© 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.

Despite the widespread use of artichoke-based food supplements for obesity control (FSOC), studies on evaluation of the quality/authenticity of these commercial products are scarce. To that aim, a new multi-analytical strategy, based on the use of gas chromatography coupled to mass spectrometry (GC–MS) and high performance liquid chromatography coupled to ultraviolet and mass spectrometry detection (HPLC-UV-MS), in combination with chemometrics, has been developed. Twenty-one artichoke FSOC and different bract and leaf extracts (used as reference samples) were analysed. Sugars, inositols, caffeoylquinic acids, dicaffeoylquinic acids, flavonoids and their glycosides were detected in reference samples and in most artichoke FSOC. Low concentrations of bioactives, and the presence of other compounds probably related to heat treatment during manufacturing (difructosyl anhydrides, 3-deoxyglucosone), or to the addition of caloric additives (maltose, maltotriose) or non-declared plants (e.g. pinitol, disaccharides, silybin derivatives) were also detected in some FSOC by either GC–MS or HPLC-UV-MS. Application of Principal Component Analysis to the combined GC–MS + HPLC-UV data matrix, proved that this multi-analytical strategy provides advantages over single analytical techniques for the detection of the wide variety of fraudulent practices affecting authenticity of artichoke FSOC and for assessment of their quality. © 2021

A convergent synthetic route to a tetrasaccharide related to PI-88, which allows the incorporation of a fluorescent BODIPY-label at the reducing-end, has been developed. The strategy, which features the use of 1,2-methyl orthoesters (MeOEs) as glycosyl donors, illustrates the usefulness of suitably-designed BODIPY dyes as glycosyl labels in synthetic strategies towards fluorescently-tagged oligosaccharides. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

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

Novel, linker-free, BODIPY-carbohydrate derivatives containing sugar residues at positions C2 and C6 are efficiently obtained by, hitherto unreported, Ferrier-typeC-glycosylation of 8-aryl-1,3,5,7-tetramethyl BODIPYs with commercially available tri-O-acetyl-glucal followed by saponification. This transformation, which involves the electrophilic aromatic substitution (SEAr) of the dipyrrin framework with an allylic oxocarbenium ion, provides easy access to BODIPY-carbohydrate hybrids with excellent photophysical properties and a weaker tendency to aggregate in concentrated water solutions. © 2021 The Authors. Published by American Chemical Society

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.

The storage capacity, trophic magnification and risk of sixty-two POPs have been evaluated in a well-characterized pelagic food web (including phytoplankton, zooplankton, six fish, and two cephalopods species) from an impacted area in NW Mediterranean Sea. Our results show the high capacity of the planktonic compartment for the storage of polybrominated diphenyl ethers (PBDEs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), consistent with their estimated low trophic magnification factors (TMF) of 0.2-2.0 (PBDEs) and of 0.3-1.1 (PCDD/Fs). ∑PBDEs dominated in the zooplankton size-class 200-1000 μm (∼330 ng g-1 lw, median), whereas ∑PCDD/Fs accumulated preferentially in phytoplankton size-class 0.7-200 μm (875 pg g-1 lw, median). In contrast, polychlorinated biphenyls (PCBs) were preferentially bioaccumulated in the higher trophic levels (six fish species and two cephalopods) with TMFs = 0.8-3.9, reaching median concentrations of 4270 and 3140 ng g-1 lw (∑PCBs) in Atlantic bonito (Sarda sarda) and chub mackerel (Scomber colias), respectively. For these edible species, the estimated weekly intakes of dioxin-like POPs for humans based on national consumption standards overpassed the EU tolerable weekly intake. Moreover, the concentrations of nondioxin-like PCBs in S. sarda were above the EU maximum levels in foodstuffs, pointing to a risk. No risk evidence was found due to consumption of all other edible species studied, neither for PBDEs. The integrated burden of POPs in the food web reached ∼18 μg g-1 lw, representing a dynamic stock of toxic organic chemicals in the study area. We show that the characterized food web could be a useful and comprehensive bioindicatorof the chemical pollution status of the study area, opening new perspectives for the monitoring of toxic chemicals in Mediterranean coastal waters. © 2021 American Chemical Society.

A bis(triflyl)ethylation [triflyl = (trifluoromethyl)sulfonyl] inserted into a sequential cyclization cascade resulted in the direct formation of gem-bis(triflyl)ated cyclopenta[b]indolines from anilide-derived allenols and alkenols. This catalyst- and irradiation-free sequence facilitated the efficient preparation of functionalized tricyclic indoline cores bearing two contiguous stereocenters. The formed cyclopenta[b]indolines can be easily transformed into a wide variety of triflylated indolines, including the tetracycle ring system found in polyveoline. © 2021 American Chemical Society.

The allene functionality has participated in one of the most exciting voyages in organic chemistry, from chemical curiosities to a recurring building block in modern organic chemistry. In the last decades, a special kind of allene, namely, allenol, has emerged. Allenols, formed by an allene moiety and a hydroxyl functional group with diverse connectivity, have become common building blocks for the synthesis of a wide range of structures and frequent motif in naturally occurring systems. The synergistic effect of the allene and hydroxyl functional groups enables allenols to be considered as a unique and sole functionality exhibiting a special reactivity. This Review summarizes the most significant contributions to the chemistry of allenols that appeared during the past decade, with emphasis on their synthesis, reactivity, and occurrence in natural products. © 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.

A series of 17 arylpiperazine derivatives of the 5-spiroimidazolidine-2,4-diones (6–22) has been explored, including variations in (i) the number of aromatic rings at position 5, (ii) the length of the linker, as well as (iii) the kind and position of the linked arylpiperazine terminal fragment. Synthesis (6–16) and X-ray crystallographic studies for representative compounds (8, 10, 14 and 18) have been performed. The ability to inhibit the tumor multidrug resistance (MDR) efflux pump P-glycoprotein (P-gp, ABCB1) overexpressed in mouse T-lymphoma cells was investigated. The cytotoxic and antiproliferative actions of the compounds on both the reference and the ABCB1-overproducing cells were also examined. The pharmacophore-based molecular modeling studies have been performed. ADMET properties in vitro of selected most active derivatives (6, 11 and 12) have been determined. All compounds, excluding 18, inhibited the cancer P-gp efflux pump with higher potency than that of reference verapamil. The spirofluorene derivatives with amine alkyl substituents at position 1, and the methyl group at position 3 (6–16), occurred the most potent P-gp inhibitors in the MDR T–lymphoma cell line. In particular, compounds 7 and 12 were 100-fold more potent than verapamil. Crystallography-supported pharmacophore-based SAR analysis has postulated specific structural properties that could explain this excellent cancer MDR-inhibitory action. © 2021 Elsevier Inc.

Invited for the cover of this issue are Andrés G. Santana, Carlos González, Juan Luis Asensio and co-workers at Instituto de Química Orgánica General, Instituto de Química-Física Rocasolano and Universidad de La Rioja. The image depicts drug selectivity using a metaphor of an arrow hitting a target. Read the full text of the article at 10.1002/chem.202005026. © 2021 Wiley-VCH GmbH

During the last decade, there has been a tremendous interest for developing non-natural biocompatible transformations in biologically relevant media. Among the different encountered strategies, the use of transition metal complexes offers unique possibilities due to their high transformative power. However, translating the potential of metal catalysts to biological settings, including living cells or small-animal models such as mice or zebrafish, poses numerous challenges associated to their biocompatibility, and their stability and reactivity in crowded aqueous environments. Herein, we describe the most relevant advances in this direction, with a particular emphasis on the systems’ structure, their mode of action and the mechanistic bases of each transformation. Thus, the key challenges from an organometallic perspective might be more easily identified. © 2020 Wiley-VCH GmbH

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

This work represents the first reported effort to build an extensive database of the organic volatile and semi-volatile contaminants present in car dust as a result of migration from materials used in auto-manufacturing. Untargeted analysis of car dust samples has been performed using comprehensive two-dimensional gas chromatography combined with time-of-fight mass spectrometry (GC×GC ‒ToF MS) after generic sample preparation. The enhanced separation power and structural confirmation capabilities provided by this technique have been used for the either positive or tentative identification of 245 GC-amenable compounds, a number of them being identified for the first time in this type of matrix. Information concerning 5 compounds remaining unidentified has also been provided. Results have been summarised in a searchable database containing chromatographic, mass spectral and normalised abundances calculated for the detected analytes in the ten investigated car dusts used to discuss the main findings of the study. Results are expected to serve other researcher to take decisions concerning priority analytes for further evaluation in this research field and for car manufacturers who might search for safer materials. © 2021 Elsevier B.V.

A selective palladium-catalyzed C(sp) arylation/carbocyclization/iodonium migration reaction sequence has been accomplished. Novel 2-iodo-1-aryl-9H-carbazoles are now easily available. As this result is contrary to the selectivity observed using gold catalysis, the formation of 2-iodocarbazoles is noticeable, suggesting a metal-controlled cyclization through chemo- and regioselective 1,2-alkyl migration and 1,4-iodonium migration. (Figure presented.). © 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.

The highly diastereoselective sulfa-Michael addition of thiolates to enantiopure 2-sulfinyl dienes leads to anti or syn 2-ene-1,4-hydroxy sulfides in good yields and selectivities dependent on the reaction conditions in a diastereodivergent process. Synthetic applications of these enantiopure hydroxy sulfides by subsequent sigmatropic rearrangements have been outlined. ©