5,6-Diphenyl triazine-thio methyl triazole hybrid as a new Alzheimer’s disease modifying agents

Yazdani, Mehdi; Edraki, Najmeh; Badri, Rashid; Khoshneviszadeh, Mahsima; Firuzi, Omidreza

doi:10.1007/s11030-019-09970-3

Cited by 30 publications

(17 citation statements)

References 33 publications

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“…According to the interaction mode of compound B, it can be understood that 1,2,3-triazole-aryl moiety led to the formation of hydrophobic interactions with amino acids of PAS and chromenone ring oriented towards CAS pocket [ 21 ]. In the case of compound C , diphenyl fit into the BuChE CAS pocket while the benzyl triazine pendant group showed H-bond interaction with the PAS of BuChE [ 22 , 23 ]. As appeared in compounds B and C , increasing bulkiness and length of drug candidate could increase the selectivity of BuChE over AChE.…”

Section: Resultsmentioning

confidence: 99%

Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer's disease

et al. 2020

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To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a new series of 1,2,3-triazole-chromenone derivatives were designed and synthesized based on the multi target-directed ligands approach. The in vitro biological activities included acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition as well as anti-Aβ aggregation, neuroprotective effects, and metal-chelating properties. The results indicated a highly selective BuChE inhibitory activity with an IC50 value of 21.71 μM for compound 10h as the most potent compound. Besides, compound 10h could inhibit self-induced Aβ1–42 aggregation and AChE-induced Aβ aggregation with 32.6% and 29.4% inhibition values, respectively. The Lineweaver–Burk plot and molecular modeling study showed that compound 10h targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of BuChE. It should be noted that compound 10h was able to chelate biometals. Thus, the designed scaffold could be considered as multifunctional agents in AD drug discovery developments.

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Section: Resultsmentioning

confidence: 99%

Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer's disease

et al. 2020

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“…1, A) [14]; however, as appeared in compounds B and C increasing bulkiness and length of drug candidate could increase the selectivity of BuChE over hAChE. Besides, this part could also exhibit metal-chelating potential [15,16]. Moreover, introducing a relatively spacious di methylamino propenone entity into our system would be a good strategy to increase selectivity toward BuChE.…”

Section: Designmentioning

confidence: 89%

Design and Development of Multi-target Directed 1,2,3-rriazole-dimethylaminoacryloyl-chromenone Derivatives with Potential use in Alzheimer's Disease

Askarani

Iraji

Rastegari

et al. 2020

Preprint

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To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a new series of 1,2,3-triazole-chromenone derivatives were designed and synthesized based on the multi target-directed ligands approach. The in vitro biological activities were evaluated including acetylcholinesterase (AChE), butylcholinesterase (BuChE), and Aβ1−42 aggregation inhibition as well as neuroprotective effects and metal-chelating properties. The results indicated highly selective BuChE inhibitory activity with IC50 values of 21.71 µM for compound 10 h as the most potent compound. Besides, compound 10 h could inhibit self-induced Aβ1−42 aggregation and AChE-induced Aβ aggregation with 32.6% and 29.4% inhibition value, respectively. A Lineweaver–Burk plot and molecular modeling study also showed that compound 10 h targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of BuChE. It should be noted that compound 10 h was potent as a selective Cu2+ chelator. Thus, the designed scaffold could be considered as multifunctional agents for AD drug discovery developments.

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“…The neuroprotective effect of compound 4e to protect neuronal PC12 cells against damage induced by Aβ 25–35 was examined according to our previous report. [ 27 ] The MTT reduction assay was used to evaluate the neuroprotectivity of compound 4e on neuronal PC12 cell damage induced by Aβ 25–35 . The cells were grown in monolayer culture on collagen‐coated plates at 37°C in a humidified atmosphere of 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Novel N‐benzylpiperidine derivatives of 5‐arylisoxazole‐3‐carboxamides as anti‐Alzheimer's agents

Saeedi

Felegari

Iraji

et al. 2020

Archiv der Pharmazie

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The complex pathophysiology of Alzheimer's disease (AD) has prompted researchers to develop multitarget‐directed molecules to find an effective therapy against the disease. In this context, a novel series of N‐(1‐benzylpiperidin‐4‐yl)‐5‐arylisoxazole‐3‐carboxamide derivatives were designed, synthesized, and evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). In vitro biological evaluation demonstrated that compound 4e was the best AChE (IC50 = 16.07 μM) and BuChE inhibitor (IC50 = 15.16 μM). A kinetic study of 4e was also conducted, which presented a mixed‐type inhibition for both enzymes. Molecular docking studies revealed that compound 4e fitted well into the active sites of AChE and BuChE, forming stable and strong interactions with key residues Glu199, Trp84, Asp72, Tyr121, and Phe288 in AChE and His438, Trp82, Ala328, Tyr332, Phe329, Thr120, and Pro285 in BuChE. Besides, the inhibition of BACE1 by 4e and the biometal chelation activity of 4e were measured. The neuroprotective assessment revealed that 4e exhibited 23.2% protection at 50 µM toward amyloid‐beta‐induced PC12 neuronal cells. Overall, this study exhibited that compound 4e was a promising compound targeting multiple factors associated with AD.

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5,6-Diphenyl triazine-thio methyl triazole hybrid as a new Alzheimer’s disease modifying agents

Cited by 30 publications

References 33 publications

Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer's disease

Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer's disease

Design and Development of Multi-target Directed 1,2,3-rriazole-dimethylaminoacryloyl-chromenone Derivatives with Potential use in Alzheimer's Disease

Novel N‐benzylpiperidine derivatives of 5‐arylisoxazole‐3‐carboxamides as anti‐Alzheimer's agents

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