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Ischemic stroke is the leading cause of disability and the second leading cause of death worldwide. However, current therapeutic strategies are scarce and of limited efficacy. The abundance of information available on the molecular pathophysiology of ischemic stroke has sparked considerable interest in developing new neuroprotective agents that can target different events of the ischemic cascade and may be used in combination with existing treatments. In this regard, nitrones represent a very promising alternative due to their renowned antioxidant and anti-inflammatory effects. In this study, we aimed to further investigate the neuroprotective effects of two nitrones, cholesteronitrone 2 (ChN2) and quinolylnitrone 23 (QN23), which have previously shown great potential for the treatment of stroke. Using an experimental in vitro model of cerebral ischemia, we compared their anti-necrotic, anti-apoptotic, and antioxidant properties with those of three reference compounds. Both ChN2 and QN23 demonstrated significant neuroprotective effects (EC50 = 0.66 ± 0.23 μM and EC50 = 2.13 ± 0.47 μM, respectively) comparable to those of homo-bis-nitrone 6 (HBN6) and N-acetylcysteine (NAC) and superior to those of α-phenyl-N-tert-butylnitrone (PBN). While primarily derived from the nitrones’ anti-necrotic capacities, their anti-apoptotic effects at high concentrations and antioxidant powers—especially in the case of QN23—also contribute to their neuroprotective effects.

Herein we report the synthesis of the new statin derivative MC609 in 80 % overall yield by sequential transformation of simvastatin including dehydration, and Michael addition of N-benzyl hydroxylamine followed by cyclization. The preparation of nitronestatins MC649 and MC645 is also described from (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-6-oxotetrahydro-2H-pyran-2-carbaldehyde by reaction with N-benzyl hydroxylamine, and N-hydroxylamine followed by reduction with sodium cyanoborohydride and coupling with commercially available 2-chloro-6-methylquinoline-3-carbaldehyde, in 77 % and 24 % overall yield, respectively., This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (grants SAF2012-33304, SAF2015-65586-R)

NLRP3 is involved in the pathophysiology of several inflammatory diseases. Therefore, there is high current interest in the clinical development of new NLRP3 inflammasome small inhibitors to treat these diseases. Novel

The multifactorial nature of Alzheimer's disease necessitates the development of agents able to interfere with different relevant targets. A series of 22 tailored chromanones was conceptualized, synthesized, and subjected to biological evaluation. We identified one representative bearing a linker-connected azepane moiety (compound 19) with balanced pharmacological properties. Compound 19 exhibited inhibitory activities against human acetyl-, butyrylcholinesterase and monoamine oxidase-B, as well as high affinity to both the σand σreceptors. Our study provides a framework for the development of further chromanone-based multineurotarget agents., T.K. was supported by a fellowship from the Jürgen Manchot Foundation, Düsseldorf, Germany. The automated cholinesterase assays were performed by A. Wosar (Bundeswehr Institute of Pharmacology and Toxicology) which is very much appreciated. The authors acknowledge support by Dr. Christian Steinebach, Nicole Schmitt, and Ablam-Thomas Koumako.

NLRP3 is involved in the pathophysiology of several inflammatory diseases. Therefore, there is high current interest in the clinical development of new NLRP3 inflammasome small inhibitors to treat these diseases. Novel N-sulfonylureas were obtained by the replacement of the hexahydroindacene moiety of the previously described NLRP3 inhibitor MCC950. These new derivatives show moderate to high potency in inhibiting IL-1β release in vitro. The greatest effect was observed for compound 4b, which was similar to MCC950. Moreover, compound 4b was able to reduce caspase-1 activation, oligomerization of ASC, and therefore, IL-1β processing. Additional in silico predictions confirmed the safety profile of compound 4b, and in vitro studies in AML12 hepatic cells confirmed the absence of toxicological effects. Finally, we evaluated in vivo anti-inflammatory properties of compound 4b, which showed a significant anti-inflammatory effect and reduced mechanical hyperalgesia at 3 and 10 mg/kg (i.p.) in an in vivo mouse model of gout., J.E. thanks Fondo de Investigaciones Sanitarias (ISCIII/ FEDER) (Programa Miguel Servet: CP19/00005 and PI19/ 00082) and Fundación Mutua Madrileñ a. D.D.-I. thanks the Spanish Ministry of Science, Innovation, and Universities for predoctoral FPU grant.

The complex nature of multifactorial diseases, such as Morbus Alzheimer, has produced a strong need to design multitarget-directed ligands to address the involved complementary pathways. We performed a purposive structural modification of a tetratarget small-molecule, that is contilisant, and generated a combinatorial library of 28 substituted chromen-4-ones. The compounds comprise a basic moiety which is linker-connected to the 6-position of the heterocyclic chromenone core. The syntheses were accomplished by Mitsunobu- or Williamson-type ether formations. The resulting library members were evaluated at a panel of seven human enzymes, all of which being involved in the pathophysiology of neurodegeneration. A concomitant inhibition of human acetylcholinesterase and human monoamine oxidase B, with IC50 values of 5.58 and 7.20 μM, respectively, was achieved with the dual-target 6-(4-(piperidin-1-yl)butoxy)-4H-chromen-4-one (7).

Herein we report the synthesis, antioxidant and neuroprotective power of homo-tris-nitrones (HTN) 1-3, designed on the hypothesis that the incorporation of a third nitrone motif into our previously identified homo-bis-nitrone 6 (HBN6) would result in an improved and stronger neuroprotection. The neuroprotection of HTNs1-3, measured against oligomycin A/rotenone, showed that HTN2 was the best neuroprotective agent at a lower dose (EC50 = 51.63 &plusmn, 4.32 &mu, M), being similar in EC50 and maximal activity to &alpha, phenyl-N-tert-butylnitrone (PBN) and less potent than any of HBNs 4-6. The results of neuroprotection in an in vitro oxygen glucose deprivation model showed that HTN2 was the most powerful (EC50 = 87.57 &plusmn, 3.87 &mu, M), at lower dose, but 50-fold higher than its analogous HBN5, and &asymp, 1.7-fold less potent than PBN. HTN3 had a very good antinecrotic (IC50 = 3.47 &plusmn, 0.57 &mu, M), antiapoptotic, and antioxidant (EC50 = 6.77 &plusmn, 1.35 &mu, M) profile, very similar to that of its analogous HBN6. In spite of these results, and still being attractive neuroprotective agents, HTNs 2 and 3 do not have better neuroprotective properties than HBN6, but clearly exceed that of PBN.

We herein report the synthesis, antioxidant power and neuroprotective properties of nine homo-bis-nitrones HBNs1–9 as alpha-phenyl-N-tert-butylnitrone (PBN) analogues for stroke therapy. In vitro neuroprotection studies of HBNs1–9 against Oligomycin A/Rotenone and in an oxygen-glucose-deprivation model of ischemia in human neuroblastoma cell cultures, indicate that (1Z,1′Z)-1,1′-(1,3-phenylene)bis(N-benzylmethanimine oxide) (HBN6) is a potent neuroprotective agent that prevents the decrease in neuronal metabolic activity (EC = 1.24 ± 0.39 μM) as well as necrotic and apoptotic cell death. HBN6 shows strong hydroxyl radical scavenger power (81%), and capacity to decrease superoxide production in human neuroblastoma cell cultures (maximal activity = 95.8 ± 3.6%), values significantly superior to the neuroprotective and antioxidant properties of the parent PBN. The higher neuroprotective ability of HBN6 has been rationalized by means of Density Functional Theory calculations. Calculated physicochemical and ADME properties confirmed HBN6 as a hit-agent showing suitable drug-like properties. Finally, the contribution of HBN6 to brain damage prevention was confirmed in a permanent MCAO setting by assessing infarct volume outcome 48 h after stroke in drug administered experimental animals, which provides evidence of a significant reduction of the brain lesion size and strongly suggests that HBN6 is a potential neuroprotective agent against stroke., We would like to thank Soledad Martinez Montero for the excellent technical assistance. This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2015-65586-R to JMC; CTQ2016- 78205-P and CTQ2016-81797-REDC to IF, and NEUROCENTRO-CM S2017/BMD3760 to RMM and DNG), and Camilo José Cela University (UCJC-2018-04) to MJOG. DDI thanks the University of Alcalá and Spanish Ministry of Science, Innovation and Universities for pre-doctoral FPU grants. BCG thanks the Spanish Ministry

In this communication, wereport the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer¿s disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 M), with Ki value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation., R.A., M.S., P.B., and K.M. were supported by European Regional Development Fund/European Social Fund (ERDF/ESF, project PharmaBrain, no. CZ.02.1.01/0.0/0.0/16_025/0007444), University of Hradec Kralove (no. SV2113-2019, VT2019-2021), and EU COST action CA15135 MuTaLig. J.M.C. thanks Ministerio de Economía (MINECO, SAF2015-65586-R) and Universidad Camilo José Cela (UCJC, grants UCJC 2020-03, and UCJC 2020-33) for support.

Herein we report in vitro metabolic stability in human liver microsomes (HLMs), interactions with cytochrome P450 isoenzymes (CYP3A4, CYP2D6, and CYP2C9), and cytotoxicity analyses on HEK-293, HepG2, Huh7, and WTIIB cell lines of our most recent multitarget directed ligands PF9601N, ASS234, and contilisant. Based on these results, we conclude that (1) PF9601N and contilisant are metabolically stable in the HLM assay, in contrast to the very unstable ASS234; (2) CYP3A4 activity was decreased by PF9601N at all the tested concentrations and by ASS234 and contilisant only at the highest concentration; CYP2D6 activity was reduced by ASS234 at 1, 10, and 25 μM and by PF9601N at 10 and 25 μM, whereas contilisant increased its activity at the same concentrations; CYP2C9 was inhibited by the three compounds; (3) contilisant did not affect cell viability in the widest range of concentrations: up to 10 μM on HEK-293 cells, up to 30 μM on Huh7 cells, up to 50 μM on HepG2 cells, and up to 30 or 100 μM on WTIIB cells. Based on these results, we selected contilisant as a metabolically stable and nontoxic lead compound for further studies in Alzheimer's disease therapy., This study received financial support from the National Science Centre Poland (Grant No. 2016/23/D/NZ7/01328). J.M.-C. thanks AEI (Government of Spain) for grants PDI- 2019-105813RB-C21 and SAF2015-65586-R. J.M.-C. and F.L.- M. thank UCJC (Grants UCJC 2020-33 UCJC 2020-03) for support.

In this report we describe the synthesis, biological evaluation and molecular modeling of new tacrine analogues such as QuinoPyranTacrines (QPTs), designed by juxtaposition of 1,4- naphthoquinone and tacrine. From these results we have identified QPT16 as a permeable, selective human acetylcholinesterase inhibitor [IC50= 1.1 0.15 mM], 3.5-fold less-hepatotoxic than tacrine at 1000 mM concentration, and consequently, a potential new hit-compound for further investigation targeted to find a new agent for AD therapy., LI thanks the Regional Council of Franche-Comte (2016YC-04540 and 04560) for financial support. OS thanks Faculty of Military Health Sciences, University of Defence, MH CZ – DRO (UHHK, 00179906) and by Long Term Development Plan – 1011 for support. JMC thank MINECO (Spain) for grant SAF2015-65586-R, and EU (COST Action CA15135: “Multi-target paradigm for innovative ligand identification in the drug discovery process”) for support.

Cerebrovascular diseases such as ischemic stroke are known to exacerbate dementia caused by neurodegenerative pathologies such as Alzheimer’s disease (AD). Besides, the increasing number of patients surviving stroke makes it necessary to treat the co-occurrence of these two diseases with a single and combined therapy. For the development of new dual therapeutic agents, eight hybrid quinolylnitrones have been designed and synthesized by the juxtaposition of selected pharmacophores from our most advanced lead-compounds for ischemic stroke and AD treatment. Biological analyses looking for efficient neuroprotective effects in suitable phenotypic assays led us to identify MC903 as a new small quinolylnitrone for the potential dual therapy of stroke and AD, showing strong neuroprotection on (i) primary cortical neurons under oxygen–glucose deprivation/normoglycemic reoxygenation as an experimental ischemia model; (ii), neuronal line cells treated with rotenone/oligomycin A, okadaic acid or β-amyloid peptide Aβ25–35, modeling toxic insults found among the effects of AD., This work was supported by the Instituto de Salud Carlos III and cofinanced by the Euro- pean Development Regional Fund (FEDER), grant number PI18/00255 and RETICS RD16/0019/0006, to A.A, Programa Miguel Servet CPII19/00005, PI19/00082 to JE, and by MINECO (Government of Spain) grant number SAF-2015-65586-R to J.M.-C. D.D.-I. thanks the Spanish Ministry of Science, Innovation and Universities for predoctoral FPU grant. A.E.-P. thanks Instituto de Salud Carlos III for the predoctoral contract IFI18/00011.

Aim: Due to the multifactorial nature of Alzheimer's disease, there is an urgent search for new more efficient, multitarget-directed drugs. Results: This paper describes the synthesis, antioxidant and in vitro biological evaluation of ten (benz)imidazopyridino tacrines (7-16), showing less toxicity than tacrine at high doses, and potent cholinesterase inhibitory capacity, in the low micromolar range. Among them, compound 10 is a nonhepatotoxic tacrine at 1000 mM, showing moderate, but totally selective electric eel acetylcholinesterase inhibition, whereas molecule 16 is twofold less toxic than tacrine at 1000 μM, showing moderate and almost equipotent inhibition for electric eel acetylcholinesterase and equine butyrylcholinesterase. Conclusion: (Benz)imidazopyridino tacrines (7-16) have been identified as a new and promising type of tacrines for the potential treatment of Alzheimer's disease.

The synthesis, cholinesterase inhibition, molecular modelling and ADME properties of novel tacrine-neocryptolepine heterodimers are described. Compound 3 [5-methyl-N-(8-(5,6,7,8-tetrahydroacridin-9-ylamino)octyl)-5H-indolo[2,3-b]quinolin-11-amine], showing a moderate inhibition of the Aβ1-42 self-aggregation (26.5% at a 1 : 5 ratio with Aβ1-42), and a calculated log BB value (0.27) indicating excellent potential BBB penetration, is a highly potent human cholinesterase inhibitor [IC50 (hAChE) = 0.95 ± 0.04 nM; IC50 (hBuChE) = 2.29 ± 0.14 nM] which can be listed among the most potent hAChE inhibitors so far identified, and is not hepatotoxic in vitro at the concentrations at which the ChEs are inhibited. A molecular modeling study was also undertaken in order to elucidate the AChE and the BuChE bind modes of all the new compounds. The docking results show that all of them bind to AChE in extended conformations and to BuChE in folded conformations. Moreover, these studies revealed that the length of the linker is crucial to binding both the catalytic anionic site and the peripheral anionic site.

We report the synthesis and relevant pharmacological properties of the quinoxalinetacrine (QT) hybrid QT78 in a project targeted to identify new non-hepatotoxic tacrine derivatives for Alzheimer&rsquo, s disease therapy. We have found that QT78 is less toxic than tacrine at high concentrations (from 100 &mu, M to 1 mM), less potent than tacrine as a ChE inhibitor, but shows selective BuChE inhibition (IC50 (hAChE) = 22.0 &plusmn, 1.3 &mu, M, IC50 (hBuChE) = 6.79 &plusmn, 0.33 &mu, M). Moreover, QT78 showed effective and strong neuroprotection against diverse toxic stimuli, such as rotenone plus oligomycin-A or okadaic acid, of biological significance for Alzheimer&rsquo, s disease.

We describe herein the synthesis and neuroprotective capacity of an array of 31 compounds comprising quinolyloximes, quinolylhydrazones, quinolylimines, QNs, and related heterocyclic azolylnitrones. Neuronal cultures subjected to oxygen-glucose deprivation (OGD), as experimental model for ischemic conditions, were treated with our molecules at the onset of recovery period after OGD and showed that most of these QNs, but not the azo molecules, improved neuronal viability 24 h after recovery. Especially, QN (Z)-N-tert-butyl-1-(2-chloro-6-methoxyquinolin-3-yl)methanimine oxide (23) was shown as a very potent neuroprotective agent. Antioxidant analysis based on the ability of QN 23 to trap different types of toxic radical oxygenated species supported and confirmed its strong neuroprotective capacity. Finally, QN 23 showed also neuroprotection induction in two in vivo models of cerebral ischemia, decreasing neuronal death and reducing infarct size, allowing us to conclude that QN 23 can be considered as new lead-compound for ischemic stroke treatment., This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (Grants SAF2012-33304 and SAF2015-65586-R) and Universidad Camilo José Cela (NitroStroke 2015-12) to J.M.-C., the Instituto de Salud Carlos III and cofinancing by the European Development Regional Fund (FEDER) (Grants PI14/00705, PI18/0255, and RETICS RD16/0019/0006) to A.A., and the Regional Madrid Government (BIPEDD-2, Grant S2010-BMD-2457) to L.I. We thank Isquaemia Biotech SL for its financial support. A.A. thanks M. Gómez-Calcerrada for technical assistance.

In this work six PBN-related indanonitrones 1–6 have been designed, synthesized, and their neuroprotection capacity tested in vitro, under OGD conditions, in SH-SY5Y human neuroblastoma cell cultures. As a result, we have identified indanonitrones 1, 3 and 4 (EC50=6.64 ± 0.28 μM) as the most neuroprotective agents, and in particular, among them, indanonitrone 4 was also the most potent and balanced nitrone, showing antioxidant activity in three experiments [LOX (100 μM), APPH (51%), DPPH (36.5%)], being clearly more potent antioxidant agent than nitrone PBN. Consequently, we have identified (Z)-5-hydroxy-N-methyl-2,3-dihydro-1Hinden- 1-imine oxide (4) as a hit-molecule for further investigation., JMC thanks MINECO (Government of Spain) (SAF2015-65586-R), and UCJC for support [UCJC-2015-12 and UCJC-2018-04).

We describe here the preparation, neuroprotective analysis, and antioxidant capacity of 11 novel quinolylnitrones (QN). The neuroprotective analysis of QN1-11 in an oxygen-glucose deprivation model, in primary neuronal cultures, has been determined, allowing us to identify QN6 as a very potent neuroprotective agent, showing significant high value at 0.5 and 10 μM (86.2%), a result in good agreement with the observed strong hydroxyl radical scavenger of QN6., This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2015-65586-R) to J.M.-C., and the Instituto de Salud Carlos III and cofinancing by the European Development Regional Fund (FEDER) (PI14/ 00705, PI18/0255 and RETICS RD16/0019/0006) to A.A. and (IFI18/00011) to A.E.-P.

New heterocyclic privileged medicinal scaffolds involving 4H-pyran, 1,4-dihydropyridine, quinazoline, and 2-aminochromene bearing a (benz)imidazole unit were prepared in good to excellent yields, and evaluated for their in vitro hepatotoxicity on HepG2 cells and antioxidant activity using DPPH radical-scavenging assay. From these results, 2-amino-4-(1-methyl-1H-imidazol-2-yl)-4H-benzo[h]chromene-3-carbonitrile has been identified as a racemic, readily available imidazole derivative, significantly less hepatotoxic than tacrine at 100 μM concentration. One compound was found to be a potent antioxidant agent. The catalytic effect of the 1-methylimidazole unit, in the synthesis of some heterocycle, was also demonstrated. Crystal X-ray structures are reported for six compounds.

Notwithstanding the combination of cholinesterase (ChE) inhibition and calcium channel blockade within a multitarget therapeutic approach is envisaged as potentially beneficial to confront Alzheimer's disease (AD), this strategy has been scarcely investigated. To explore this promising line, a series of 5- amino-4-aryl-3,4,6,7,8,9-hexahydropyrimido [4,5-b]quinoline-2(1H)-thiones (tacripyrimidines) (4a-l) were designed by juxtaposition of tacrine, a ChE inhibitor (ChEI), and 3,4-dihydropyrimidin-2(1H)-thiones, as efficient calcium channel blockers (CCBs). In agreement with their design, all tacripyrimidines, except the unsubstituted parent compound and its p-methoxy derivative, acted as moderate to potent CCBs with activities generally similar or higher than the reference CCB drug nimodipine and were modest-to-good ChEIs. Most interestingly, the 30-methoxy derivative (4e) emerged as the first well balanced ChEI/CCB agent, acting as low micromolar hChEI (3.05 mM and 3.19 mM on hAChE and hBuChE, respectively) and moderate CCB (30.4% at 1 mM) with no significant hepatotoxicity toward HepG2 cells and good predicted oral absorption and blood brain barrier permeability, EB and FP thank Erasmus for support. JMC thanks MINECO (Government of Spain) for grants SAF2012-33304 and CTQ-68380- R. JMC and MLB thank EU (COST Action 15135). MB and MLB gratefully acknowledges the University of Bologna and the Italian Ministry of Education, Universities and Research (MIUR)

This study describes CholesteroNitrone 2 as an antioxidant and neuroprotective agent against ischemic injury. Neuroprotection was assessed using in vitro and in vivo experimental ischemia models. The compound significantly increased cell viability, induced neuroprotection following ischemic reperfusion, and decreased neurological deficit scores in treated animals, supporting the next preclinical studies as a potential agent for the treatment of stroke. (Figure Presented)., A.A. thanks M. Gómez-Calcerrada and Valerio Frezza for their technical assistance. This work was supported by ISCIII and FEDER grants to A.A. (PI1/00334 and PI14/00705).

The reaction of racemic 2-amino-4H-pyrans, such as 3-amino-1-aryl-1H-benzo[f]chromene-2-carbonitriles, with N-bromosuccinimide (NBS), in CH2 Cl2, at room temperature, is a very quick, regio, stereoselective, and high yielding process, affording major racemic (1S,2S)-2-bromo-3-imino-benzo[f]chromene or racemic (1S,2S)-2-bromo-3-(bromoimino)-benzo[f]chromene derivatives, when using 1.0 or 2.2 equivalents of NBS, respectively. This reaction, extended to isomeric 2-amino-4-aryl-4H-benzo[h]chromene-3-carbonitriles, showed an unexpected reactivity, affording racemic (3S,4S)-3-bromo-2-(bromoimino)-benzo[h]chromene-3-carbonitriles or 2-oxo-2H-benzo[h]chromene-3-carbonitriles, when using 2.2 or 1.0 equivalents of NBS, respectively. The reaction of alkyl 6-amino-5-cyano-2-methyl-4H-pyran-3-carboxylates has yielded unstable racemic (3S,4S)-alkyl 3-bromo-2-(bromoimino)-3-cyano-6-methyl-3,4-dihydro-2H-pyran-5-carboxylates. The mechanism of these reactions has been investigated by computational methods.

There is a need to develop additional effective therapies for ischemic stroke. Nitrones, which were first developed as reactive oxygen species (ROS)-trapping compounds, have been proposed as neuroprotective agents for ischemic stroke, a ROS-related disorder. The previous reported ROS-trapping compound, quinolyl nitrone RP19, is here being assayed to induce neuroprotection to ischemia-reperfusion injury in three experimental ischemia models: (i) oxygen-glucose deprivation (OGD) on primary neuronal cultures; (ii) transient global cerebral ischemia in four-vessel occlusion model; and (iii) transient focal cerebral ischemia in middle cerebral artery occlusion (tMCAO) model. RP19 (50 μM) induced long-term neuroprotection at 5 days of recovery after OGD in primary neuronal cultures, evaluated by cell viability assay, and decreased both ROS formation and lipid peroxidation upon recovery after OGD. Furthermore, treatment of animals with RP19 at the onset of reperfusion after either global or focal ischemia, at the dose range that was demonstrated to be neuroprotective in neuronal cultures, decreased neuronal death and apoptosis induction, reduced the size of infarct, and improved the neurological deficit scores after 48 h or 5 days of reperfusion after ischemia. The molecule proposed, quinolyl nitrone RP19, induced substantial neuroprotection on experimental ischemia in neuronal cells, and against ischemic injury following transient brain ischemia in treated animals. This molecule may have potential therapeutic interest in ischemic stroke and to reduce the reoxygenation-induced injury after induced reperfusion.

The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H

5-Methyl-N-(8-(5,6,7,8-tetrahydroacridin-9-ylamino)octyl)-5H-indolo[2,3-b]quinolin-11-amine is a very potent human ChE inhibitor [IC50 (hAChE) = 0.95 ± 0.04 nM].

Aim: Due to the complex nature of Alzheimer's disease, there is a renewed search for multitarget directed drugs. Results: This paper describes the synthesis and in vitro biological evaluation of six racemic 13-aryl-2,3,4,13-tetrahydro-1H,12H-benzo[6,7]chromeno[2,3-d]pyrido[1,2-a]pyrimidine-7,12,14-triones (1a-6a), and six racemic 15-aryl-8,9,10,11,12,15-hexahydro-14H-benzo[6′,7′]chromeno[2′,3:4,5] pyr-imido [1,2-a]azepine-5,14,16-triones (1b-6b), showing antioxidant and cholinesterase inhibitory capacity. Among these compounds, 13-phenyl-2,3,4,13-tetrahydro-1H,12H-benzo[6,7]chromeno[2,3-d]pyrido[1,2-a]pyrimidine-7,12,14-trione (1a) is a nonhepatotoxic at 300 μmol/l dose concentration, and a selective EeAChE inhibitor showing good antioxidant power. Conclusion: A new family of racemic benzochromenopyrimidinetriones has been investigated for their potential use in the treatment of Alzheimer's disease.

In this communication we have described the synthesis of 2-amino-6-oxo-1,6-dihydropyridine-3-carbonitrile (4), and the preparation of 5-amino-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridin-2(1H)-one (3 a), a non-hepatotoxic, antioxidant agent, showing moderate, but selective human acetylcholinesterase inhibition., JMC thanks MINECO (SAF2012-33304), and Universidad Camilo José Cela (MULTIMOL 2013–20) for support

The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood–brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits., J.M.C. thanks MINECO (SAF2012-33304 and SAF2015- 65586-R). J.M.C., F.L.M., and A.R. thank UCJC for grants 2015-12, 2014-35, and 2015-21, respectively. J.E. thanks the Fondo de Investigaciones Sanitarias (FIS) (ISCIII/FEDER) (Programa Miguel Servet: CP14/00008 and PI16/00735) and Fundación Mutua Madrileña. O.S. and J.J. thank MHCZDRO (UHHK 00179906) for support. R.R.R., H.S., and J.M.C. acknowledge the EU COST Actions CM1103 and CM15135. E.P. and H.S. thank the German Research Foundation (DFG; PRO 1405/2-2, PRO 1405/4-1, SFB 1039 A07, and INST208/664-1).

The reaction of 4-amino-5,5-dimethyl-5H-1,2-oxathiole 2,2-dioxide (1) with 2-(arylidene)malononitriles 2 in ethanol, at reflux, using piperidine as catalyst, afforded 5-amino-3,3-dimethyl-7-aryl-3H-[1,2]oxathiolo[4,3-b]pyridine-6-carbonitrile 1,1-dioxides (3) in moderate chemical yields.

We report herein the silver-catalyzed cycloisomerization of readily available N-(prop-2-yn-1-yl)pyridine-2-amines as a new and practical method for the synthesis of differently substituted 3-methylimidazo[1,2-a]pyridines. The isomerization reactions proceeded under mild reactions conditions to give good yields and excellent regioselectivity. A DFT-based mechanistic analysis is also reported.

We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line., JMC thanks Government of Spain for support (SAF2016-65586-R), JJ and OS thank MH CZ- DRO (UHHK 00179906)., We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI).

Given the complex nature of Alzheimer's disease (AD), compounds that are able to simultaneously address two or more AD-associated targets show greater promise for development into drugs for AD therapy. Herein we report an efficient two-step synthesis and biological evaluation of new racemic benzochromene derivatives as antioxidants, inhibitors of cholinesterase and β-amyloid (Aβ1-42 ) aggregation. Based on the results of the primary screening, we identified 15-(3-methoxyphenyl)-9,11,12,15-tetrahydro-10H,14H-benzo[5,6]chromeno[2,3-d]pyrido[1,2-a]pyrimidin-14-imine (3 e) and 16-(3-methoxyphenyl)-9,10,11,12,13,16-hexahydro-15H-benzo[5',6']chromeno[2',3':4,5]pyrimido[1,2-a]azepin-15-imine (3 f) as new potential multitarget-directed ligands for AD therapy. Further in-depth biological analysis showed that compound 3 f is a good human acetylcholinesterase inhibitor [IC50 =(0.36±0.02) μm], has strong antioxidant activity (3.61 μmol Trolox equivalents), and moderate Aβ1-42 antiaggregating power (40.3 %).

This document is the accepted manuscript version of a Published Work that appeared in final form in ACS Chemical Neuroscience 7.8, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see DOI: 10.1021/acschemneuro.6b00122, A series of multitarget directed propargylamines, as well as other differently susbstituted piperidines have been screened as potential modulators of neuronal nicotinic acetylcholine receptors (nAChRs). Most of them showed antagonist actions on α7 nAChRs. Especially, compounds 13, 26, and 38 displayed submicromolar IC50 values on homomeric α7 nAChRs, whereas they were less effective on heteromeric α3β4 and α4β2 nAChRs (up to 20-fold higher IC50 values in the case of 13). Antagonism was concentration dependent and noncompetitive, suggesting that these compounds behave as negative allosteric modulators of nAChRs. Upon the study of a series of less complex derivatives, the N-benzylpiperidine motif, common to these compounds, was found to be the main pharmacophoric group. Thus, 2-(1-benzylpiperidin-4-yl)-ethylamine (48) showed an inhibitory potency comparable to the one of the previous compounds and also a clear preference for α7 nAChRs. In a neuroblastoma cell line, representative compounds 13 and 48 also inhibited, in a concentration-dependent manner, cytosolic Ca2+ signals mediated by nAChRs. Finally, compounds 38 and 13 inhibited 5-HT3A serotonin receptors whereas they had no effect on α1 glycine receptors. Given the multifactorial nature of many pathologies in which nAChRs are involved, these piperidine antagonists could have a therapeutic potential in cases where cholinergic activity has to be negatively modulated., This work was supported by grants SAF2011-22802 to S.S., SAF2012-33304 to J.M.-C., CSD2008-00005 (the Spanish Ion Channel Initiative-CONSOLIDER INGENIO 2010) to M.C. from the Spanish Ministry of Science and Innovation (Ministerio de Economía y Competitividad).