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    Design of novel benzimidazole-propane hydrazide derivatives as α-glucosidase and α-amylase inhibitors: in vitro and in silico studies
    (Springer Birkhauser, 2025) Mohammadizadeh, Shiva; Karimian, Somaye; Dastyafteh, Navid; Noori, Milad; Doraghi, Fatemeh; Mohammadi-Khanaposhtani, Maryam; Larijani, Bagher
    A new series of benzimidazole-propane hydrazide derivatives 9a-k were designed, synthesized, and evaluated for their inhibition ability against alpha-glucosidase and alpha-amylase. The results of the in vitro evaluations showed that all the tested compounds exhibited significant inhibition against alpha-glucosidase and alpha-amylase. Title compounds 9a-k exhibited varying degrees of inhibitory ability against alpha-glucosidase, with IC50 values in the range of 73.86-151.54 nM, in comparison to the standard acarbose drug with IC50 value of 174.50 nM. Similarly, these compounds demonstrated varying degrees of alpha-amylase inhibitory ability (the IC50 values ranged from 42.50 to 78.58 nM in comparison to acarbose with IC50 of 79.05 nM). Among the synthesized compounds, compound 9 h demonstrated the highest alpha-glucosidase inhibitory activity and compound 9 f demonstrated the highest anti-alpha-amylase activity. To further investigation on the potential of these derivatives as alpha-glucosidase and alpha-amylase inhibitors, molecular docking were conducted on all the synthesized compounds 9a-k. Docking results were in agreement with in vitro results. Molecular dynamics of compound 9 h showed that complex compound 9h-alpha-glucosidase had acceptable stability and flexibility. Calculations of physicochemical properties of compound 9a-k showed that these compounds fallowed of the main drug-likeness rules. Furthermore, the prediction of pharmacokinetics and toxicity profiles of compound 9 h showed that this compound can be considered as a lead drug structure.
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    New 1E,1′E-hydrazine-bis(phenoxy-1,2,3-triazol-acetamide) derivatives as potent inhibitors against acetylcholinesterase, butyrylcholinesterase, and α-glucosidase
    (Royal Soc Chemistry, 2025) Kermaninia, Shahab; Mohammadi-Khanaposhtani, Maryam; Senol, Halil; Khajeh Mohammadilar, Fatemeh Sadat; Dastyafteh, Navid; Moradkhani, Fatemeh; Saeedi, Saeedeh
    In this study, novel 1E,1 ' E-hydrazine-bis(phenoxy-1,2,3-triazol-acetamide) derivatives 10a-n were synthesized, and because of their structural features, they were evaluated against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and alpha-glucosidase. AChE and BChE are two important targets in the treatment of Alzheimer's disease (AD), and alpha-glucosidase is a carbohydrate-hydrolyzing enzyme with therapeutic importance in diabetes. Furthermore, cell studies were performed on the title compounds against SH-SY5Y neuroblastoma cells as a cancer cell line and HEK293 cells as a normal cell line. In vitro enzymatic evaluations demonstrated that these new compounds were active against the studied enzymes in comparison to standard inhibitors. In this regard, all the synthesized compounds were more potent than the standard inhibitors tacrine and donepezil against BChE, and most of these compounds were more potent than tacrine against AChE. Moreover, most of the target synthesized compounds were more potent than the standard inhibitor acarbose against alpha-glucosidase. The most potent compound against AChE and BChE was the 2,4-dichloro derivative 10k, and the most potent compound against alpha-glucosidase was the 2-chloro derivative 10h. Moreover, in vitro cell studies demonstrated that compounds 10k and 10h with a selectivity index of >10 demonstrated more cytotoxic effects on the cancer cell line SH-SY5Y than on the normal cell line HEK293. A docking study showed that the latter compounds attached to the active sites of the target enzymes with binding energies more favorable than those of the selected standard inhibitors. Furthermore, docking studies demonstrated that compound 10k interacted with both the catalytic and peripheral anionic sites of AChE and BChE. This property led to the better efficacy of the compound in the treatment of AD.
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    New benzimidazole-indole-amide derivatives as potent α-glucosidase and acetylcholinesterase inhibitors
    (Wiley-V C H Verlag Gmbh, 2024) Naimi, Narges; Karimian, Somaye; Dastyafteh, Navid; Noori, Mild; Mohammadi-Khanaposhtani, Maryam; Dadgar, Armin; Larijani, Bagher
    New derivatives 6a-m with benzimidazole-indole-amide scaffold were developed, synthesized, and assessed for potential inhibitory effects on alpha-glucosidase and acetylcholinesterase (AChE). These compounds were synthesized by various amine derivatives. With the exception of two compounds, the alpha-glucosidase inhibitory activities of the title derivatives were more than that of the positive control acarbose. Moreover, the anti-AChE activity of these compounds, with the exception of one compound, was better than that of tacrine (standard inhibitor). The most potent compound against alpha-glucosidase was 3-methylphenyl derivative 6i and the most potent compound against AChE was 3,4-dimethoxyphenethyl derivative 6m. All the synthesized compounds were placed in the active sites of alpha-glucosidase and AChE by in silico docking method and the obtained binding energies were approximately in agreement with the in vitro observed data. Interaction modes of the most potent compounds 6i and 6m demonstrated that these compounds interacted with important residues of their target enzymes. Molecular dynamics simulation was conducted specifically on compound 6i in complex with alpha-glucosidase to obtain deeper insights into the behavior of this molecule. Furthermore, in silico pharmacokinetic and toxicity studies on the most potent compound predicted that these compounds have good profiles in terms of oral absorption and toxicity.
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    Novel diazen-bis(phenoxy-1,2,3-triazole-N-phenylacetamide) derivatives as potent anti-cholinesterase, anti-α-glycosidase and anti-a-amylase agents: In vitro and in silico evaluations
    (Elsevier, 2025) Kermaninia, Shahab; Mohammadi-Khanaposhtani, Maryam; Bagherian, Nafiseh; Dastyafteh, Navid; Moradkhani, Fatemeh; Saeedi, Saeedeh; Larijani, Bagher
    In this work, new diazen-bis(phenoxy-1,2,3-triazole-N-phenylacetamide) derivatives 9a-n were designed, synthesized, and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors that are two important targets in the treatment of Alzheimer's disease (AD). These compounds were also evaluated against alpha-amylase and alpha-glycosidase because they were structurally similar to some inhibitors of these enzymes. In vitro evaluations demonstrated that, with the exception of alpha-glycosidase, most of the new synthesized compounds showed significant inhibitory effect against the studied enzymes. In this regard, the most potent compound against AChE and BChE (compound 9 h) was around 2 times more potent than standard inhibitor (tacrine) against these enzymes. Moreover, the most potent compound against alpha-amylase (compound 9i) was around 3.8 folds more potent than standard inhibitor (acarbose). Molecular modeling study demonstrated that these most potent compounds were attached to the active sites of the related target enzymes with the binding energies more favorable than used standard inhibitors. Furthermore, docking studies exhibited that compound 9 h interacted with both the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of the binding sites AChE and BChE. These interactions are valuable to select a compound as the lead compound in the treatment of AD.
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    Rhodanine-pyridinium derivatives as a new category of cholinesterase inhibitors: Design, synthesis, in vitro and in silico enzymatic evaluations
    (Elsevier, 2025) Noori, Milad; Karimian, Somaye; Dastyafteh, Navid; Ghafouri, Seyedeh Niloufar; Mohammadi-Khanaposhtani, Maryam; Safapoor, Sajedeh; Ghomi, Minoo Khalili
    Rhodanine-pyridinium derivatives 10a-q were designed and synthesized based on reported cholinesterase (ChE) inhibitors and evaluated as potent anti-Alzheimer's disease agents. The in vitro anti-ChE activity of the title compounds was evaluated against two main forms of this enzyme: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The obtained in vitro results showed that all the synthesized derivatives were more potent than positive control tacrine against AChE. Moreover, most of the new synthesized compounds were more potent than tacrine against BChE. Among the synthesized compounds, compound 10p was the most potent compound against AChE and compound 10f was the most potent compound against BChE. In vitro kinetic study demonstrated that compounds 10p and 10f were competitive inhibitors against AChE and BChE, respectively. Both these compounds had a 4-CF3 substituent on phenyl ring of benzyl pyridinium moiety. Docking study on compounds 10p and 10f demonstrated that these compounds with favorable binding energies in comparison to tacrine attached to the active sites of AChE and BChE. Molecular dynamics simulations were performed on the 10p-AChE and 10f-BChE complexes to gain deeper insights into the behavior of these compounds in the active sites of target enzymes.