https://dx.doi.org/10.21577/0103-5053.

20240131

Article J. Braz. Chem. Soc. 2025, 36, 2, e-20240131, 1-13

©2025 Sociedade Brasileira de Química

Selenoacetylenes Protect against Beta-Amyloid Peptide-Induced Paralysis and

Promote Longevity in Caenorhabditis elegans

Maria Isabela S. Figueiredo, a Ivani S. Mello, a Sabrina K. Targanski,a Juliana S. Duarte,b

Leonardo G. Vasconcelos,b André Luiz A. Stein b and Marcos Antonio Soares *,a
a
Laboratório de Biotecnologia e Ecologia Microbiana, Instituto de Biociências, Universidade Federal de Mato Grosso,
78060-900 Cuiabá-MT, Brazil
b
Laboratório de Pesquisas em Química de Produtos Naturais e Novas Metodologias Sintéticas em Química Orgânica,
Departamento de Química, Instituto de Ciências Exatas e da Terra, Universidade Federal de Mato Grosso,
78060-900 Cuiabá-MT, Brazil

Selenium-containing compounds exhibit diverse biological activities, such as antioxidative,

anti-inflammatory, and cancer preventive effects. Using Caenorhabditis elegans as a model
organism, we assessed the toxicity, neuroprotective, antioxidant properties, and impact on longevity
of 11 selenoacetylenes. Their toxicity and bioactivities varied based on molecular structure.
Selenoacetylenes with butyl substituents were toxic to Galleria mellonella larvae. The presence of
but-3-in-2-ol radical increased antiprotozoal activity against Tetrahymena pyriformis. Compared to
the positive control (Nimitz® EC), selenoacetylenes were less toxic to nematode worms and eggs.
Selenoacetylenes significantly reduced amyloid beta (Aβ) paralysis in C. elegans CL4176 worms,
increased longevity by 18 to 22%, along with improving survival after oxidative or thermal stress.
Galantamine, showed inferior results. These findings enhance our understanding of selenoacetylenes
on neuroprotection, antioxidant activity, and longevity in C. elegans. Future mammalian studies
will further elucidate mechanisms and explore the potential therapeutic use of selenoacetylenes
in treating Alzheimer’s disease and longevity.

Keywords: selenoacetylenes, neuroprotection, antioxidant activity, longevity,

Caenorhabditis elegans, amyloid beta induced paralysis

Introduction to the World Population Prospects report,12 the global

population aged 65 or older in 2022 (771 million people)
Aging is a natural and multifactorial process that was approximately three times greater compared to
induces molecular, cellular, and histological changes in 1980 (258 million).12 The growth of younger age groups
living organisms. These alterations depend on physiological (0 to 14 years and 15 to 59 years) is being outpaced by
plasticity and time. 1,2 Aging is primarily caused by the growth of groups aged 60 or older at approximately
accumulation of time-dependent cellular damage.3 This 3% per year.13 As the global population ages, the incidence
accumulation is reduced by joint action of the heat shock of neurodegenerative diseases is predicted to increase,14
response complex (HSR),4 the insulin signaling pathway and the number of people with dementia is expected
(IGF-1),5 the mitochondrial function,6 and sirtuins,7 which to triple by 2050, reaching 152 million up from the
decline over time. Such decline renders individuals more current 50 million.13,15 In this scenario, neurodegenerative
susceptible and hampers their ability to self-adjust,8 not diseases such as Alzheimer’s disease (AD), Parkinson’s
to mention that it is a risk factor for neurodegenerative disease (PD), and other forms of dementia are a growing
diseases. global health setback affecting thousands of people
Increased life expectancy in developed countries worldwide.16 AD is the most common form of dementia and
accounts for human population aging. 9-11 According accounts for 60-70% of the dementia cases in the world.17
This progressive disease impairs mainly cognitive abilities
*e-mail: drmasoares@gmail.com and memory and interferes with the affected individual’s
Editor handled this article: Brenno A. D. Neto quality of life.18

This is an open-access article distributed under the terms of the Creative Commons Attribution License.
Figueiredo et al. Selenoacetylenes Protect against Beta-Amyloid Peptide-Induced Paralysis and Promote Longevity in Caenorhabditis elegans

In Brazil, the prevalence of dementia among individuals Nevertheless, merely having biological activity does not
aged 65 or older resembles the prevalence in other Latin suffice for a molecule to be used in living organisms, their
American countries, standing at approximately 7%.19,20 toxicity must be determined to ensure that they are safe for
Brazilians are undergoing rapid aging, which explains both living organisms and the environment.
why Brazil ranked second in terms of age-standardized Toxicity assays demand that organisms from different
prevalence of AD and other dementias in 2016.21 taxonomic groups be employed.58 Tetrahymena pyriformis
The causes leading to AD onset and progression are cells (protozoan),59 Galleria mellonella larvae60 (arthropod),61
multifactorial, which complicates treatment. Cholinergic and C. elegans (nematode)62 are some examples of models
deficiency,22 amyloid beta peptide (Aβ) toxicity,23 tau that are used to assess bioactive compound toxicity. This
protein hyperphosphorylation,24 synaptic dysfunction,25 approach allows one to evaluate several effects qualified
oxidative stress,26 and neuroinflammation27 are some and quantified on the basis of parameters such as mortality,
factors that contribute to AD development. Extracellular growth, and physiological, molecular, or reproductive
Aβ deposits in senile plaques (SP) and formation of effects.63
intracellular neurofibrillary tangles are the main AD In this study, we have employed C. elegans, recognized
neuropathological features.28-31 as a model organism to study complex neurological
Despite advanced research, no pharmacological diseases, including AD, 48,64 to investigate whether
treatment can slow down or interrupt AD progression, 11 selenoacetylene derivatives can reduce Aβ-induced
damage, and neuron destruction. 32 Some medications toxicity and improve longevity. We have also determined
like tacrine (1993),33 donepezil (1996),34 rivastigmine their antioxidant capacity in nematodes and their toxicity
(2000),35 and galantamine (2001)36 can reduce cognitive in different biological models (insect larvae, protozoan
and memory impairment through cholinergic inhibition or cells, and nematodes).
N-methyl D-aspartate (NMDA) receptor blockade and are
recommended for AD.37,38 Experimental
Efforts to develop treatments for AD have been
focused on discovering molecules that continuously Synthesis and characterization of selenoacetylenes
relieve symptoms by mitigating or avoiding abnormal
Aβ accumulation and reducing oxidative damage.39 Some The selenoacetylenes were synthesized by using the
authors40 have suggested that donepezil, rivastigmine, and methodology described by Bieber et al.65 All reagents and
galantamine can reduce Aβ production and Aβ-induced materials were supplied by Sigma-Aldrich (São Paulo,
toxicity. Brazil). Diorganoyl diselenide (1 mmol L–1), dimethyl
In this context, compounds containing the essential sulfoxide (DMSO), and copper iodide (CuI, 0.1 mmol L–1)
trace element selenium are promising, particularly were combined in a test tube containing terminal alkyne
because human selenoproteins, including thioredoxin (2 mmol L–1) (Figure 1). The solution was stirred at 25 °C
reductases (TrxR), glutathione peroxidases (GPx), and for 24 h. After incubation, the solution was washed with
thyroid hormone deiodinases (DIO), participate in redox 10 mL of an aqueous NH4Cl solution (0.3 mol L–1).
regulation of intracellular signaling30,41 and help to regulate
neurodegenerative disorders.31
Advances in AD treatment require a model
system that recapitulates the AD hallmark features.42
Caenorhabditis elegans is a free-living nematode that has
proven an excellent model organism in various areas of Figure 1. General scheme of selenoacetylene synthesis.
knowledge,43-46 even in the study of intricate neurological
diseases like AD.47,48 Molecular conservation of neuronal The reaction product was extracted with ethyl acetate
signaling pathways in this invertebrate has allowed related (in three steps, 10 mL in each step), dried with magnesium
pathways to be identified in vertebrate models and drugs sulfate (MgSO4) (Sigma-Aldrich, São Paulo, Brazil) to
to be cost-effectively assessed in vivo.49 remove moisture and concentrated under reduced pressure
The numerous biological activities associated with to remove the solvent. The resulting products, labeled 1a‑1k
selenium derivatives have made these compounds (Table 1), were purified by silica gel chromatography;
prominent in the field of medicinal chemistry.50 Selenium- hexane was used as eluent. Subsequently, the products
containing molecules are considered key elements in were characterized by hydrogen-1 nuclear magnetic
cancer prevention51-55 and anti-inflammatory effects.56,57 resonance (1H NMR) and carbon-13 nuclear magnetic

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Selenoacetylenes Protect against Beta-Amyloid Peptide-Induced Paralysis and Promote Longevity in Caenorhabditis elegans Figueiredo et al.

resonance (13C NMR) spectroscopy on a Bruker Ascend used, with 250 × 4.6 mm internal diameter, with a particle
500TM spectrometer (Billerica, Massachusetts, USA). size of 4.6 μm and porosity of 12 nm. The mobile phases
The samples were analyzed using a high-performance were 0.1% (v/v) formic acid in ultrapure water (A) and
liquid chromatography (HPLC) system (LC-20A methanol (B). The elution condition applied was 0-5 min,
Prominence, Shimadzu®, Kyoto, Japan) equipped with linear gradient of 90-100% B, 5-15 min in isocratic mode
two quaternary pumps (LC-20AD), degasser (DGU‑20A3), with 100% B followed by reconditioning the column
autosampler (SIL-20A), oven (CTO-20A), diode array in 15‑25 min of 100‑90% B, with flow of 1 mL min–1.
detector (SPD-M20A) and a communication module The injection volume was 10 μL. All reagents used in
(CBM-20A). For separation, a reversed phase column the analysis were HPLC grade and deionized water
(Shim-pack VP-ODS, Shimadzu®, Kyoto, Japan) was was obtained from a Milli-Q water purification system

Table 1. Molecular structure of selenoacetylene derivatives

Alkyne Diorganoyl diselenide Product

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Figueiredo et al. Selenoacetylenes Protect against Beta-Amyloid Peptide-Induced Paralysis and Promote Longevity in Caenorhabditis elegans

(Millipore Corporation®, Watford, United Kingdom). treated with 10 μL of a selenoacetylene solution (4 g L–1)
LabSolutions software (version 5.3, Japan) was used for prepared in saline solution (0.8%). The negative control was
data acquisition and processing. carried out with saline solution. After that, the larvae were
The NMR spectra were recorded with chemical kept in the dark at room temperature. Larval mortality was
shifts (d) adjusted in parts per million (ppm), referenced assessed daily for seven days. All the assays were performed
to the residual solvent peak of tetramethylsilane (TMS, in triplicate, and the results are expressed as the mean and
used as internal standard for proton spectra) in CDCl3 standard deviation of the percentage of mortality.68,69
(Sigma-Aldrich, São Paulo, Brazil). The multiplicity of The T. pyriformis cells were cultured according to
each peak is designated by the following abbreviations: s Maurya et al.70 protocol. Approximately 1 × 106 cells of
(singlet), d (doublet), t (triplet), q (quartet), quint (quintet), T. pyriformis mL–1 were added to 96-well plates containing a
sext (sextet), and m (multiplet). Coupling constants (J) are selenoacetylene. The plates were kept at 28 °C for 24 h. Then,
reported in hertz (Hz). the number of cells was counted by using a microscope. The
negative control was performed with 10% DMSO.
Caenorhabditis elegans strains and maintenance
Selenoacetylene toxicity to nematodes
All the C. elegans strains used in this study are described
in Table 2. The C. elegans worms were maintained at The nematicidal activity of the selenoacetylenes was
15 °C on solid nematode growth medium (NGM) seeded estimated in C. elegans N2 in a population previously
with Escherichia coli OP50 as a food source, following synchronized in the L4 stage.71 After synchronization,
Brenner’s protocol.66 L4 worms (n = 30) or eggs (n = 20) were transferred
to 96-well plates containing different concentrations of
Preparation of stock selenoacetylene solutions for toxicity the evaluated compounds diluted in K medium.72 The
and bioactivity assays plates were kept in a biological oxygen demand (BOD)
incubator model TE-402/240L Tecnal (Piracicaba, SP) at
Each selenoacetylene was dissolved at 20 g L–1 in pure 20 °C for 24 h. After that, the mortality of L4 individuals
DMSO (Sigma-Aldrich, São Paulo, Brazil) or methanol or the hatching percentage was counted with the aid
(MeOH) (Sigma-Aldrich, São Paulo, Brazil) and stored at of a magnifier. M. incognita eggs were obtained from
–4 °C. At the time of the assays, diluted selenoacetylene infected tomato plants and kept in a greenhouse, so
solutions were prepared at the desired concentration. The that the J2 infective form would be obtained according
final DMSO or methanol concentration used in negative to Nitao et al.73 The assays were conducted in 96-well
controls was 10% (v/v). In the assays conducted with plates as described for C. elegans; M. incognita eggs
heat-killed bacteria, a concentrated suspension of E. coli (n = 20) or juveniles (J2, n = 20) were used. With the aid
OP50 cells was previously prepared and killed by heat in of a magnifier, the number of hatched eggs and dead J2
an autoclave.67 individuals were counted. The commercial nematicide
Nimitz® EC and DMSO were employed as positive and
Selenoacetylene toxicity to Galleria mellonella larvae and negative control, respectively. The obtained data were
Tetrahymena pyriformis cells used to estimate the concentrations that were able to kill
50% (LC50) and 90% (LC90) of the population. LC50 and
Selenoacetylene toxicity was assessed in G. mellonella LC90 were estimated by using the R software74 and the
larvae as described by Ramarao et al. 68 Ten (10) calculate.lc function.75
G. mellonella larvae weighing between 0.2 and 0.3 g were

Table 2. C. elegans strains used in this study

Strain Transgene Phenotype

N2 – wild type
CL4176 dvIs27 [myo-3p::A-Beta (1‑42)::let-851 3’UTR) + rol‑6(su1006)] expression of human amyloid-β in muscle cell walls
CL802 smg-1 (cc546) I; rol-6 (su1006) II. standard control for CL4176
BA17 fem-1 (hc17) IV population feminization at 25 °C
expression of phase II detoxification gene gamma-
LD1171 Is[gcs-1p::GFP]
glutamine cysteine synthetase-1 (GCS-1)

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Selenoacetylenes Protect against Beta-Amyloid Peptide-Induced Paralysis and Promote Longevity in Caenorhabditis elegans Figueiredo et al.

Selenoacetylene ability to inhibit Aβ-induced paralysis in to NGM plates containing 0.003 mmol L–1 H2O2 to induce
C. elegans oxidative stress. The number of living and dead animals
was assessed every 30 min. The assay was repeated three
The populations of C. elegans CL4176 and its control times with negative (MeOH) and positive (galantamine at
strain CL802 were obtained through synchronization. 0.05 g L–1) controls.79
The worms were kept at 15 °C until they reached the The thermal stress assay was conducted according
third larval stage (L3). Then, they were transferred to the previously reported method. After treatment, the
(n = 20) to 12‑well plates containing NGM seeded worms were transferred to NGM plates for thermal stress
with heat-inactivated E. coli OP50 bacterial cells and a assessment. The number of dead worms was recorded every
selenoacetylene (at 0.1 or 0.05 g L–1). Next, the plates 6 h after the worms were transferred from a 20 °C culture
were then moved to an incubator model TE-402/240L environment to a 35 °C culture environment.
Tecnal (Piracicaba, SP) at 25 °C. After incubation at 25 °C
for 20 h, paralyzed worms were counted every 2 h for a In vivo antioxidant activity
total of 8 h. Worms were considered paralyzed if they did
not respond to repeated stimuli or if a bacterial “halo” The LD1171 strain (gcs-1p::GFP) was used to study how
was found around their heads, indicating that they were the selenoacetylenes affected the phase II detoxification
unable to move their bodies.76 MeOH and galantamine at gene glutamine cysteine synthetase-1 (gcs-1). In K medium,
0.05 g L–1 were used as negative and positive controls, synchronized worms of the LD1171 strain were treated with
respectively. The results are expressed as the mean values each selenoacetylene at 0.05 g L–1 or the vehicle MeOH (in
along with the standard deviation. volumes proportional to the volumes used in the treatments)
For the subsequent assays, the selenoacetylenes at at 20 °C for 72 h. Galantamine at 0.05 g L–1 was employed
0.05 g L–1 that reduced C. elegans paralysis by over 80% as positive control. The worms were visualized under a
were evaluated. fluorescence microscope with a 10× objective. The ImageJ
software80 was used to measure the intestinal fluorescence
Longevity assay in each image. Only the fluorescence intensity detected in
the green channel was used for quantifying GCS-1 in the
To evaluate whether the lifespan was extended, the intestinal area.81
C. elegans BA17 strain was employed.77,78 Synchronized
L3 stage larvae were obtained from eggs hatched at 25 °C. Statistical analyses
Twenty worms were transferred to 12-well plates containing
NGM seeded with heat-inactivated E. coli OP50 bacterial All the results were evaluated for normality and
cells and a selenoacetylene. The lifespan was assessed homogeneity by using the Shapiro-Wilk test and Levene’s
daily until all the individuals were dead. The worms that test, respectively. Groups with normally distributed
showed no spontaneous movement during evaluation data were compared by using Student’s t-test; one-way
were considered dead. Dead worms displaying internally analysis of variance (ANOVA) with Dunnett’s post hoc
hatched progeny, extruded gonads, or desiccation caused test was performed to compare multiple groups. GraphPad
by crawling out of the agar well boundaries were excluded Prism 5.082 was used to plot the graphs and to determine
from the data. Galantamine at 0.05 g L–1 and MeOH were significant differences between survival curves by means
used as positive and negative controls, respectively. The of log-rank tests (Mantel-Cox).
data were obtained from three independently conducted
assays, and the results are expressed as the mean and Results
standard deviation.
Synthesis and characterization of selenoacetylenes
Selenoacetylene ability to protect C. elegans against
oxidative and thermal stress It was obtained 11 selenoacetylenes as products of
coupling reactions in up to 92% yield (Table 3). These
The ability of selenoacetylenes to reduce oxidative compounds were characterized by 1H NMR and 13C NMR,
stress in C. elegans was assessed by using worms at the and the purity was determined by HPLC (Figures S1-S31,
L1 stage. The worms were treated with a selenoacetylene Supplementary Information (SI) section). All compounds
(0.05 g L–1) at 20 °C until they reached the L4 stage. After have a purity greater than 90% by HPLC.
treatment, adult worms (20 worms per group) were added

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Figueiredo et al. Selenoacetylenes Protect against Beta-Amyloid Peptide-Induced Paralysis and Promote Longevity in Caenorhabditis elegans

Table 3. Yield and purity of selenoacetylene derivatives after synthesis

Compound Name Yield / % Purity / %

1a 1-phenylseleno-2-phenylacetylene 92 96
1b 1-(4’-chlorophenyl)seleno-2-phenylacetylene 72 98
1c 1-(4’-fluorophenyl)seleno-2-phenylacetylene 82 91
1d 1-(4’-methylphenyl)seleno-2-phenylacetylene 91 96
1e 1-(3’-trifluoromethylphenyl)seleno-2-phenylacetylene 74 99
1f 1-butylseleno-2-phenylacetylene 62 98
1g 2-methyl-4-(phenylsulfanyl) but-3-in-2-ol 78 97
1h 1-phenylseleno-2-butylacetylene 64 99
1i 2-methylseleno-4-(4’-chlorophenylsulfanyl) but-3-in-2-ol 59 99
1j 1-phenylseleno-2-(4’-chlorophenylacetylene) 78 94
1k 1-(4’-chlorophenylseleno)-2-(4’-chlorophenylacetylene) 65 95

Toxicity bioassays 1b (4.71 ± 0.15 log cell mL–1) showed lower toxicity,
including induced protozoan growth compared to the
The toxicity of the selenoacetylene derivatives to control (4.32 ± 0.10 log cell mL–1). Galantamine was not
insect larvae, protozoa, and nematodes (worms and eggs) toxic to T. pyriformis cells.
(Table 4) were examined. Only compound 1f was toxic to We observed that C. elegans and M. incognita worms
G. mellonella larvae (mortality: 70 ± 10%); galantamine did and eggs were sensitive to the selenoacetylenes (Table 4).
not kill G. mellonella larvae (0% mortality). The toxicity of Toxicity varied according to the nematode species and
the selenoacetylene derivatives to protozoa and nematodes developmental stage and to the selenoacetylene structure.
(worms and eggs) (Table 4) were examined. Compounds 1c and 1k were more toxic to nematode worms
As for the population of the ciliated protozoan (L4 and J2) and displayed the lowest LC50: 0.78 mmol L–1
T. pyriformis, it responded differently depending on the (0.64-0.95 mmol L–1) and 1.40 mmol L–1 (NaN-NaN,
selenoacetylene. Compounds 1i (100% cell death) and where NaN means not a number), respectively, whereas
1g (3.68 ± 0.07 log cell mL–1) were more toxic to T. pyriformis compounds 1b and 1f were the least toxic 5.70 and
cells, while compounds 1a (4.76 ± 0.15 log cell mL–1) and 5.90 mmol L–1, respectively.

Table 4. Nematicidal and ovicidal activity of selenoacetylenes (1a-1k) for C. elegans and M. incognita populations and for T. pyriformis cell

C. elegans M. incognita
T. pyriformis /
Compound L4 Eggs J2 Eggs
(log cell mL–1)
LC50a (lw-up) LC90b (lw-upc) LC50 (lw-up) LC 90 (lw-up) LC50 (lw-up) LC90 (lw-up) LC50 (lw-up) LC90 (lw-up)
1a 2.10 (1.86-2.35) 4.25 (3.81-4.93) 2.16 (1.71-2.61) 6.82 (5.85-8.33) 2.27 (1.60-2.94) 6.48 (5.05-11.03) 0.15 (0.11-0.19) 1.13 (1.05-1.22) 4.76 ± 0.15***
1b 5.70 (5.20--6.42) 9.24 (8.49-10.42) 5.96 (5.25-6.68) 11.24 (10.10-13.05) 5.69 (5.19-6.19) 7.83 (7.21-9.18) 0.22 (0.14-0.30) 2.33 (2.16-2.52) 4.71 ± 0.15***
1c 0.78 (0.64-0.95) 2.13 (1.90-2.67) 4.62 (3.85-5.38) 10.62 (9.23-12.93) 5.59 (4.78-6.40) 10.45 (9.15-12.95) 0.12 (0.04-0.19) 1.75 (1.61-1.90) 4.61 ± 0.01**
1d 1.91 (1.70-2.11) 3.27 (2.95-3.79) 4.58 (4.10-5.05) 9.96 (9.04-11.27) 4.44 (3.88-5.00) 7.41 (6.60-9.02) 1.28 (1.21-1.28) 3.06 (2.91-3.25) 4.56 ± 0.04*
1e 1.48 (1.27-1.70) 3.31 (2.91-3.95) 2.32 (2.04-2.59) 5.23 (4.69-6.03) 3.79 (3.45-4.14) 5.07 (4.69-5.94) 0.47 (0.45-0.50) 0.98 (0.93-1.04) 4.59 ± 0.10**
1f 1.14 (1.01-1.27) 2.33 (2.10-2.68) 3.05 (2.61-3.49) 7.81 (6.87-9.21) 5.90 (5.30-6.50) 8.67 (7.91 -10.18) 0.34 (0.25-0.44) 2.82 (2.62-3.05) 4.65 ± 0.13***
1g 1.20 (1.09-1.31) 2.02 (1.85-2.30) 2.95 (2.60-3.30) 4.54 (4.08-5.50) 3.66 (3.12-4.21) 6.69 (5.86-8.37) 1.05 (0.99-1.12) 2.81 (2.66-3.00) 3.68 ± 0.07***
1h 0.81 (0.63-0.99) 2.67 (2.26-3.34) 3.35 (2.89-3.81) 5.52 (4.88-6.91) 4.84 (4.23-5.46) 8.08 (7.21-9.78) 2.05 (1.94-2.16) 4.59 (4.35-4.86) 3.79 ± 0.06***
1i 3.07 (2.89-3.25) 3.99 (3.78-4.35) 3.93 (3.48-4.39) 5.95 (5.37-7.21) 4.38 (3.94-4.82) 6.10 (5.52-8.07) 0.82 (0.77-0.870 2.11 (1.99-2.24) 0***
1j 5.12 (4.78-5.47) 6.34 (6.00-7.00) 2.40 (2.16-2.65) 3.77 (3.43-4.39) 4.39 (3.94-4.83) 6.37 (5.80-7.60) 0.08 (0.06-0.11) 0.62 (0.57-0.67) 3.95 ± 0.08***
1k 4.80 (4.51-5.09)c 6.08 (5.78-6.59) 3.23 (3.01-3.62) 5.08 (4.57-6.11) 1.40 (NaN-NaN)d 1.52 (NaN-NaN) 0.09 (0.06-0.12) 1.09 (1.01-1.18) 3.91 ± 0.03***
Galantamine > 0.0139 > 0.0139 > 0.0139 > 0.0139 > 0.0139 > 0.0139 > 0.0139 > 0.0139 4.12 ± 0.05
0.33 0.47 0.10 0.16 0.015 0.034 0.013 0.034
Controls 4.32 ± 0.10f
(0.32-0.35)e (0.45-0.50)e (0.08-0.11)e (0.15-0.20)e (0.013-0.018)e (0.029-0.041)e (0.012-0.014)e (0.032-0.04)e
LC50: concentration capable of killing 50% of the worm population or inhibiting egg hatching; bLC90: concentration capable of killing 90% of the worm population or inhibiting egg hatching;
a

lower limit (lw) and upper limit (up) with 95% confidence interval; dnot a number. eNimitz®; fdimethyl sulfoxide (DMSO). *Dunnett post hoc ANOVA (***p < 0.001, **p < 0.01, *p < 0.05).
c

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Selenoacetylenes Protect against Beta-Amyloid Peptide-Induced Paralysis and Promote Longevity in Caenorhabditis elegans Figueiredo et al.

As in the case of nematode worms, nematode eggs

were susceptible to the selenoacetylenes. Compounds 1a
and 1j were the most toxic to C. elegans and M. incognita
egg hatching (2.16 and 0.08 mmol L–1, respectively),
whilst compounds 1b and 1h were the least toxic (5.96 and
2.05 mmol L–1, respectively). Galantamine was not toxic
to the tested nematode worms or eggs.

Effect of selenoacetylenes on Aβ-induced paralysis in

C. elegans CL4176 worms

The mobility curves indicate the assay efficiency

in assessing how Aβ affects C. elegans by comparing Figure 2. Paralysis in C. elegans CL4176 worms treated with
the CL4176 strain and its control CL802 (Figure S32, selenoacetylenes. The data represent the mean ± SD (standard deviation)
SI section). Our results show that treatment with the of moving worm. Vehicle MeOH (– control), galantamine at 0.05 g L–1
(+ control). Bars followed by * represent statistical difference in relation
selenoacetylenes reduced the percentage of paralyzed to the vehicle (– control) as revealed by Dunnett’s test (***p < 0.001,
worms compared to untreated worms in vehicle MeOH **p < 0.01, *p < 0.05).
(negative control) and worms treated with the positive
control (galantamine at 0.05 g L–1). increased the worm longevity (Table 5). Compounds 1c
The worm paralysis curves reveal that the evaluated and 1e provided the highest increase (22.7%), while
compounds, including galantamine, reduced the percentage compounds 1i and 1j resulted in slightly lower increase
of paralyzed worms compared to the vehicle MeOH (18.2%).
(negative control) (log-rank Mantel-Cox test, p < 0.001) The curves in Figure 3 show that compounds 1c, 1e,
(Figure S32). The negative and positive controls paralyzed 1f, 1i, and 1j extended the C. elegans BA17 worm survival
80 and 45% of the worm population after 28 h, indicating (Figure 3a) compared to the vehicle MeOH (negative
that galantamine reduced the percentage of paralyzed control) (log-rank Mantel-Cox test, p < 0.05). Galantamine
worms due to its protective effect against Aβ-induced did not interfere with C. elegans BA17 worm survival
paralysis in C. elegans (Dunnett’s test, p < 0.05) (Figure 2). (log‑rank Mantel-Cox test, p < 0.05).
In the presence of compounds 1f (0.21 mmol L –1),
1e (0.13 mmol L–1), 1c (0.19 mmol L–1), 1j (0.17 mmol L–1), Protection against oxidative and thermal stress
or 1i (0.18 mmol L–1) at 0.05 g L–1, the percentage of
paralyzed C. elegans worms was only 2.4, 8.9, 10.3, 15, and Compounds 1c, 1e, 1f, 1i, and 1j significantly increased
15.6%, respectively (Figure 2) (Dunnett’s test, p < 0.05). C. elegans N2 survival in hours following acute oxidative
stress induced by H2O2 (Table 6). Compound 1c was the
Selenoacetylenes increase C. elegans BA17 longevity most efficient (227.3% higher compared to the vehicle
MeOH (negative control)), followed by compounds 1f, 1e,
The five selenoacetylenes (1c, 1e, 1f, 1i, and 1j) that 1j, and 1i (209.1, 190.9, 190.9, and 172.7%, respectively,
reduced the percentage of C. elegans worm paralysis also compared to the vehicle MeOH (negative control)).

Table 5. Longevity of C. elegans BA17 worms treated with selenoacetylenes. Data are represented as mean ± SD (standard deviation) of the worms lifespan

Compound Average lifetime / days Median lifetime / days Average lifetime increase / %
1c 27.00 ± 0.00* 25 22.7
1e 27.00 ± 0.00* 23 22.7
1f 26.33 ± 0.58* 23 19.7
1i 26.00 ± 0.00* 24 18.2
1j 26.00 ± 0.00* 25 18.2
Positive control 21.67 ± 0.58 18 –1.52
Negative control 22.00 ± 0.00 19
Means followed by * indicate statistical difference by Dunnet’s test (p < 0.001) compared to the vehicle MeOH (negative control). Galantamine at 0.05 g L–1
(positive control).

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Figueiredo et al. Selenoacetylenes Protect against Beta-Amyloid Peptide-Induced Paralysis and Promote Longevity in Caenorhabditis elegans

Table 6. C. elegans N2 survival after oxidative and thermal stress in the presence of selenoacetylenes. Data are represented as mean ± SD (standard
deviation) of the worms lifetime

Treatment Compound Average lifetime / h Median lifetime / h Average lifetime increase / %

1c 12.00 ± 1.15* 8 227.3
1e 10.67 ± 1.15* 10 190.9
1f 11.33 ± 0.00* 10 209.1
H2O2 1i 10.00 ± 0.00* 10 172.7
1j 10.00 ± 0.00* 10 190.9
positive control 4.50 ± 0.00 3.5 22.7
negative control 3.67 ± 0.29 2.5
1c 66.00 ± 0.00* 54 83.3
1e 60.00 ± 0.00* 36 66.7
1f 62.00 ± 3.46* 48 72.2
35 °C 1i 60.00 ± 0.00* 42 66.7
1j 62.00 ± 3.46* 54 72.2
positive control 38.00 ± 3.46 24 5.6
negative control 36.00 ± 0.00 21
Means followed by * indicate statistical difference by Dunnet’s test (p < 0.001) compared to the vehicle MeOH (negative control). Galantamine at 0.05 g L–1
(positive control).

Figure 3. C. elegans worm survival. (a) C. elegans BA17 worm survival in days; (b) C. elegans N2 survival in hours after H2O2 oxidative stress;
(c) C. elegans N2 survival in hours after heat shock. The curves show significant differences (log-rank Mantel-Cox test, p < 0.05) compared to treatment
with the vehicle MeOH (negative control), as determined by the log-rank test (Mantel-Cox). (●) 1c, (■) 1e, (▲) 1f, (▼) 1i, (●) 1j, (●) vehicle MeOH
(negative control), (●) galantamine at 0.05 g L–1 (positive control).

The selected selenoacetylenes promoted thermotolerance In vivo antioxidant activity

in C. elegans N2 (Dunnett’s test, p < 0.05) (Table 6). Worms
treated with the selenoacetylenes resisted heat shock, Treatment with the selenoacetylenes increased GCS‑1
which increased their survival as assessed in hours. Worms expression in C. elegans LD1171 compared to the vehicle
treated with compound 1c had 83.3% longer survival on MeOH (negative control) (Dunnett’s test, p < 0.05).
average compared to worm survival in the control group Compound 1f regulated GCS-1 expression the most
vehicle MeOH (negative control) (Table 6). The other effectively (208% increase), followed by compounds 1c and
selenoacetylenes increased worm survival after heat 1e, which increased GCS-1 expression by 164 and 140%,
shock by between 66.7 and 72.2%. Galantamine did not respectively (Figure 4). In contrast, galantamine (positive
protect C. elegans N2 against heat shock (Dunnett’s test, control) did not induce GCS-1 expression in C. elegans
p < 0.05). LD1171 compared to the negative control (Dunnett’s test,
The worm survival curves demonstrate the oxidative p < 0.05) (Figure 4).
(Figure 3b) and thermal (Figure 3c) protection effects of
compounds 1c, 1e, 1f, 1i, and 1j, which increased the worm Discussion
lifespan compared to the vehicle MeOH (negative control)
(log-rank Mantel-Cox test, p < 0.0001). Galantamine The selenoacetylenes evaluated herein delayed
(positive control) did not provide any oxidative or thermal Aβ‑induced paralysis and enhanced resistance to oxidative
protection to C. elegans N2. and thermal stress in C. elegans worms. We found that

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Selenoacetylenes Protect against Beta-Amyloid Peptide-Induced Paralysis and Promote Longevity in Caenorhabditis elegans Figueiredo et al.

Figure 4. Quantification of fluorescence in C. elegans LD1171 intestines. Fluorescence images in worms: compound (a) 1c; (b) 1e; (c) 1f; (d) 1i; (e) 1j;
(f) vehicle MeOH (negative control); (g) galantamine at 0.05 g L–1 (positive control); (h) mean fluorescence values expressed as corrected total cell
fluorescence (CTCF), * represents statistical difference compared to the negative control (Dunnett’s test, p < 0.05). Scale bar = 0.15 mm.

treatment with the selenoacetylenes was associated with of Aβ aggregates in C. elegans CL4176 muscles depends
various health benefits in C. elegans worms, including on temperature, paralyzing the worms, and results in a clear
increased longevity, and that these compounds displayed and easily observable phenotype, that is, an Aβ-dependent
low toxicity in different model organisms. In addition, paralysis phenotype.87 Selenoacetylenes 1c, 1e, 1f, 1i,
the selenoacetylenes exerted more pronounced effects and 1j specifically protected C. elegans CL4176 against
compared to the positive control galantamine, a compound Aβ-induced toxicity in vivo. Compounds 1c, 1e, 1f, 1i,
that can reduce cognitive and memory impairment and is and 1j reduced the percentage of paralyzed worms more
recommended for treating AD.40 effectively than galantamine, known for decreasing Aβ
We verified that selenoacetylene toxicity varied production and Aβ-induced toxicity.40
depending on the employed biological model, and that This information adds evidence to the efficacy of
the selenoacetylene structure influenced the biological compounds that modulate Aβ plaque formation by inhibiting
activity profile. The presence of the phenyl group in the their production, aggregation, and even disaggregation, to
selenoacetylene molecule was important for antiprotozoal interrupt or to delay AD progression.88-90 Other selenium
activity, as in the case of indazole derivatives.83 Compounds 1g derivatives such as N-γ-(L-glutamyl)-L-selenomethionine91
and 1i bear the but-3-in-2-ol radical, which was essential and selenoesters92 attenuate Aβ aggregation in C. elegans.
for increasing the antiprotozoal activity. Treatment with These data contribute to identifying and characterizing
these compounds significantly reduced T. pyriformis cells, new anti-AD agents.
with 100% cell mortality being achieved for compound 1i. The antioxidant property of diphenyl diselenide is related
Just like selenoacetylenes, other selenium derivatives to its ability to reduce the percentage of Aβ-induced paralysis
such as β-selenoamines84 and selenium-xylofuranosides85 in C. elegans worms.93 Notably, selenoacetylenes 1c, 1e, 1f,
have low toxicity in C. elegans, and their biological activity 1i, and 1j exerted antioxidant activities and protected against
depends on the substituent groups. The structure-activity thermal stress by increasing the survival time of worms
relationship is crucial when selecting compounds with subjected to H2O2 and heat shock. Although galantamine
different biological activities as well as the concentrations exerted a mild effect on the survival of worms subjected to
to be evaluated in assays. 53 The toxicity (LC 90) of H2O2, it did not affect the survival of worms subjected to heat
compounds in C. elegans is on average 10 times higher shock. The antioxidant properties of selenium compounds
than their effective concentrations employed during affect aging and longevity positively.85 Chaperones known as
neuroprotection assays, indicating that the selenoacetylenes heat shock proteins (HSPs) assist conformational changes,
evaluated herein are safe.86 These results are promising protein folding, and protein aggregation. HSP70 plays an
because toxicity is one of the side effects of therapeutic important neuroprotective role in AD by preventing plaque
agents used in AD therapy.35 formation and Aβ aggregation.94 How selenoacetylenes 1c,
Specific inhibition of the Aβ toxic species is the key 1e, 1f, 1i, and 1j affect chaperone expression needs to be
for developing new therapeutic drugs to treat AD and investigated further.
has been validated in transgenic C. elegans.86 C. elegans Another possible antioxidant mechanism of
CL4176 expresses human Aβ in muscle cells. Deposition selenoacetylenes is activation of protective signaling

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Figueiredo et al. Selenoacetylenes Protect against Beta-Amyloid Peptide-Induced Paralysis and Promote Longevity in Caenorhabditis elegans

pathways, similarly to selenonein (2-selenyl-Nα, Nα, Author Contributions

Nα-trimethyl-L-histidine);95 they could also act through
GPx-like antioxidant activity, as observed in diselenides.96 Maria Isabela S. Figueiredo was responsible for conceptualization,
Here, we verified that the selenoacetylenes activated GCS‑1 data analysis, formal analysis, investigation, methodology validation,
expression, promoting antioxidant protection. Oxidative visualization and writing (original draft, review and editing); Ivani
stress is one of the main mechanisms of aging, and S. Mello and Sabrina K. Targanski for some trials with model
upregulating antioxidant enzymes is pivotal for protecting organisms; Juliana S. Duarte, Leonardo G. Vasconcelos and André
against oxidative stress.97,98 Luiz A. Stein for the methodology, synthesis and characterization
In C. elegans, aging is associated with physiological of selenoacetylenes by NMR and HPLC; Marcos Antonio Soares
and neurological decline, resembling aging in mammals, for conceptualization, resources, supervision, formal analysis,
including humans.99 Aging can induce stress, reduce investigation support and original writing support.
the overall health, and trigger age-related neurological
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