A novel small molecule based on benzothiazole-piperazine has been identified as an effective multi-target-directed ligand (MTDL) against Alzheimer's disease (AD). Employing a medicinal chemistry ...approach, combined with molecular docking, MD simulation, and binding free energy estimation, compound 1 emerged as a potent MTDL against AD. Notably, compound 1 demonstrated efficient binding to both AChE and Aβ1–42, involving crucial molecular interactions within their active sites. It displayed a binding free energy (ΔGbind) −18.64± 0.16 and −16.10 ± 0.18 kcal/mol against AChE and Aβ1–42, respectively. In-silico findings were substantiated through rigorous in vitro and in vivo studies. In vitro analysis confirmed compound 1 (IC50=0.42 μM) as an effective, mixed-type, and selective AChE inhibitor, binding at both the enzyme's catalytic and peripheral anionic sites. Furthermore, compound 1 demonstrated a remarkable ability to reduce the aggregation propensity of Aβ, as evidenced by Confocal laser scanning microscopy and TEM studies. Remarkably, in vivo studies exhibited the promising therapeutic potential of compound 1. In a scopolamine-induced memory deficit mouse model of AD, compound 1 showed significantly improved spatial memory and cognition. These findings collectively underscore the potential of compound 1 as a promising therapeutic candidate for the treatment of AD.
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•A benzothiazole-piperazine-based small molecule has been developed as an effective MTDL against AD.•Compound 1 (IC50=0.421 μM) was a potent, mixed-type, and selective AChE inhibitor.•Compounds 1 at 50 μM effectively reduced the aggregation propensity of Aβ by 80.708%.•Compound 1 demonstrated potent neuroprotection in cells induced with H2O2 and OKA neurotoxicity.•Compound 1 showed improved spatial memory and cognition in the scopolamine-induced memory deficit mouse model of AD.
2-(piperazin-1-yl)N-(1H-pyrazolo3,4-bpyridin-3-yl)acetamides are described as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and amyloid β aggregation inhibitors. ...Formation of synthesized compounds (P1P9) was justified via H1 NMR, C13 NMR, mass spectra and single crystal X-Ray diffraction study. All compounds were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activity, inhibition of self-mediated Aβ aggregation and Cu(II)-mediated Aβ aggregation. Also, docking study carried out was in concordance with in vitro results. The most potent molecule amongst the derivatives exhibited excellent anti-AChE activity (IC50 = 4.8 nM). Kinetic study of P3 suggested it to be a mixed type inhibitor. In vitro study revealed that all the compounds are capable of inhibiting self-induced β-amyloid (Aβ) aggregation with the highest inhibition percentage to be 81.65%. Potency of P1 and P3 to inhibit self-induced Aβ1-42 aggregation was ascertained by TEM analysis. Compounds were also evaluated for their Aβ disaggregation, antioxidation, metal-chelation activity.
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•2-(piperazin-1-yl)-N-(1H-pyrazolo3,4-bpyridin-3-yl)acetamides are described as new multifunctional anti-Alzheimer’s agents.•They possess AChE and BChE inhibition, Aβ aggregation inhibition, Aβ disaggregation, antioxidation and metal-chelation properties.•The most potent molecule amongst the derivatives exhibited excellent anti-AChE activity with IC50 = 4.8 nM.•In vitro study revealed compounds to be capable of inhibiting self-induced β-amyloid aggregation with the highest inhibition percentage 81.65%.•Aβ1-42 aggregation was ascertained by TEM analysis.
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In an attempt to construct potential anti-Alzheimer’s agents Naphthalene-triazolopyrimidine hybrids were synthesized and screened in vitro against the two cholinesterases (ChE)s, ...amyloid β aggregation and for antioxidation activity. Single-crystal X-ray crystallography was utilized for crystal structure determination of one of the compounds. In vitro study of compounds revealed that most of the compounds are capable of inhibiting acetylcholinesterase and Butyrylcholinesterase activity. Particularly, the compounds 4e and 4d exhibited IC50 values ranging from 8.6 to 14 nM against AChE lower than the standard drug Donepezil (IC50 49 nM). Best result was found for compound 4e with IC50 of 8.6 nM (for AChE) and 150 nM (for BuChE). Selectivity upto that of Donepezil and even more was observed for 4a, 4c and 4h. Investigation by electron microscopy, transmission electron microscopy and ThT fluorescence assay unveils the fact that synthesized hybrids exhibit amyloid β self-aggregation inhibition. The compounds 4i and 4j revealed highest inhibitory potential, 85.46% and 72.77% at 50 μM respectively; above the standard Aβ disaggregating agent, Curcumin. Their antioxidation profile was also analyzed. Studies from DPPH free radical scavenging assay and ORAC assay depicts molecules to possess low antioxidation profile. Results suggest that triazolopyrimidines are potential candidate for Acetylcholinesterase (AChE), Butyrylcholinesterase (BuChE), and amyloid β aggregation inhibition. In silico ADMET profiling indicates drug-like properties with a very low toxic influence. Such synthesized compounds provide a strong vision for further development of potential anti-Alzheimer’s agents.
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•A series of novel carbazole derivatives has been developed as potent multifunctional agents against Alzheimer’s disease.•These compounds appeared to be potent AChE inhibitors, Aβ ...aggregation inhibitors, anti-oxidant and neuroprotective agents.•MT-1 and MT-6 were most potent multifunctional agents in the entire series.•MT-6 have shown effective neuroprotective action against H2O2 induce toxicity in SHSY-5Y cells.•MT-6 was evaluated against scopolamine induced dementia model of mice and this compound actively improved memory deficit and cognition impairment in this model.
Carbazole based novel multifunctional agents has been rationally designed and synthesized as potential anti-Alzheimer agents. Multi-functional activity of these derivatives have been assessed by performing various in-vitro assays and these compounds appeared to be potent AChE inhibitors, Aβ aggregation inhibitors, anti-oxidant and neuroprotective agents. Among the entire series, MT-1 and MT-6 were most potent multifunctional agents which displayed effective and selective AChE inhibition, Aβ disaggregation, anti-oxidant and metal chelation action. Neuroprotective activity of MT-6 has been examined against H2O2 induced toxicity in SHSY-5Y cells and they have shown effective neuroprotection. Additionally, MT-6 did not display any significant toxicity in SHSY-5Y cells, indicating its non-toxic nature. Molecular docking and MD simulation studies have been also performed to explore molecular level interaction with AChE and Aβ. Finally, MT-6 was evaluated against scopolamine induced dementia model of mice and this compound actively improved memory deficit and cognition impairment in scopolamine treated mice. Thus, novel carbazole derivative MT-6 has been explored as an effective and safe multifunctional agent against AD and this molecule may be used as a suitable lead for development of effective anti-Alzheimer agents in future.
A novel series of benzothiazole-piperazine hybrids were rationally designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD). The synthesized hybrid molecules ...illustrated modest to strong inhibition of acetylcholinesterase (AChE) and Aβ
aggregation. Compound 12 emerged as the most potent hybrid molecule exhibiting balanced functions with effective, uncompetitive and selective inhibition against AChE (IC
= 2.31 μM), good copper chelation, Aβ
aggregation inhibition (53.30%) and disaggregation activities. Confocal laser scanning microscopy and TEM analysis also validate the Aβ fibril inhibition ability of this compound. Furthermore, this compound has also shown low toxicity and is capable of impeding loss of cell viability elicited by H
O
neurotoxicity in SHSY-5Y cells. Notably, compound 12 significantly improved cognition and spatial memory against scopolamine-induced memory deficit in a mouse model. Hence, our results corroborate the multifunctional nature of novel hybrid molecule 12 against AD and it may be a suitable lead for further development as an effective therapeutic agent for therapy in the future.
Diallyl disulfide (DADS), a principal organosulfur component of garlic, is known for its medicinal properties including anti-cancer activity. Prior studies have demonstrated that the compounds ...containing Diallyl disulfide moieties exhibited diverse therapeutic potential with promising biological activities. In the present study, we have investigated the in vitro anticancer activity of Diallyl disulfide derivatives (5a-5l and 7e-7m) against human cancer cell lines.
The effect of DADS analogs on different cancer cell lines was measured through MTT assay. Cell cycle progression, apoptosis, DNA fragmentation and levels of ROS were analyzed through FACS and confocal imaging.
Bis3-(3-fluorophenyl)prop-2-enedisulfide (compound 5b) was the most potent compound among the tested DADS derivatives. FACS analysis revealed that increase in ROS generation by compound 5b was accompanied by cell cycle arrest in the G2/M phase and apoptosis in MIA PaCa-2 cells. Further, the apoptosis was confirmed by TUNEL assay. Western blot analysis showed that compound 5b induces G2/M phase arrest via ROS mediated DNA-damage, which in turn, induces phosphorylation of Chk1/Cdc25c/Cdc2 pathway. Furthermore, altered levels of ROS triggers intrinsic apoptotic cascade, as evidenced by dissipated mitochondrial membrane potential (ψ), decrease in Bcl-2/Bax ratio, cytochrome c release and cleavage of procaspase-3. Scavenging of ROS by antioxidant N-acetyl-cysteine (NAC) reversed the compound 5b induced augmented intracellular ROS levels and cell death.
Taken together, the anti-proliferative effects of compound 5b were attributed to intracellular ROS accumulation, which in turn, triggers apoptosis by mediating DNA damage-induced G2/M phase arrest and evoking mitochondrial apoptotic pathway in MIA PaCa-2 cells.
In the journey towards the development of potent multi-targeted ligands for the treatment of Alzheimer's disease, a series of Aβ aggregation inhibitors having quinoline scaffold were designed ...utilizing computational biology tools, synthesized and characterized by various spectral techniques including single-crystal X-ray crystallography. Organic syntheses relying upon convergent synthetic routes were employed. Investigations
ThT fluorescence assay, electron microscopy and transmission electron microscopy revealed the synthesized derivatives to exhibit Aβ self-aggregation inhibition. Molecules
and
showed the highest inhibitory potential, 53.73% and 53.63% at 50 μM respectively; higher than the standard Aβ disaggregating agent, curcumin. Molecules
and
disaggregated AChE-induced (58.26%, 47.36%) Aβ aggregation more than two fold more than the standard drug-donepezil (23.66%) and inhibited Cu
-induced Aβ aggregation. A docking study significantly showed their interaction with key residues of Aβ and the results were in accordance with the study. Besides, these compounds also exhibited potential antioxidant activity (
, 2.7240 Trolox equivalent by ORAC assay) and metal chelating property. Furthermore, the stoichiometric ratio of Cu (ii)-
and Cu(ii)-
complexes were found by Job's method (0.5 : 1 for
and 0.8 : 1 for
).
ADMET profiling showed these derivatives to have drug like properties with very low toxicity effects in the pharmacokinetic study. Overall, these results displayed a multi-activity profile with promising Aβ aggregation inhibition and antioxidation and metal chelation activity that could be helpful for developing new multifunctional agents against Alzheimer's disease.
In the journey towards the development of potent multi-targeted ligands for the treatment of Alzheimer's disease, a series of Aβ aggregation inhibitors having quinoline scaffold were designed ...utilizing computational biology tools, synthesized and characterized by various spectral techniques including single-crystal X-ray crystallography. Organic syntheses relying upon convergent synthetic routes were employed. Investigations
via
ThT fluorescence assay, electron microscopy and transmission electron microscopy revealed the synthesized derivatives to exhibit Aβ self-aggregation inhibition. Molecules
5g
and
5a
showed the highest inhibitory potential, 53.73% and 53.63% at 50 μM respectively; higher than the standard Aβ disaggregating agent, curcumin. Molecules
5g
and
5a
disaggregated AChE-induced (58.26%, 47.36%) Aβ aggregation more than two fold more than the standard drug-donepezil (23.66%) and inhibited Cu
2+
-induced Aβ aggregation. A docking study significantly showed their interaction with key residues of Aβ and the results were in accordance with the study. Besides, these compounds also exhibited potential antioxidant activity (
5a
, 2.7240 Trolox equivalent by ORAC assay) and metal chelating property. Furthermore, the stoichiometric ratio of Cu (
ii
)-
5a
and Cu(
ii
)-
5g
complexes were found by Job's method (0.5 : 1 for
5a
and 0.8 : 1 for
5g
).
In silico
ADMET profiling showed these derivatives to have drug like properties with very low toxicity effects in the pharmacokinetic study. Overall, these results displayed a multi-activity profile with promising Aβ aggregation inhibition and antioxidation and metal chelation activity that could be helpful for developing new multifunctional agents against Alzheimer's disease.
N
-(4-((7-Chloroquinolin-4-yl)oxy)-3-ethoxybenzyl)amines as new amyloid beta-disaggregating agents.
N
-(4-((7-Chloroquinolin-4-yl)oxy)-3-ethoxybenzyl)amines as new amyloid beta-disaggregating agents.
In the journey towards the development of potent multi-targeted ligands for the treatment of ...Alzheimer's disease, a series of Aβ aggregation inhibitors having quinoline scaffold were designed utilizing computational biology tools, synthesized and characterized by various spectral techniques including single-crystal X-ray crystallography. Organic syntheses relying upon convergent synthetic routes were employed. Investigations
via
ThT fluorescence assay, electron microscopy and transmission electron microscopy revealed the synthesized derivatives to exhibit Aβ self-aggregation inhibition. Molecules
5g
and
5a
showed the highest inhibitory potential, 53.73% and 53.63% at 50 μM respectively; higher than the standard Aβ disaggregating agent, curcumin. Molecules
5g
and
5a
disaggregated AChE-induced (58.26%, 47.36%) Aβ aggregation more than two fold more than the standard drug-donepezil (23.66%) and inhibited Cu
2+
-induced Aβ aggregation. A docking study significantly showed their interaction with key residues of Aβ and the results were in accordance with the study. Besides, these compounds also exhibited potential antioxidant activity (
5a
, 2.7240 Trolox equivalent by ORAC assay) and metal chelating property. Furthermore, the stoichiometric ratio of Cu (
ii
)–
5a
and Cu(
ii
)–
5g
complexes were found by Job's method (0.5 : 1 for
5a
and 0.8 : 1 for
5g
).
In silico
ADMET profiling showed these derivatives to have drug like properties with very low toxicity effects in the pharmacokinetic study. Overall, these results displayed a multi-activity profile with promising Aβ aggregation inhibition and antioxidation and metal chelation activity that could be helpful for developing new multifunctional agents against Alzheimer's disease.
A novel series of benzothiazole-piperazine hybrids were rationally designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD). The synthesized hybrid molecules ...illustrated modest to strong inhibition of acetylcholinesterase (AChE) and Aβ
1-42
aggregation. Compound
12
emerged as the most potent hybrid molecule exhibiting balanced functions with effective, uncompetitive and selective inhibition against AChE (IC
50
= 2.31 μM), good copper chelation, Aβ
1-42
aggregation inhibition (53.30%) and disaggregation activities. Confocal laser scanning microscopy and TEM analysis also validate the Aβ fibril inhibition ability of this compound. Furthermore, this compound has also shown low toxicity and is capable of impeding loss of cell viability elicited by H
2
O
2
neurotoxicity in SHSY-5Y cells. Notably, compound
12
significantly improved cognition and spatial memory against scopolamine-induced memory deficit in a mouse model. Hence, our results corroborate the multifunctional nature of novel hybrid molecule
12
against AD and it may be a suitable lead for further development as an effective therapeutic agent for therapy in the future.
A novel series of benzothiazole-piperazine hybrids were rationally designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD).
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