Novel multi-targeted agents for Alzheimer's disease: Synthesis, biological evaluation, and molecular modeling of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazoles

Özadali-Sari, Keriman; Küçükkılınç, Tuba Tüylü; Ayazgök, Beyza; Balkan, Ayla; Tan, Oya Ünsal

doi:10.1016/j.bioorg.2017.04.018

Cited by 34 publications

(16 citation statements)

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“…Introduction of the hydrophobic substituent (-Cl, -Me, -CF 3 ) as well as -OMe on the heterocyclic ring or -Cl in the aryl moiety enhances biological activity of analogs in comparison to the unsubstituted bib-1,3-diol. The activity of compounds with the ethyl ester group is moderate (8)(9)(10) and it deteriorates with the addition of the hydroxyl substituent. On the other hand, taking into account the values of the calculated descriptors (Table 5), the low tPSA as well as MR favor the activity.…”

Section: Sar Studiesmentioning

confidence: 99%

“…Moderate BuChE inhibitors were found in a group of 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazoles. The most active compounds showed an inhibitory effect on the self-mediated amyloid β-peptide(1-40) (Aβ(1-40)) aggregation [8].…”

Section: Introductionmentioning

confidence: 99%

“…Most of the mentioned compounds are the multitargeted agents: carbonic anhydrase inhibitors [11], antioxidants [7], interrupters of cell cycle [9], Fe 2+ ion chelators [11]. Some of them show anticancer potency [9,15] or neuroprotective properties [8]. Benzimidazole derivatives are also known as β-glucuronidase [16,17], α-glucosidase [18,19], urease [20], and α-amylase enzymes inhibitors [21].…”

Section: Introductionmentioning

confidence: 99%

“…Yield: 84%; m.p. : 340-341 • C; EI MS (m/z, %): 260 (M + , 100), 231(6), 197(17), 169(25), 143(5), 116(6), 92(5), 69 (4), 65(7), 63(5), 52 (3), 36(17);1 H NMR (500 MHz, DMSO-d 6 ) δ: 14.12 (s, 1H, NH), 11.46 (s, 1H, C(3)-OH), 10.44 (s, 1H, C(1)-OH),8.27 (s, 1H, C(5)-H), 7.80 (m, 2H, C(4 ,7 )-H), 7.49 (m, 2H, C(5 ,6 )-H), 7.03 (s, 1H, C(2)-H) ppm;13 C NMR (125 MHz, DMSO-d 6 ) δ: 161.1, 157.3, 152.3, 140.3 (2C), 129.3, 123.2 (2C), 114.8 (2C), 112.6, 111.9, 103.1 ppm; IR (KBr, cm −1 ): 3281 (OH), 3051 (C-H), 1608 (C=N), 1572 (C=N), 1518 (C=C), 1503 (C=C), 1460, 1403, 1390, 1344, 1308, 1285, 1243, 1229 (C-OH), 1215, 1153, 1098, 1041, 1003, 951, 895, 849, 816, 779, 757, 737, 704. Anal.…”

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confidence: 99%

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Biological Evaluation, Molecular Docking, and SAR Studies of Novel 2-(2,4-Dihydroxyphenyl)-1H- Benzimidazole Analogues

et al. 2019

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In the present study, new 4-(1H-benzimidazol-2-yl)-benzene-1,3-diols, modified in both rings, have been synthesized and their efficacies as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors have been determined.The modified Ellman's spectrophotometric method was applied for the biological evaluation. The compounds showed strong (IC 50 80-90 nM) AChE and moderate (IC 50 5-0.2 µM) BuChE inhibition in vitro. Some compounds were effective toward AChE/BuChE, exhibiting high selectivity ratios versus BuChE, while the other compounds were active against both enzymes. The structure-activity relationships were discussed. The compounds inhibited also in vitro self-induced Aβ(1-42) aggregation and exhibited antioxidant properties. The docking simulations showed that the benzimidazoles under consideration interact mainly with the catalytic site of AChE and mimic the binding mode of tacrine.

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Section: Sar Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Biological Evaluation, Molecular Docking, and SAR Studies of Novel 2-(2,4-Dihydroxyphenyl)-1H- Benzimidazole Analogues

et al. 2019

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“…In particular, 2-arylbenzimidazole derivatives were evaluated as inhibitors of c-Jun N-terminal kinase 3 (JNK3) in the treatment of neurodegenerative symptoms [6,7]. In addition, a novel cholinesterase (ChE) inhibitor with 2-arylbenzoimidazoles skeleton was helpful in reversing the memory impairments associated with Alzheimer's disease [8]. 2-arylbenzimidazole derivatives also inhibited the increase of inducible nitric oxide synthase (iNOS) when peripheral nerve injury occurred (Figure 1) [9].…”

Section: Introductionmentioning

confidence: 99%

Copper-Catalyzed Synthesis, Bio-Evaluation, and in Silico Studies of 2-Aryl-N-alkylbenzimidazoles as Neuroprotective Agents

et al. 2018

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2-aryl-N-alkylbenzimidazole derivatives synthesized by CuI/PPh3 promoted direct coupling of N-alkylbenzimidazoles with aryl bromides. In vitro neurotoxicities of 20 compounds were evaluated, and the neuroprotective abilities of low-neurotoxic compounds (3b, 3g, 3h, 3i, 3j, 3k, 3o, 3q, 3s and 3t) were investigated against toxicity induced by 1-methyl-4-phenylpyridinium ion (MPP+) in SH-SY5Y neuronal cells. In silico studies revealed that compound 3g could have molecule docking with the following proteins: the bone morphogenetic protein receptor type 1B (BMPR1B), human cytochrome P450 1B1(CYP1B1), Metabotropic glutamate receptor 7 (GRM7), histone deacetylase 6 (HDAC6), 5-hydroxytryptamine receptor 5A (HTR5A), human topoisomerase II beta (TOP2B). A molecular docking simulation of model compound 3g and model protein CYP1B1 has been shown.

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Multifunctional cholinesterase inhibitors for Alzheimer's disease: Synthesis, biological evaluations, and docking studies of o/p‐propoxyphenylsubstituted‐1H‐benzimidazole derivatives

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Parlar

et al. 2018

Archiv der Pharmazie

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This study indicates the synthesis, cholinesterase (ChE) inhibitory activity, and molecular modeling studies of 48 compounds as o- and p-(3-substitutedethoxyphenyl)-1H-benzimidazole derivatives. According to the ChE inhibitor activity results, generally, para series are more active against acetylcholinesterase (AChE) whereas ortho series are more active against butyrylcholinesterase (BuChE). The most active compounds against AChE and BuChE are compounds A12 and B14 with IC values of 0.14 and 0.22 μM, respectively. Additionally, the most active 16 compounds against AChE/BuChE were chosen to investigate the neuroprotective effects, and the results indicated that most of the compounds have free radical scavenging properties and show their effects by reducing free radical production; moreover, some of the compounds significantly increased the viability of SH-SY5Y cells exposed to H O . Overall, compounds A12 and B14 with potential AChE and BuChE inhibitory activities, high neuroprotection against H O -induced toxicity, free radical scavenging properties, and metal chelating abilities may be considered as lead molecules for the development of multi-target-directed ligands against Alzheimer's disease.

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Novel multi-targeted agents for Alzheimer's disease: Synthesis, biological evaluation, and molecular modeling of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazoles

Cited by 34 publications

References 38 publications

Biological Evaluation, Molecular Docking, and SAR Studies of Novel 2-(2,4-Dihydroxyphenyl)-1H- Benzimidazole Analogues

Biological Evaluation, Molecular Docking, and SAR Studies of Novel 2-(2,4-Dihydroxyphenyl)-1H- Benzimidazole Analogues

Copper-Catalyzed Synthesis, Bio-Evaluation, and in Silico Studies of 2-Aryl-N-alkylbenzimidazoles as Neuroprotective Agents

Multifunctional cholinesterase inhibitors for Alzheimer's disease: Synthesis, biological evaluations, and docking studies of o/p‐propoxyphenylsubstituted‐1H‐benzimidazole derivatives

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