New Tacrine Dimers Alleviate the Intracellular Amyloid-β-induced Cognitive Disturbance and Oxidative Stress in Mice

GONÇALVES, ANA ELISA; SPIGARIOL, OTTO; SILVA, LUÍSA M. DA; REGO, YURI F.; HERRERA-AROZAMENA, CLARA; RODRÍGUEZ-FRANCO, MARÍA ISABEL; FÁTIMA, ÂNGELO DE; DORING, THIAGO HENRIQUE; ARAUJO, LUCAS AUGUSTO; MACEDO, MARIA LÍGIA R.; SABA, SUMBAL; RAFIQUE, JAMAL; OLIVEIRA, ALDO S. DE; SOUZA, MÁRCIA MARIA DE

doi:10.1590/0001-3765202520241163

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BIOMEDICAL SCIENCES • An. Acad. Bras. Ciênc. 97 (Suppl. 2) • 2025 • https://doi.org/10.1590/0001-3765202520241163 linkcopy

New Tacrine Dimers Alleviate the Intracellular Amyloid-β-induced Cognitive Disturbance and Oxidative Stress in Mice

Authorship SCIMAGO INSTITUTIONS RANKINGS

This study aimed to investigate <italic>in vivo</italic> and <italic>ex-vivo</italic> the effects of tacrine dimers (TD1, TD2, TD3 and TD4) in mice with Alzheimer’s disease (AD) induced by amyloid peptide (A<italic>β</italic>42) and, respectively, evaluated in behavioral tests of cognition, oxidative stress and neuroinflammation. All dimers reduced the cognitive deficit caused by A<italic>β</italic>42, oxidative stress and neuroinflammation, especially the compound TD4. By ADMET analysis (SwissADME and pkCSM 2.10 platforms), TD4 exhibited favorable pharmacokinetic properties with the control drug. The results suggest a therapeutic potential for AD for these compounds, given their distinct cognitive and neuroprotective effects in AD models induced by A<italic>β</italic>42.

Key words
Tacrine Dimers; Amyloid-β (Aβ42); Cognitive Disturbance; Oxidative Stress; Neuroprotection

Authorship

person ANA ELISA GONÇALVES

Data curation · Investigation · Roles/Writing – original draft · Writing – review and editing.

0000-0002-5148-7184

person OTTO SPIGARIOL

Data curation · Investigation · Roles/Writing – original draft · Writing – review and editing.

0009-0008-5638-4716

person LUÍSA M. DA SILVA

Conceptualization · Formal analysis · Funding acquisition · Resources · Roles/Writing – original draft · Writing – review and editing.

schoolUniversidade do Vale do Itajaí (UNIVALI), Programa de Pós-Graduação em Ciências Farmacêuticas, Rua Uruguai, 468, 88301-320 Itajaí, SC, Brazil Universidade do Vale do Itajaí (UNIVALI)BrazilItajaí, SC, BrazilUniversidade do Vale do Itajaí (UNIVALI), Programa de Pós-Graduação em Ciências Farmacêuticas, Rua Uruguai, 468, 88301-320 Itajaí, SC, Brazil schoolUniversidade Federal de Santa Catarina (UFSC), Laboratório de Farmacologia do Trato Gastrointestinal e suas Interações, Programa de Pós-graduação em Farmacologia, Campus Universitário, s/n, Sala 208, Bloco E, Prédio Administrativo, Córrego Grande, Trindade, 88040-900 Florianópolis, SC, Brazil Universidade Federal de Santa Catarina (UFSC)BrazilFlorianópolis, SC, BrazilUniversidade Federal de Santa Catarina (UFSC), Laboratório de Farmacologia do Trato Gastrointestinal e suas Interações, Programa de Pós-graduação em Farmacologia, Campus Universitário, s/n, Sala 208, Bloco E, Prédio Administrativo, Córrego Grande, Trindade, 88040-900 Florianópolis, SC, Brazil

0000-0001-5329-7301

person YURI F. REGO

Synthesis of compounds · Writing – review and editing.

schoolUniversidade Federal de Minas Gerais (UFMG), GEQOB, Departamento de Química, ICEx, Av. Pres. Antônio Carlos, 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil Universidade Federal de Minas Gerais (UFMG)BrazilBelo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais (UFMG), GEQOB, Departamento de Química, ICEx, Av. Pres. Antônio Carlos, 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil

0000-0003-4660-6852

person CLARA HERRERA-AROZAMENA

PAMPA-BBB Data curation.

schoolInstituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/ Juan de la Cierva 3, E-28006 Madrid, Spain Instituto de Química MédicaSpainC/ Juan de la Cierva 3, E-28006 Madrid, SpainInstituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/ Juan de la Cierva 3, E-28006 Madrid, Spain

0000-0002-5894-128X

person MARÍA ISABEL RODRÍGUEZ-FRANCO

PAMPA-BBB Assays · Funding acquisition · Resources · Writing and review.

0000-0002-6500-792X

person ÂNGELO DE FÁTIMA

Conceptualization · Funding acquisition · Resources · Writing – review and editing.

0000-0003-2344-5590

person THIAGO HENRIQUE DORING

Formal Analysis · Investigation · Writing – original draft.

schoolUniversidade Federal de Santa Catarina (UFSC), Departamento de Ciências Exatas e Educação, Rua João Pessoa, 2750, Bairro Velha, 89036-002 Blumenau, SC, Brazil Universidade Federal de Santa Catarina (UFSC)BrazilBlumenau, SC, BrazilUniversidade Federal de Santa Catarina (UFSC), Departamento de Ciências Exatas e Educação, Rua João Pessoa, 2750, Bairro Velha, 89036-002 Blumenau, SC, Brazil

0000-0002-3611-9105

person LUCAS AUGUSTO ARAUJO

Formal Analysis.

0009-0001-7902-6136

person MARIA LÍGIA R. MACEDO

Formal Analysis.

0000-0001-6969-6307

person SUMBAL SABA

Funding acquisition · Resources · Investigation · Writing – review and editing.

0000-0002-6134-7249

person JAMAL RAFIQUE

Funding acquisition · Resources · Formal analysis · Investigation · Writing – review and editing.

schoolUniversidade Federal de Goiás (UFG), LabSO, Instituto de Química (IQ), Av. Esperança, s/n, Campus Samambaia, 74690-900 Goiânia, GO, Brazil Universidade Federal de Goiás (UFG)BrazilGoiânia, GO, BrazilUniversidade Federal de Goiás (UFG), LabSO, Instituto de Química (IQ), Av. Esperança, s/n, Campus Samambaia, 74690-900 Goiânia, GO, Brazil schoolUniversidade Federal do Mato Grosso do Sul (UFMS), Centro de Pesquisa e Inovação em Bioprospecção e Síntese de Produtos para a Saúde Humana e Animal (CIBSint), Instituto de Química (INQUI), Av. Costa e Silva, s/n, 79074-460 Campo Grande, MS, Brazil Universidade Federal do Mato Grosso do Sul (UFMS)BrazilCampo Grande, MS, BrazilUniversidade Federal do Mato Grosso do Sul (UFMS), Centro de Pesquisa e Inovação em Bioprospecção e Síntese de Produtos para a Saúde Humana e Animal (CIBSint), Instituto de Química (INQUI), Av. Costa e Silva, s/n, 79074-460 Campo Grande, MS, Brazil

0000-0002-2336-040X

person ALDO S. DE OLIVEIRA

Methodology · Writing – review and editing.

0000-0001-7760-4484

person MÁRCIA MARIA DE SOUZA

Conceptualization · Formal analysis · Funding acquisition · Resources · Supervision · Roles/Writing – original draft · Writing – review and editing.

0000-0002-6297-9635

Correspondence to: Sumbal Saba, Jamal Rafique, Aldo S. de Oliveira, Márcia Maria de Souza
emailsumbalsaba@ufg.br, jamal.rafique@ufms.br,

SCIMAGO INSTITUTIONS RANKINGS

Universidade do Vale do Itajaí (UNIVALI), Programa de Pós-Graduação em Ciências Farmacêuticas, Rua Uruguai, 468, 88301-320 Itajaí, SC, Brazil Universidade do Vale do Itajaí (UNIVALI)BrazilItajaí, SC, BrazilUniversidade do Vale do Itajaí (UNIVALI), Programa de Pós-Graduação em Ciências Farmacêuticas, Rua Uruguai, 468, 88301-320 Itajaí, SC, Brazil

Universidade Federal de Santa Catarina (UFSC), Laboratório de Farmacologia do Trato Gastrointestinal e suas Interações, Programa de Pós-graduação em Farmacologia, Campus Universitário, s/n, Sala 208, Bloco E, Prédio Administrativo, Córrego Grande, Trindade, 88040-900 Florianópolis, SC, Brazil Universidade Federal de Santa Catarina (UFSC)BrazilFlorianópolis, SC, BrazilUniversidade Federal de Santa Catarina (UFSC), Laboratório de Farmacologia do Trato Gastrointestinal e suas Interações, Programa de Pós-graduação em Farmacologia, Campus Universitário, s/n, Sala 208, Bloco E, Prédio Administrativo, Córrego Grande, Trindade, 88040-900 Florianópolis, SC, Brazil

Universidade Federal de Minas Gerais (UFMG), GEQOB, Departamento de Química, ICEx, Av. Pres. Antônio Carlos, 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil Universidade Federal de Minas Gerais (UFMG)BrazilBelo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais (UFMG), GEQOB, Departamento de Química, ICEx, Av. Pres. Antônio Carlos, 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil

Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/ Juan de la Cierva 3, E-28006 Madrid, Spain Instituto de Química MédicaSpainC/ Juan de la Cierva 3, E-28006 Madrid, SpainInstituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/ Juan de la Cierva 3, E-28006 Madrid, Spain

Universidade Federal de Santa Catarina (UFSC), Departamento de Ciências Exatas e Educação, Rua João Pessoa, 2750, Bairro Velha, 89036-002 Blumenau, SC, Brazil Universidade Federal de Santa Catarina (UFSC)BrazilBlumenau, SC, BrazilUniversidade Federal de Santa Catarina (UFSC), Departamento de Ciências Exatas e Educação, Rua João Pessoa, 2750, Bairro Velha, 89036-002 Blumenau, SC, Brazil

Universidade Federal de Goiás (UFG), LabSO, Instituto de Química (IQ), Av. Esperança, s/n, Campus Samambaia, 74690-900 Goiânia, GO, Brazil Universidade Federal de Goiás (UFG)BrazilGoiânia, GO, BrazilUniversidade Federal de Goiás (UFG), LabSO, Instituto de Química (IQ), Av. Esperança, s/n, Campus Samambaia, 74690-900 Goiânia, GO, Brazil

Universidade Federal do Mato Grosso do Sul (UFMS), Centro de Pesquisa e Inovação em Bioprospecção e Síntese de Produtos para a Saúde Humana e Animal (CIBSint), Instituto de Química (INQUI), Av. Costa e Silva, s/n, 79074-460 Campo Grande, MS, Brazil Universidade Federal do Mato Grosso do Sul (UFMS)BrazilCampo Grande, MS, BrazilUniversidade Federal do Mato Grosso do Sul (UFMS), Centro de Pesquisa e Inovação em Bioprospecção e Síntese de Produtos para a Saúde Humana e Animal (CIBSint), Instituto de Química (INQUI), Av. Costa e Silva, s/n, 79074-460 Campo Grande, MS, Brazil

Figures | Tables

Figures (11)
Tables (2)

Thumbnail

Figure 1 Tacrine dimers TD1, TD2, TD3 and TD4.

Thumbnail

Figure 2 Panel a: schematic representation of the experimental protocol. Panel b: Means ± SD of recognition index of familiar object of mice submitted to the Novel Object Recognition test, calculated by dividing the amount of exploration of the novel object by the total amount of object exploration. n = 8 per group. One-way ANOVA, Tukey’s post hoc test: ** p < 0.01 and *** p < 0.001 compared to the Control group (vehicle-treated mice).

Thumbnail

Figure 3 Panel a: schematic representation of the experimental protocol. Panel b: Mean ±SD of time spent on target quadrant (s) during the probe trail after 5 days of daily training. n = 8 per group. One-way ANOVA, Tukey’s post hoc test: *** p < 0.001 compared to the Control group (vehicle-treated mice).

Thumbnail

Figure 4 Panel a: schematic representation of the experimental protocol. Panel b: Latency of descent (s) of mice submitted in Inhibitory Avoidance test 24h after training. n = 8 per group. One-way ANOVA, Tukey’s post hoc test: ** p < 0.01 and *** p < 0.001 compared to the Control group (vehicle-treated mice).

Thumbnail

Figure 5 Redocking of the Dihydrotanshinone (1YL) ligand at the human acetylcholinesterase binding site (PDB ID 4M0E; peripheral anionic site). In green: is the best pose of the crystallized ligand generated by the GoldScore function; in blue: is crystallographic conformation. The figure was generated by the Biovia Discovery Studio Visualizer software (v21.1.0.20298, BIOVIA, San Diego, CA, USA).

Thumbnail

Figure 6 The 3D (left) and 2D (right) diagrams show the interactions of tacrine at the catalytic site of human acetylcholinesterase (PD ID 4M0E). The figure was generated by the Biovia Discovery Studio Visualizer software (v21.1.0.20298, BIOVIA, San Diego, CA, USA).

Thumbnail

Figure 7 The 3D (left) and 2D (right) diagrams show the interactions of TD1 at the catalytic site of human acetylcholinesterase (PD ID 4M0E). The figure was generated by the Biovia Discovery Studio Visualizer software (v21.1.0.20298, BIOVIA, San Diego, CA, USA).

Thumbnail

Figure 8 The 3D (left) and 2D (right) diagrams show the interactions of TD2 at the binding site of human acetylcholinesterase (PD ID 4M0E). The figure was generated by the Biovia Discovery Studio Visualizer software (v21.1.0.20298, BIOVIA, San Diego, CA, USA).

Thumbnail

Figure 9 The 3D (left) and 2D (right) diagrams show the interactions of TD3 at the binding site of human acetylcholinesterase (PD ID 4M0E). The figure was generated by the Biovia Discovery Studio Visualizer software (v21.1.0.20298, BIOVIA, San Diego, CA, USA).

Thumbnail

Figure 10 The 3D (left) and 2D (right) diagrams show the interactions of TD4 at the binding site of human acetylcholinesterase (PD ID 4M0E). The figure was generated by the Biovia Discovery Studio Visualizer software (v21.1.0.20298, BIOVIA, San Diego, CA, USA).

Thumbnail

Figure 11 Surfaces of HOMO and LUMO to tacrine, TD1, TD2, TD3, and TD4 were obtained through the DFT method using the def2-TZVPP set of basic functions and B3LYP functional. In red are the positive phases and in blue are the negative phases of the orbitals.

Thumbnail

Table I Molecular docking punctuation with Gold score function for the best poses.

Thumbnail

Table II HOMO, LUMO, and Gap (eV) energy values for the studied compounds.

imageFigure 1 Tacrine dimers TD1, TD2, TD3 and TD4. open_in_new

imageFigure 2 Panel a: schematic representation of the experimental protocol. Panel b: Means ± SD of recognition index of familiar object of mice submitted to the Novel Object Recognition test, calculated by dividing the amount of exploration of the novel object by the total amount of object exploration. n = 8 per group. One-way ANOVA, Tukey’s post hoc test: p < 0.01 and * p < 0.001 compared to the Control group (vehicle-treated mice). open_in_new

imageFigure 3 Panel a: schematic representation of the experimental protocol. Panel b: Mean ±SD of time spent on target quadrant (s) during the probe trail after 5 days of daily training. n = 8 per group. One-way ANOVA, Tukey’s post hoc test: *** p < 0.001 compared to the Control group (vehicle-treated mice). open_in_new

imageFigure 4 Panel a: schematic representation of the experimental protocol. Panel b: Latency of descent (s) of mice submitted in Inhibitory Avoidance test 24h after training. n = 8 per group. One-way ANOVA, Tukey’s post hoc test: p < 0.01 and * p < 0.001 compared to the Control group (vehicle-treated mice). open_in_new

imageFigure 5 Redocking of the Dihydrotanshinone (1YL) ligand at the human acetylcholinesterase binding site (PDB ID 4M0E; peripheral anionic site). In green: is the best pose of the crystallized ligand generated by the GoldScore function; in blue: is crystallographic conformation. The figure was generated by the Biovia Discovery Studio Visualizer software (v21.1.0.20298, BIOVIA, San Diego, CA, USA). open_in_new

imageFigure 6 The 3D (left) and 2D (right) diagrams show the interactions of tacrine at the catalytic site of human acetylcholinesterase (PD ID 4M0E). The figure was generated by the Biovia Discovery Studio Visualizer software (v21.1.0.20298, BIOVIA, San Diego, CA, USA). open_in_new

imageFigure 7 The 3D (left) and 2D (right) diagrams show the interactions of TD1 at the catalytic site of human acetylcholinesterase (PD ID 4M0E). The figure was generated by the Biovia Discovery Studio Visualizer software (v21.1.0.20298, BIOVIA, San Diego, CA, USA). open_in_new

imageFigure 8 The 3D (left) and 2D (right) diagrams show the interactions of TD2 at the binding site of human acetylcholinesterase (PD ID 4M0E). The figure was generated by the Biovia Discovery Studio Visualizer software (v21.1.0.20298, BIOVIA, San Diego, CA, USA). open_in_new

imageFigure 9 The 3D (left) and 2D (right) diagrams show the interactions of TD3 at the binding site of human acetylcholinesterase (PD ID 4M0E). The figure was generated by the Biovia Discovery Studio Visualizer software (v21.1.0.20298, BIOVIA, San Diego, CA, USA). open_in_new

imageFigure 10 The 3D (left) and 2D (right) diagrams show the interactions of TD4 at the binding site of human acetylcholinesterase (PD ID 4M0E). The figure was generated by the Biovia Discovery Studio Visualizer software (v21.1.0.20298, BIOVIA, San Diego, CA, USA). open_in_new

imageFigure 11 Surfaces of HOMO and LUMO to tacrine, TD1, TD2, TD3, and TD4 were obtained through the DFT method using the def2-TZVPP set of basic functions and B3LYP functional. In red are the positive phases and in blue are the negative phases of the orbitals. open_in_new

table_chartTable I Molecular docking punctuation with Gold score function for the best poses.

Compound	Gold score Punctuation
Tacrine	58.64
1YL	50.76
TD1	68.36
TD2	72.01
TD3	71.94
TD4	74.39

table_chartTable II HOMO, LUMO, and Gap (eV) energy values for the studied compounds.

Compound	HOMO (eV)	LUMO (eV)	Gap (eV)
Tacrine	-5.668	-1.150	4.518
TD1	-5.472	-1.483	3.989
TD2	-5.487	-1.552	3.935
TD3	-5.257	-1.506	3.751
TD4	-5.269	-1.525	3.744

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