Isomerization Mechanism in Hydrazone-Based Rotary Switches: Lateral Shift, Rotation, or Tautomerization?

Two intramolecularly hydrogen-bonded arylhydrazone (aryl = phenyl or naphthyl) molecular switches have been synthesized, and their full and reversible switching between the E and Z configurations have been demonstrated. These chemically controlled configurational rotary switches exist primarily as the E isomer at equilibrium and can be switched to the protonated Z configuration (Z-H^+) by the addition of trifluoroacetic acid. The protonation of the pyridine moiety in the switch induces a rotation around the hydrazone C═N double bond, leading to isomerization. Treating Z-H^+ with base (K_(2)CO_3) yields a mixture of E and “metastable” Z isomers. The latter thermally equilibrates to reinstate the initial isomer ratio. The rate of the Z → E isomerization process showed small changes as a function of solvent polarity, indicating that the isomerization might be going through the inversion mechanism (nonpolar transition state). However, the plot of the logarithm of the rate constant k vs the Dimroth parameter (E_T) gave a linear fit, demonstrating the involvement of a polar transition state (rotation mechanism). These two seemingly contradicting kinetic data were not enough to determine whether the isomerization mechanism goes through the rotation or inversion pathways. The highly negative entropy values obtained for both the forward (E → Z-H^+) and backward (Z → E) processes strongly suggest that the isomerization involves a polarized transition state that is highly organized (possibly involving a high degree of solvent organization), and hence it proceeds via a rotation mechanism as opposed to inversion. Computations of the Z ↔ E isomerization using density functional theory (DFT) at the M06/cc-pVTZ level and natural bond orbital (NBO) wave function analyses have shown that the favorable isomerization mechanism in these hydrogen-bonded systems is hydrazone–azo tautomerization followed by rotation around a C–N single bond, as opposed to the more common rotation mechanism around the C═N double bond

Psicomotricity and retrogenesis: considerations about aging and Alzheimer's disease

CONTEXTO: A teoria da retrogênese refere-se às mudanças nas habilidades psicomotoras que ocorrem de forma inversa à aquisição do desenvolvimento motor normal. Tais mudanças ocorrem ao longo do processo de envelhecimento e também são ilustradas por mudanças degenerativas ocorridas na doença de Alzheimer (DA). OBJETIVOS: Revisar o conceito de retrogênese no envelhecimento e na DA e discutir os artigos publicados sobre o assunto nos últimos 10 anos. MÉTODOS: Foi realizada uma pesquisa nas bases de dados PubMed (MEDLINE), Lilacs, Cochrane e Sci SciELO com as palavras-chave "retrogenesis" (retrogênese), "elderly" (idoso) e "Alzheimer's disease" (doença de Alzheimer). RESULTADOS: A busca bibliográfica resultou em seis artigos, dois dos quais publicados nos primeiros meses de 2009, sendo realizadas análise descritiva e interpretação crítica deles. Foi possível observar que o estudo da retrogênese na velhice tem sido feito fundamentalmente com base na DA, principalmente por meio de revisões bibliográficas e explorações teóricas. Esses trabalhos correlacionam manifestações observadas na DA com determinadas alterações fisiológicas, seguindo o sentido oposto ao do desenvolvimento normal do ser humano. CONCLUSÃO: A partir da revisão realizada, destacou-se o modelo da retrogênese funcional que ilustra as alterações involutivas que ocorrem em pacientes acometidos em pacientes com DA. Modelos experimentais utilizando-se de técnicas de ressonância magnética com medidas de anisotropia, identificando alterações de substância branca, têm sido apresentados para testar as hipóteses teóricas da retrogênese.BACKGROUND: The theory of retrogenesis refers to changes in psychomotor abilities that occur in the reverse order in which they are acquired in normal psychomotor development. Such changes occur along the aging process and are also illustrated by the degenerative changes that occur in Alzheimer's disease (AD). OBJECTIVES: To review the concept of retrogenesis in aging and in AD and to discuss the articles published on the subject in the last ten years. METHODS: A search was conducted in the databases PubMed (MEDLINE), Lilacs, Cochrane and SciELO with the keywords "retrogenesis", "elderly" and "Alzheimer's disease". RESULTS: The literature search resulted in six articles, two of which recently published. We conducted a descriptive analysis of them. We observed that the study of retrogenesis in old age has been done primarily on the basis of AD, mainly through literature reviews and theoretical explorations. These works correlate events observed in AD with some physiological changes, following the opposite direction to the normal development of human beings. DISCUSSION: Based on available literature, we support the notion that functional retrogenesis model illustrate the changes that occur in patients with AD. This notion is supported by experimental models using diffusion tensor imaging and addressing white-matter changes that occur along the aging and the disease processes

Kinetic and Thermodynamic Approaches for the Efficient Formation of Mechanical Bonds

Among the growing collection of molecular systems under consideration for nanoscale device applications, mechanically interlocked compounds derived from electrochemically switchable bistable [2]rotaxanes and [2]catenanes show great promise. These systems demonstrate dynamic, relative movements between their components, such as shuttling and circumrotation, enabling them to serve as stimuli-responsive switches operated via reversible, electrochemical oxidation−reduction rather than through the addition of chemical reagents. Investigations into these systems have been intense for a number of years, yet limitations associated with their synthesis have hindered incorporation of their mechanical bonds into more complex architectures and functional materials. We have recently addressed this challenge by developing new template-directed synthetic protocols, operating under both kinetic and thermodynamic control, for the preparation of bistable rotaxanes and catenanes. These methodologies are compatible with the molecular recognition between the π-electron-accepting cyclobis(paraquat-p-phenylene) (CBPQT4+) host and complementary π-electron-donating guests. The procedures that operate under kinetic control rely on mild chemical transformations to attach bulky stoppering groups or perform macrocyclizations without disrupting the host−guest binding of the rotaxane or catenane precursors. Alternatively, the protocols that operate under thermodynamic control utilize a reversible ring-opening reaction of the CBPQT4+ ring, providing a pathway for two cyclic starting materials to thread one another to form more thermodynamically stable catenaned products. These complementary pathways generate bistable rotaxanes and catenanes in high yields, simplify mechanical bond formation in these systems, and eliminate the requirement that the mechanical bonds be introduced into the molecular structure in the final step of the synthesis. These new methods have already been put into practice to prepare previously unavailable rotaxane architectures and novel complex materials. Furthermore, the potential for utilizing mechanically interlocked architectures as device components capable of information storage, the delivery of therapeutic agents, or other desirable functions has increased significantly as a result of the development of these improved synthetic protocols

Efficacy of cognitive and functional remediation in bipolar disorder: a meta-analysis of randomized controlled trials

Introduction: A significant percentage of people with bipolar disorder (BD) exhibit conspicuous deficits in everyday functioning, even when appropriately treated and after symptomatic recovery is achieved. Given that cognitive impairment is one of the strongest correlates of socio-occupational outcomes and quality of life in BD, cognitive remediation (CR) has been proposed in recent years as a promising treatment that could help bridge the gap between symptomatic and full functional recovery. The aim of this study was to explore the efficacy of CR in improving executive deficits and functional outcomes in BD patients.Method: PubMed, PsycINFO, and CENTRAL were searched from inception to August 2022. Only randomized controlled trials exploring the effects of CR on cognition or functional adjustment in adult BD patients were eligible. Change-score effect sizes (Hedges’ g) were obtained and combined by means of meta-analytic procedures (PROSPERO, CRD42022306504). Results: Nine studies reporting the results of six independent trials (n = 544) were included. Meta-analytic findings revealed small durable improvements in working memory (g = 0.34; 95% CI = 0.12 to 0.56) and planning (g = 0.30; 95% CI = 0.03 to 0.56). However, no significant effects of CR were observed on functional outcomes at treatment completion or at follow-up assessment. Conclusion: Though CR may produce a modest improvement in some aspects of executive functioning, it has not proven to exert any effect on the functional outcomes of BD patients. The best evidence available does not support the inclusion of CR as recommendation in treatment guidelines.Fil: Samame, Cecilia. Universidad Católica del Uruguay; Uruguay. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Centro Interdisciplinario de Investigaciones en Psicología Matemática y Experimental Dr. Horacio J. A. Rimoldi; ArgentinaFil: Aprahamian, Ivan. University Of Groninhen; Países Bajos25th Annual Conference of the International Society for Bipolar DisordersChicagoEstados UnidosInternational Society for Bipolar Disorder

A Redox-Switchable α-Cyclodextrin-Based [2]Rotaxane

A bistable [2]rotaxane comprising an α-cyclodextrin (α-CD) ring and a dumbbell component containing a redox-active tetrathiafulvalene (TTF) ring system within its rod section has been synthesized using the Cu(I)-catalyzed azide−alkyne cycloaddition, and the redox-driven movements of the α-CD ring between the TTF and newly formed triazole ring systems have been elucidated. Microcalorimetric titrations on model complexes suggested that the α-CD ring prefers to reside on the TTF rather than on the triazole ring system by at least an order of magnitude. The fact that this situation does pertain in the bistable [2]rotaxane has not only been established quantitatively by electrochemical experiments and backed up by spectroscopic and chiroptical measurements but also been confirmed semiquantitatively by the recording of numerous cyclic voltammograms which point, along with the use of redox-active chemical reagents, to a mechanism of switching that involves the oxidation of the neutral TTF ring system to either its radical cationic (TTF^(•+)) or dicationic (TTF^(2+)) counterparts, whereupon the α-CD ring, moves along the dumbbell to encircle the triazole ring system. Since redox control by both chemical and electrochemical means is reversible, the switching by the bistable [2]rotaxane can be reversed on reduction of the TTF^(•+) or TTF^(2+) back to being a neutral TTF

The importance of the rotor in hydrazone-based molecular switches

Abstract The pH-activated E/Z isomerization of a series of hydrazone-based systems having different functional groups as part of the rotor (R = COMe, CN, Me, H), was studied. The switching efficiency of these systems was compared to that of a hydrazone-based molecular switch (R = COOEt) whose E/Z isomerization is fully reversible. It was found that the nature of the R group is critical for efficient switching to occur; the R group should be a moderate H-bond acceptor in order to (i) provide enough driving force for the rotor to move upon protonation, and (ii) stabilize the obtained Z configuration, to achieve full conversion. Findings Nature is full of elegant examples of perfectly designed biological motors and machines Previously, we have shown that hydrazone-based rotary switches can change their configuration (i.e., E/Z isomerization) as a function of pH Scheme 2: The hydrazone-based molecular systems that were analysed in this paper, each having different rotors. The stable isomer(s) in solution and their protonation products are shown. PPH-1-Z-H + , which is the more stable isomer. During this process, an E/Z isomerization takes place, which can be fully reversed by the addition of base to the solution. In order to fine tune the properties of the hydrazone switches, we studied the effect of different R groups in the rotor part (Scheme 2) on the switching cycle. The target hydrazones were Beilstein J. Org. Chem. 2012, 8, 872-876. 874 synthesized either by the direct condensation of phenylhydrazine with the corresponding aldehyde (PPH-2) or ketone (PPH-3), or by Japp-Klingemann reaction (PPH-4, PPH-5) In certain cases it has been shown that intramolecularly H-bonded hydrazones exist predominantly as the kinetically stable Z isomer in solution On the other hand, PPH-4, in which R is a strong electron-withdrawing group (-CN) shows two sets of signals in the 1 H NMR spectrum (CD 3 CN), indicating that two isomers, having a 4:1 ratio, coexist in solution. The major isomer shows a hydrazone N-H signal at 9.60 ppm, indicating that it is the Z isomer, in which an intramolecular H-bond is not present. On the other hand, the hydrazone N-H signal of the minor isomer resonates at 15.12 ppm, which is characteristic of H-bonded N-H signals, suggesting that the minor isomer is actually the E configuration. Such an unusual E/Z isomer ratio was reported before for similar systems, and it was attributed to kinetic stability of the Z isomer, in addition to solvent effects Structurally, PPH-5 is the closest to PPH-1, that is, instead of an acyl ester group, PPH-5 has an acetyl residue as the R group. The 1 H NMR spectrum of PPH-5 in CD 3 CN shows only one set of signals, and a sharp singlet at 14.54 ppm for the hydrazone N-H proton, indicating that it is H-bonded to the pyridyl nitrogen. Since the acetyl group is a less effective H-bond acceptor than ethyl ester, it is reasonable that PPH-5 exists exclusively in the E form in solution. When TFA is added to the solution, a second set of signals arises, which grows as the amount of acid increases. The protonation of the pyridyl ring results in the downfield shift of the aromatic signals, except for proton H1, which shifts from 8.92 to 8.70 ppm as it is no longer affected by the H-bond In order to rationalize the different behaviour of the structurally similar switches, PPH-1 and PPH-5, a quantitative evaluation of the thermodynamic process is necessary. Taking a look at the acid-activated switching process of PPH-1 (Scheme 1), we can formulate the following equations for the acid-induced E/Z isomerization: (1) Conclusion In summary, we have synthesized four hydrazone-based systems having different R groups as part of the rotor section. The role of the R group was assessed vis-à-vis the switching of the system, and it was found that for the switch to operate effectively it is crucial that (1) the R group be able to offer a second H-bond-accepting site in order to provide enough driving force for the rotor to move; and (2) the R group be a moderate H-bond acceptor, otherwise the isomer generated will not be stable enough to enable full conversion (isomerization)

The clock drawing test in diagnostic screening of Alzheimer's disease in Brazil elderly

Orientador: Monica Sanches YassudaDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias MedicasResumo: O Teste do Desenho do Relógio (TDR) é o segundo teste mais utilizado no mundo para o rastreio das demências. Contudo, há ainda dúvida sobre seu papel no processo diagnóstico da demência em termos de sensibilidade, especificidade, forma de aplicação e análise. OBJETIVOS: avaliar o desempenho do TDR no processo diagnóstico de uma amostra de idosos brasileiros portadores e não portadores da doença de Alzheimer (DA). Avaliar a sensibilidade (S) e a especificidade (E) do TDR, segundo as escalas de Shulman, Mendez e Sunderland, com as do Mini-Exame do Estado Mental (MEEM) e do Cambridge Cognitive Examination (CAMCOG), a bateria neuropsicométrica do Cambridge Examination for Mental Disorder of the Elderly (CAMDEX). METODOLOGIA: Estudo retrospectivo no qual foram analisados prontuários de pacientes idosos, 121 com DA e 99 controles normais, submetidos ao CAMDEX entre os anos de 2002 e 2007 dentro do Instituto de Geriatria e Gerontologia de Jundiaí seguindo protocolo padronizado. Todos os pacientes avaliados neste estudo passaram por avaliação médica detalhada anterior à realização do CAMDEX, incluindo exames laboratoriais e de neuroimagem. O CAMDEX apresenta duração média de duas horas, incluindo o CAMCOG, a bateria neuropsicométrica, que possui o MEEM e o TDR em sua avaliação. O TDR foi analisado separadamente utilizando-se três escalas comumente utilizadas na literatura (Shulman, Mendez e Sunderland). Os resultados do TDR foram comparados com os do CAMCOG e do MEEM. RESULTADOS: Encontrou-se correlação significativa entre os resultados do TDR com os do MEEM (0,700 - 0,730; p < 0,001) e do CAMCOG (0,753 - 0,779; p < 0,001). As três escalas de TDR utilizadas apresentam resultados semelhantes, sendo a melhor a escala de Shulman (S = 74,2 - 84,8%; E = 66,7 - 89,9%). A utilização conjunta do TDR com o MEEM melhora a sensibilidade e especificidade no rastreio cognitivo dos pacientes (S = 89,2 - 90%; E = 71,7 - 79,8%). Houve aumento da S e E do TDR com a baixa escolaridade. CONCLUSÃO: O TDR é um bom teste de rastreio quando comparado com o MEEM e o CAMCOG, independente da escala de interpretação utilizada. A combinação do TDR com o MEEM melhora seu rendimento. A influência da escolaridade merece estudo posterior.Abstract: The Clock Drawing test (CDT) is the second most used test in the world for the screening of dementia. Although, there is still doubt over its paper in the diagnostic process of dementia in terms of sensitivity, specificity, application and interpretation. OBJECTIVES: evaluate the performance of the CDT in diagnostic process of a Brazilian elderly sample with and without Alzheimer's disease (AD). Evaluate the sensitivity (SE) and specificity (SP) of CDT, according to Shulman, Mendez and Sunderland, with the Mini-Mental State Examination (MMSE) and the Cambridge Cognitive Examination (CAMCOG), the neuropsychiatric battery of the Cambridge Examination for Mental Disorder of the Elderly (CAMDEX). METHODS: Retrospective study of 121 AD and 99 elderly controls medical charts that were submitted to the CAMDEX following a standardized protocol between 2002 and 2007 at the Jundiai's Geriatric and Gerontology Institute. All subjects were clinically evaluated and submitted to laboratory and neuroimaging studies. The CAMDEX has a mean time of two hours, including the CAMCOG, a neuropsychiatric battery that has the MMSE and the CDT in its evaluation. The CDT were analyzed separately using three common scales ((Shulman, Mendez and Sunderland). The results of the CDT were compared with the CAMCOG and the MMSE. RESULTS: There were significant correlation between the results of the CDT and the MMSE (0,700 - 0,730; p < 0,001) and between the CDT and the CAMCOG (0,753 - 0,779; p < 0,001). The three CDT scales showed similar results, but the Shulman's scales was slightly better (SE = 74,2 - 84,8%; SP = 66,7 - 89,9%). The combination between the CDT and the MMSE improved sensitivity and specificity in the cognitive screening of the subjects (SE = 89,2 - 90%; SP = 71,7 - 79,8%). There was improvement of sensitivity and specificity in patients with low level of formal education. CONCLUSION: The CDT is a good screening test when compared with the MMSE or the CAMCOG, independently of the scale used for its interpretation. The combination with the MMSE improves its performance significantly. The influence of education in the CDT deserves further studies.MestradoMestre em Gerontologi

The Importance of the Rotor in Hydrazone-Based Molecular Switches

The pH-activated E/Z isomerization of a series of hydrazone-based systems having different functional groups as part of the rotor (R = COMe, CN, Me, H), was studied. The switching efficiency of these systems was compared to that of a hydrazone-based molecular switch (R = COOEt) whose E/Z isomerization is fully reversible. It was found that the nature of the R group is critical for efficient switching to occur; the R group should be a moderate H-bond acceptor in order to (i) provide enough driving force for the rotor to move upon protonation, and (ii) stabilize the obtained Z configuration, to achieve full conversion