, which was transformed into 6 A ,6 D -di- O -(prop-2-methyl-1,3-dienyl)-α-cyclodextrin, 6 A ,6 D -di- O -(prop-2-formyl-2-hydroxy-1,3-dienyl)-α-cyclodextrin, 6 A ,6 D -di- O -(prop-2-aminomethyl-2-hydroxy-1,3-dienyl)-α-cyclodextrin, 6 A ,6 D -di- O -(prop-2-hydroxymethylidene-1,3-dienyl)-α-cyclodextrin, 6 A ,6 D -di- O -(prop-2-formyl-1,3-dienyl)-α-cyclodextrin, 6 A ,6 D -di- O -(prop-2-carboxy-1,3-dienyl)-α-cyclodextrin and 6 A ,6 D -di- O -(prop-2-methoxycarbonyl-1,3-dienyl)-α-cyclodextrin. The new compounds were evaluated for their ability to affect amine and alcohol oxidations in the presence of hydrogen peroxide.

The stereoselective preparation of diosgenin-derived thio(seleno)ureas and glycomimetics bearing a 1,2,3-triazolyl tether on C-3 has been accomplished. The key steps in the synthetic pathway are the incorporation of an amino moiety and its further transformation into thio- and selenoureas, and also a click chemistry reaction involving a propargyl residue and an azido moiety to afford carbohydrate-derived 1,2,3-triazoles; subsequent BF 3 -promoted acetolysis of the spiranic moiety afforded the corresponding 22-oxocholestanic structure. The N -phenyl selenourea, an hitherto unknown steroidal derivative, turned out to be a potent ROS scavenger, in particular against free radicals (EC 50 = 29.47 ± 2.33 μM, DPPH method), and as a glutathione peroxidase mimic in the elimination of H 2 O 2 (t 1/2 = 4.8 min, 1% molar ratio). 22-Oxocholestane structures bearing a C-3 azido, propargyl, thioureido, and particularly selenoureido moiety behaved as strong antiproliferative agents against HeLa cells (IC 50 1.87–11.80 μM). N -phenyl selenourea also exhibited IC 50 values lower than 6.50 μM for MDA-MB-231, MCF-7 and HepG2 cancer cells; apoptosis was found to be involved in its mode of action. Such compound was also capable of efficiently eliminating ROS endogenously produced by HeLa cells. Antiproliferative properties of thioxo and selenoxo derivatives were stronger than diosgenin.

An efficient method for the preparation of urea-bridged cyclodextrins using triphosgene in the isocyanation step in an aqueous two-phase system is reported. Per- O -acetylated glycopyranosylamines and 2-amino-2-deoxy-α and β- d -glucose were also transformed into the corresponding isocyanates using either an aqueous two-phase or an anhydrous dichloromethane medium, and converted in situ into ureas. An alternative method for the preparation of sugar-derived ureas consisting of desulfurization of sugar thioureas with mercury oxide is also presented.

β- d -Gluco and mannopyranosyl selenoureas have been prepared by coupling of the corresponding glycosylamines with phenyl isoselenocyanate in aqueous pyridine. Alkyl and aryl isoselenocyanates, and 1,4-phenylene diisoselenocyanate have been obtained from the corresponding formamides with an excess of triphosgene, black selenium and triethylamine. Treatment of the O -unprotected β- d -glucopyranosyl selenourea with aqueous oxygen peroxide afforded a 1,2- trans -fused bicyclic isourea.

The preparation of a urea-bridged β-cyclodextrin dimer and of a 6-monodeoxy-6-mono[3-(β- d -glucopyranos-2-yl)ureido]-β-cyclodextrin has been developed, using triphosgene as the isocyanation agent in an aqueous two-phase system. Per- O -acetylated β- d -gluco and mannopyranosylamines and 2-amino-2-deoxy-α- and β- d -glucose were also transformed into the corresponding isocyanates and converted in situ into ureas by coupling with aromatic and aliphatic amines.

A series of furan C -nucleosides having a sulfur atom in the sugar ring were synthesised. The α and β anomers of 3-ethoxycarbonyl-2-methyl-5-(4′-thio- d -erythrofuranosyl)furans 10 and 11 were obtained by acid treatment of (4′- S -acetyl-4′-thio- d - arabino -tetritol-1-yl)furan 9 . Oxidation of 10 with m -chloroperbenzoic acid gave sulfoxide 12 as one epimer at the sulfur atom whereas 11 was transformed into sulfoxide 13 as an epimeric mixture. S -Methylation of 10 and 11 with methyl triflate led to sulfonium salts 14 and 15 . The prepared compounds were found to be moderate inhibitors of α- l -fucosidase.

The synthesis of (3 S ,4 R ,5 R )-3,4-dihydroxypiperidin-2-one-5-carboxylic acid (‘isofagomine lactam uronate’) from d -arabinose is reported. The product is a potent inhibitor in the low nanomolar range ( K i 36 nM) for bovine liver β-glucuronidase.

2-(Alkylamino, dialkylamino, arylamino)tetrahydropyrano[2,3-d]oxazoles are prepared in good yield by a one-pot three-step synthesis from O-unprotected β- d -glucopyranosylamine, by its transformation into glucopyranosyl isothiocyanate in dioxane–water, coupling with amines, and reaction of the corresponding thioureas with yellow mercury(II) oxide in the same reaction medium. In the case of diethylamine prolonged reaction time during the last step, with an extra portion of yellow HgO, led to N,N-diethyl-N′-(β- d -glucopyranosyl)urea in a one-pot four-step synthesis. 2-(β- d -Glucopyranosylamino)tetrahydropyrano[2,3-d]oxazole, an analogue of trehazolin, is obtained in good yield by cyclocondensation of 1,3-bis(β- d -glucopyranosyl)thiourea.

A series of isosteric phenolic thio- and selenosemicarbazones have been obtained by condensation of naturally-occurring phenolic aldehydes and thio(seleno)semicarbazides. Title compounds were designed as potential multi-target drugs, and a series of structure-activity relationships could be established upon their in vitro assays: antioxidant activity, α-glucosidase inhibition and antiproliferative activity against six human tumor cell lines: A549 (non-small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon). For the antiradical activity, selenium atom and 2 or 3 phenolic hydroxyl groups proved to be essential motifs; remarkably, the compound with the most potent activity, with a trihydroxyphenyl scaffold (EC50 = 4.87 ± 1.57 μM) was found to be stronger than natural hydroxytyrosol, a potent antioxidant present in olive oil (EC50 = 13.80 ± 1.41 μM). Furthermore, one of the thiosemicarbazones was found to be a strong non-competitive inhibitor of α-glucosidase (Ki = 9.6 ± 1.6 μM), with an 8-fold increase in activity compared to acarbose (Ki = 77.9 ± 11.4 μM), marketed for the treatment of type-2 diabetes. Most of the synthesized compounds also exhibited relevant antiproliferative activities; in particular, seleno derivatives showed GI50 values lower than 6.0 μM for all the tested cell lines; N-naphthyl mono- and dihydroxylated derivatives behaved as more potent antiproliferative agents than 5-fluorouracil or cisplatin.

An expeditious and high-yielding one-pot procedure to prepare different types of O -unprotected N -β- d -glycopyranosyl, N ′-substituted thioureas and di-β- d -glucopyranosyl thioureido bolaamphiphiles from β- d -glycopyranosylamines via O -unprotected glycopyranosyl isothiocyanates has been developed.

Practical, facile and high-yielding one-pot syntheses of different O-unprotected glycopyranosyl thioureas and thioureido bolaamphiphiles (two-step synthesis) and of 2-amino-4,5-dihydro-(1,2-dideoxy-β-d-glucopyranoso)[1,2-d]oxazoles (three-step synthesis) from glycopyranosylamines are reported. The method involves the preparation of O-unprotected β-d-gluco (and d-galacto)pyranosyl isothiocyanates which are in equilibrium with the corresponding 1,2-cyclic thiocarbamates, coupling with amines to afford glycosyl thioureas and treatment with yellow mercury (II) oxide to give trans-fused bicyclic isoureas. A d-gluco trehazolin analogue is prepared in this way. In situ transformation of N,N-dialkyl, N′-glucopyranosyl thioureas into the corresponding ureas is also reported.