© 2021 Wiley-VCH GmbH.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.

© 2021 by the authors. Licensee MDPI, Basel, Switzerland.Alzheimer’s disease (AD) is the most common form of dementia over the age of 65. It is estimated that 115.4 million people will be affected by AD by 2050. Acetylcholinesterase inhibitors (AChEI) are the only available and approved treatment for AD. The aim of the present study was to analyse the evidence on the efficacy of the AChEI in the treatment of cognitive symptoms of Alzheimer’s disease. For that purpose, a review of review of the systematic reviews (SRs) on this topic was carried out by Web of Science, PubMed, and The Cochrane Library, among others, were searched until 24 September 2021. Thirteen of the 1773 articles evaluated the efficacy of AChEI on cognitive function and/or general condition and/or behavioural disturbances of patients with mild to moderate AD. Methodological quality and risk of bias were rated using the ROBIS scale. The quality of the identified studies was high for nine of them, unclear for two, and finally only in two of the 13 studies did we detect low quality. Overall, AChEI showed very low efficacy in improving cognition in patients with mild to moderate AD. Better results were obtained in improving global state, with donepezil being the most effective treatment. No improvements in behavioural disturbances were found. Few high-quality reviews provide clear evidence of the effects of AChEI on cognition, global change, behaviour, and mortality. The data suggest that AChEI stabilize or slow cognitive deterioration, improving global status. In addition, data indicate that the use of AChEI decreases mortality in patients with mild to moderate AD. However, there is no evidence that they improve patient behaviour. Donepezil is the best therapeutic alternative at a dose of 10 mg/day.

Herein I present a review on the synthesis of ipsenol and ipsdienol, two aggregation pheromones of bark beetles, isolated from different species of genus Ips, and serious pests of conifer forests. I have covered the literature for around fifty years, since 1968 to 2020. This account has been divided in different sections and sub-sections, including a general and brief outlook on their isolation, structure and biological activity, to continue with the reported synthesis of racemic ipsenol and ipsdienol, including my own contribution to topic, and the presentation of reports describing the synthesis of enantiomerically pure ipsenol and ipsdienol. Particular attention has been devoted to identify and highlight racemic or enantiomerically pure “isoprene synthons”, and isoprenylation methods employed in the synthesis of ipsenol and ipsdienol, of general interest for related terpene derivatives synthesis. © 2021 The Chemical Society of Japan & Wiley-VCH GmbH

Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3β and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±)-BIGI-3h was identified as a promising new hit compound showing in vitro balanced activities toward the aforementioned recognized AD targets. Additional in vitro studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and β-amyloid peptide. The in vivo studies have shown that (±)-BIGI-3h (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits. © 2021 American Chemical Society.

Herein, we report the neuroprotective and antioxidant activity of 1,1′-biphenyl nitrones (BPNs) 1–5 as α-phenyl-N-tert-butylnitrone analogues prepared from commercially available [1,1′-biphenyl]-4-carbaldehyde and [1,1′-biphenyl]-4,4′-dicarbaldehyde. The neuroprotection of BPNs1-5 has been measured against oligomycin A/rotenone and in an oxygen–glucose deprivation in vitro ischemia model in human neuroblastoma SH-SY5Y cells. Our results indicate that BPNs 1–5 have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone (PBN), and they are quite similar to N-acetyl-L-cysteine (NAC), which is a well-known antioxidant agent. Among the nitrones studied, homo-bis-nitrone BPHBN5, bearing two N-tert-Bu radicals at the nitrone motif, has the best neuroprotective capacity (EC50 = 13.16 ± 1.65 and 25.5 ± 3.93 μM, against the reduction in metabolic activity induced by respiratory chain blockers and oxygen–glucose deprivation in an in vitro ischemia model, respectively) as well as anti-necrotic, anti-apoptotic, and antioxidant activities (EC50 = 11.2 ± 3.94 μM), which were measured by its capacity to reduce superoxide production in human neuroblastoma SH-SY5Y cell cultures, followed by mononitrone BPMN3, with one N-Bn radical, and BPMN2, with only one N-tert-Bu substituent. The antioxidant activity of BPNs1-5 has also been analyzed for their capacity to scavenge hydroxyl free radicals (82\% at 100 μM), lipoxygenase inhibition, and the inhibition of lipid peroxidation (68\% at 100 μM). Results showed that although the number of nitrone groups improves the neuroprotection profile of these BPNs, the final effect is also dependent on the substitutent that is being incorporated. Thus, BPNs bearing N-tert-Bu and N-Bn groups show better neuroprotective and antioxidant properties than those substituted with Me. All these results led us to propose homo-bis-nitrone BPHBN5 as the most balanced and interesting nitrone based on its neuroprotective capacity in different neuronal models of oxidative stress and in vitro ischemia as well as its antioxidant activity. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Herein we report the reaction of 2-(5-aryl-4H-1,2,4-triazol-3-yl)acetonitriles 1 a,b with appropriate Michael acceptors 2–4 to give novel [1,2,4]triazolo[1,5-a]pyridines 5–8, whose antioxidant properties have been investigated. A plausible reaction mechanism, supported by DFT calculations, has been proposed to explain the total observed regioselective formation of [1,2,4]triazolo[1,5-a]pyridine derivatives depending on the type of substituents on the Michael acceptor. Triazoles are well-known agents exhibiting antimicrobial,[1] antitumor,[2] anti-inflammatory,[3] antihypertensive,[4] anticonvulsant,[5] antiviral[6] and analgesic[7] biological activities. On the other hand, pyridine is the key core of heterocyclic derivatives showing a variety of pharmacological properties.[8–12] Several studies have revealed that a combination of different bioactive molecules, having different mechanisms of action, is a current strategy affording useful therapeutic agents.[13] This is the case of the [1,2,4]triazolo[1,5-a] pyridine heterocyclic motif,[14] present in a number of bioactive compounds,[15] and largely used in materials chemistry.[16] Accordingly, diverse synthetic methods have been described for the synthesis of differently substituted [1,2,4]triazolo[1,5-a]pyridines.[17–24] Our group has recently reported the ultrasound-promoted facile and convenient “one-pot” procedure for the synthesis of novel [1,2,4]triazolo[1,5-a]pyridines in short reaction times and high yields, based on the reaction of 2-(5-aryl-4H-1,2,4-triazol-3-yl)acetonitriles, malononitrile (or ethyl cyanoacetate) and aromatic aldehydes, in absolute ethanol, in the presence of IRA-400.[25]. © 2021 Wiley-VCH GmbH

Herein, we have updated the progress and developments of the Carbanion-mediated Sulfonate (or Sulfonamide) Intermolecular Coupling, and Intramolecular Cyclization, abbreviated as CSIC reaction (CSICr), in the last seventeen years from the seminal review published in 2003 in this same Journal. CSICr has proven to be a useful and versatile synthetic tool, efficiently providing a number of open-chain [alkane(sulfonamide)sulfonates] or cylic (sultams and sultones) synthetic intermediates or final products of high value in organic and medicinal chemistry. © 2021 Wiley-VCH GmbH

Herein we report the synthesis of (E)-3-aryl-2-(5-aryl-4H-1,2,4-triazol-3-yl)acrylonitriles 3 a–k whose fluorescence properties have been investigated for the first time. A plausible reaction mechanism has been proposed to explain the total observed stereospecific formation of the E-isomers of compounds 3 a–k. The fluorescence analysis of compounds 3a-f has revealed relatively low values of the fluorescence emission quantum yields in a range of ∼1 to 10 \%, depending in the nature of the substituents. © 2021 Wiley-VCH GmbH.

Alzheimer's disease is a progressive brain disorder with characteristic symptoms and several pathological hallmarks. The concept of “one drug, one target” has not generated any new drugs since 2004. The new era of drug development in the field of AD builds upon rationally designed multi-target directed ligands that can better address the complexity of AD. Herewith, we designed ten novel derivatives of 2-propargylamino-naphthoquinone. The biological evaluation of these compounds includes inhibition of monoamine oxidase A/B, inhibition of amyloid-beta aggregation, radical-scavenging, and metal-chelating properties. Some of the compounds possess low cytotoxicity profile with an anti-inflammatory ability in the lipopolysaccharide-stimulated cellular model. All these features warrant their further testing in the field of AD. © 2020 Elsevier Masson SAS

Herein we have reviewed our recent developments for the identification of new tacrine analogues for Alzheimer's disease (AD) therapy. Tacrine, the first cholinesterase inhibitor approved for AD treatment, did not stop the progression of AD, producing only some cognitive improvements, but exhibited secondary effects mainly due to its hepatotoxicity. Thus, the drug was withdrawn from the clinics administration. Since then, many publications have described non-hepatotoxic tacrines, and in addition, important efforts have been made to design multitarget tacrines by combining their cholinesterase inhibition profile with the modulation of other biological targets involved in AD. © 2020 The Chemical Society of Japan & Wiley-VCH GmbH

Nitrones are potent antioxidant molecules able to reduce oxidative stress by trapping reactive oxygen and nitrogen species. The antioxidant potential of nitrones has been extensively tested in multiple models of human diseases. Sensorineural hearing loss has a heterogeneous etiology, genetic alterations, aging, toxins or exposure to noise can cause damage to hair cells at the organ of Corti, the hearing receptor. Noxious stimuli share a battery of common mechanisms by which they cause hair cell injury, including oxidative stress, the generation of free radicals and redox imbalance. Therefore, targeting oxidative stress-mediated hearing loss has been the subject of much attention. Here we review the chemistry of nitrones, the existing literature on their use as antioxidants and the general state of the art of antioxidant treatments for hearing loss. © Copyright © 2021 Varela-Nieto, Murillo-Cuesta, Rodríguez-de la Rosa, Oset-Gasque and Marco-Contelles.

Sigma (σ) receptors represent attractive targets for the development of potential agents for the treatment of several disorders, including Alzheimer's disease and neuropathic pain. In the search for multitarget small molecules (MSMs) against such disorders, we have re-discovered chromenones as new affine σ1/σ2 ligands. 6-(4-(Piperidin-1-yl)butoxy)-4H-chromen-4-one (7), a previously identified MSM with potent dual-target activities against acetylcholinesterase and monoamine oxidase B, also exhibited σ1/σ2 affinity. 6-(3-(Azepan-1-yl)propoxy)-4H-chromen-4-one (20) showed a Ki value for σ1 of 27.2 nM (selectivity (σ1/σ2) = 28), combining the desired σ1 receptor affinity with a dual inhibitory capacity against both acetyl- and butyrylcholinesterase. 6-((5-Morpholinopentyl)oxy)-4H-chromen-4-one (12) was almost equipotent to S1RA, an established σ1 receptor antagonist. © The Royal Society of Chemistry.

Considering the multifactorial nature of Alzheimer's disease (AD), multitarget small molecules (MTSMs) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer's disease therapy. Thus, new Pyrimidotacrines were designed and synthesized by merging pyrimidine scaffold and tacrine. Among them, 4-(4-nitrophenyl)-2-phenyl-6,7,8,9-tetrahydropyrimido[4,5-b]quinolin-5-amine (4 j) was identified as less hepatotoxic than tacrine at high concentration, a submicromolar inhibitor against both acetylcholinesterase (AChE) (IC50=677±28 nM) and butyrylcholinesterase (BuChE) (IC50=756±41 nM) showing potent antioxidant properties (2.43 TE) and displaying a strong neuroprotection effect against hydrogen peroxide (H2O2) and Oligomycin Rotenone. Consequently, 4 j is a potential new hit-ligand for AD therapy for further biological exploration. © 2021 Wiley-VCH GmbH

Our endeavors in the design, synthesis, and biological assessment of five-membered-ring-fused tacrines as potential therapeutic agents for Alzheimer's disease are summarized. Particularly, we have identified racemic 4-(2-methoxyphenyl)-3-methyl-2,4,6,7,8,9-hexahydropyrazolo[4′,3′:5,6]pyrano[2,3-b]quinolin-5-amine, a pyranopyrazolotacrine, as having the best nontoxic profile at the highest concentrations used (300 μM); this allows cell viability, is less hepatotoxic than tacrine, and is a potent noncompetitive AChE inhibitor (IC 50 = 1.52 ± 0.49 μM). It is able to completely inhibit the Ee AChE-induced Aβ 1-40 aggregation in a statistically significant manner without affecting the Aβ 1-40 self-aggregation at 25 μM, and shows strong neuroprotective effects (EC 50 = 0.82 ± 0.17 μM). 1 Introduction 2 Furo-, Thieno-, and Pyrrolotacrines 3 Pyrazolo-, Oxazolo-, and Isoxazolotacrines 4 Indolotacrines 5 Pyrano- and Pyridopyrazolotacrines 6 Conclusions and Outlook. © 2021. Thieme. All rights reserved.

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. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Multidrug resistance constitutes a serious obstacle of the treatment success of cancer by chemotherapy. Mostly it is driven by expression of ABC transport proteins that actively efflux the anticancer agents out of the cell. This work describes the design and synthesis of 12 new pyrimidopyrimidines, as well as their inhibition of ABCG2 a transporter referred also to as breast cancer resistance protein, the selectivity versus ABCB1 (P-glycoprotein/P-gp) and ABCC1 as well as the investigation of their accumulation in single cells. From these results, N-(3,5-dimethoxyphenyl)-2-methyl-7-phenyl-5-(p-tolyl)pyrimido[4,5-d]pyrimidin-4-amine 7 h was identified as promising hit that deserves further investigation showing a selective and effective inhibition of ABCG2 with IC50 equal to 0.493 µM only 2-fold less active than Ko143. © 2021 Elsevier Inc.

Alzheimer’s disease (AD) is a complex, neurodegenerative pathology showing, among others, high cholinergic and neurotransmitter deficits, oxidative stress, inflammation, Aβ-aggregation resulting in senile plaques formation, and hyperphosphorylation of tau-protein leading to neurofibrillary tangles. Due to its multifactorial and complex nature, multitarget directed small-molecules able to simultaneously inhibit or bind diverse biological targets involved in the progress and development of AD are considered now the best therapeutic strategy to design new compounds for AD therapy. Among them, tacrine is a very well known standard-gold ligand, and natural products have been a traditional source of new agents for diverse therapeutic treatments. In this review, we will update recent developments of multitarget tacrinenatural products hybrids for AD therapy. © 2020 Bentham Science Publishers.

In this communication, we report 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 µM), 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. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Tacrine was the first acetylcholinesterase inhibitor approved for the treatment of Alzheimer's disease although its use has been limited and finally abandoned because of side effects including hepatic toxicity. Based on 1,2,3,4-tetrahydroquinolino[2,3-b]quinoxalin-12-amine (QT78), a recently reported cholinesterase inhibitor, less toxic and potent than tacrine as acetylycholinesterase inhibitor, but more selective against butyrylcholinesterase, herein we report the synthesis of novel quinoxalinetacrines QT1-11, a series of hybrids designed by juxtaposition of tacrine and quinoxaline. The target compounds have been obtained in moderate yields from 3-aminoquinoxaline-2-carbonitrile and suitable commercially available ketones, under microwave-promoted Friedländer reactions catalyzed by aluminium trichloride or indium trichloride. These compounds were synthesized remotely in Eli Lilly's Automated Synthesis Laboratory as part of their Open Innovation Drug Discovery program. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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 (EC50 = 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. © 2020, The Author(s).