Synthesis, SAR study, and biological evaluation of novel 2,3-dihydro-1H-imidazo[1,2-a]benzimidazole derivatives as phosphodiesterase 10A inhibitors

Chino, Ayaka; Honda, Shugo; Morita, Masataka; Yonezawa, Koichi; Hamaguchi, Wataru; Amano, Y.; Moriguchi, Hiroyuki; Yamazaki, Mayako; Aota, Masaki; Tomishima, Masaki; Masuda, Naoyuki

doi:10.1016/j.bmc.2019.07.010

Cited by 7 publications

(4 citation statements)

References 38 publications

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“…Benzimidazole acetamide derivatives treatment reversed the memory impairment in ethanol-treated rats and improved memory via reduced escape latency time during trial session, increased number of platform crossings and more time spent in the target quadrant during the probe test, and increased spontaneous alteration behavior % in the Y-maze task (Figure A–E). Our study is consistent with previous data, suggesting that benzimidazole derivatives could attenuate neuroinflammation and memory impairment. , …”

Section: Resultssupporting

confidence: 94%

“…Our study is consistent with previous data, suggesting that benzimidazole derivatives could attenuate neuroinflammation and memory impairment. 65,66 The neurotoxicity in AD includes several morphological anomalies, molecular lesions, synaptic dysfunctioning, and abundance of misfolded proteins in the aging brain that subsequently result in proinflammatory cytokines release and oxidative stress. Considering the fact, inhibition of neurotoxicity through controlling inflammation and oxidative stress would be a promising strategy.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis and Biological Evaluation of Benzimidazole Derivatives as Potential Neuroprotective Agents in an Ethanol-Induced Rodent Model

Imran

Shah

Nadeem

et al. 2021

ACS Chem. Neurosci.

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Alzheimer's disease (AD) is the most devastating and progressive neurodegenerative disease in middle to elder aged people, which can be exacerbated by lifestyle factors. Recent longitudinal studies demonstrated that alcohol consumption exacerbates memory impairments in adults. However, the underlying mechanism of alcohol-induced memory impairment is still elusive. The increased cellular manifestation of reactive oxygen species (ROS) and the production of numerous proinflammatory markers play a critical role in the neurodegeneration and pathogenesis of AD. Therefore, reducing neurodegeneration by decreasing oxidative stress and neuroinflammation may provide a potential therapeutic roadmap for the treatment of AD. In this study, eight new benzimidazole acetamide derivatives (FP1, FP2, FP5−FP10) were synthesized and characterized to investigate its neuroprotective effects in ethanol-induced neurodegeneration in a rat model. Further, three derivatives (FP1, FP7, and FP8) were selected for in vivo molecular analysis based on preliminary in vitro antioxidant screening assay. Molecular docking analysis was performed to assess the affinity of synthesized benzimidazole acetamide derivatives against selected proinflammatory targets (TNF-α, IL-6). Biochemical analysis revealed elevated expression of neuroinflammatory markers (TNF-α, NF-κB, IL-6, NLRP3), increased cellular oxidative stress, and reduced antioxidant enzymes in ethanol-exposed rats brain. Notably, pretreatment with new benzimidazole acetamide derivatives (FP1, FP7, and FP8) significantly modulated the ethanol-induced memory deficits, oxidative stress, and proinflammatory markers (TNF-α, NF-κB, IL-6, NLRP3) in the cortex. The multipurpose nature of acetamide containing benzimidazole nucleus and its versatile affinity toward numerous receptors highlight its multistep targeting potential. These results indicated the neuroprotective potential of benzimidazole acetamide derivatives (FP1, FP7, and FP8) as novel therapeutic candidates in ethanol-induced neurodegeneration which may partially be due to inhibition of the neuroinflammatory−oxidative stress vicious cycle.

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Section: Resultssupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Evaluation of Benzimidazole Derivatives as Potential Neuroprotective Agents in an Ethanol-Induced Rodent Model

Imran

Shah

Nadeem

et al. 2021

ACS Chem. Neurosci.

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“…Based on the inclusion criteria, 11 diverse compounds with IC50 for PDE1B ranging from 0.06 nM to 70 nM as well as 29 molecules with IC50 of 0.008 nM to 64 nM for PDE10A were chosen as the training set. [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64] The remaining 8 PDE1B and 9 PDE10A inhibitors obtained which were structurally diverse chemical compounds from the training set served as the test set to assess the predictive ability of the resultant pharmacophore. By using the merged feature pharmacophore generation method, a total of 10 pharmacophore models were synthesized for both targets, where the models with the highest t score were selected.…”

Section: Design Of Novel Selective Pde1b and Pde10a Inhibitorsmentioning

confidence: 99%

New Dual PDE1B and PDE10A Inhibitors Identified via Ligand-Based Pharmacophore Modelling and Virtual Screening

Soon

Gaurav

Gautam

2023

Preprint

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Context Schizophrenia is a chronic neuropsychiatric disorder affecting over 1% of the world population. Current antipsychotic therapy shows inadequacy in mitigating the negative and cognitive symptoms, besides causing undesirable extrapyramidal side effects. Inhibition of PDE1B and PDE10A simultaneously can mitigate positive, negative, and cognitive symptoms. Thus, this study was aimed at identifying new dual PDE1B and PDE10A inhibitors using ligand-based pharmacophore modelling, virtual screening, and molecular docking. Pharmacophore models for PDE1B and PDE10A produced Gunner-Henry (GH) scores of 0.83 and 0.71, respectively. Pharmacophore model based virtual screening and molecular docking led to the identification of UNPD167314 as the lead compound with good binding affinity for PDE1B (-8.4 kcal/mol) and PDE10A (-9.7 kcal/mol). The binding interactions include hydrophobic interactions with P-clamp and hydrogen bonding with invariant glutamine. Structural modifications resulted in the design of 51 novel inhibitors, with compound 18 exhibiting the highest binding affinity for both PDE1B (-10.6 kcal/mol) and PDE10A (-11.7 kcal/mol) following substitution of tertbutyl at R1, hydroxyl at R2, and carboxyl at R3. Methods LigandScout 4.4.8 was used to generate, validate, and refine the ligand-based pharmacophore models for PDE1B and PDE10A, followed by sequential virtual screening of the Universal Natural Products Database. The hits were screened further using DruLiTo software to ensure BBB penetration. Pan Assay Interference Compounds were removed using PAINS-Remover server. SwissADME and PreADMET were used to deduce pharmacokinetic parameters of the screened compounds. Finally, Molecular docking and visualization of the dual hits were performed using Autodock Vina 1.2.0, followed by structural modifications to improve interaction affinity.

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“…Several studies use MK-801 to induce working memory deficits, in many cases seeking to analyze whether or not this situation could be reversed by test drugs. In these cases, the group that receives only MK-801 constitutes the positive control group of the experiments (Brown et al, 2013;Lainiola et al, 2014;Zemanova et al, 2013;Ohno and Watanabe, 1995;Chino et al, 2019;Shiraishi et al, 2016;Rosenbrock et al, 2019).…”

Section: Y-maze Testmentioning

confidence: 99%

Effects of ortho-eugenol on anxiety, working memory and oxidative stress in mice

Godoy,

Macedo,

Gervazio

et al. 2023

Braz. J. Biol.

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Ortho-eugenol is a synthetic derivative from eugenol, the major compound of clove essential oil, which has demonstrated antidepressant and antinociceptive effects in pioneering studies. Additionally, its effects appear to be dependent on the noradrenergic and dopaminergic systems. Depression and anxiety disorders are known to share a great overlap in their pathophysiology, and many drugs are effective in the treatment of both diseases. Furthermore, high levels of anxiety are related to working memory deficits and increased oxidative stress. Thus, in this study we investigated the effects of acute treatment of ortho-eugenol, at 50, 75 and 100 mg/kg, on anxiety, working memory and oxidative stress in male Swiss mice. Our results show that the 100 mg/kg dose increased the number of head-dips and reduced the latency in the hole-board test. The 50 mg/kg dose reduced malondialdehyde levels in the prefrontal cortex and the number of Y-maze entries compared to the MK-801-induced hyperlocomotion group. All doses reduced nitrite levels in the hippocampus. It was also possible to assess a statistical correlation between the reduction of oxidative stress and hyperlocomotion after the administration of ortho-eugenol. However, acute treatment was not able to prevent working memory deficits. Therefore, the present study shows that ortho-eugenol has an anxiolytic and antioxidant effect, and was able to prevent substance-induced hyperlocomotion. Our results contribute to the elucidation of the pharmacological profile of ortho-eugenol, as well as to direct further studies that seek to investigate its possible clinical applications.

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Synthesis, SAR study, and biological evaluation of novel 2,3-dihydro-1H-imidazo[1,2-a]benzimidazole derivatives as phosphodiesterase 10A inhibitors

Cited by 7 publications

References 38 publications

Synthesis and Biological Evaluation of Benzimidazole Derivatives as Potential Neuroprotective Agents in an Ethanol-Induced Rodent Model

Synthesis and Biological Evaluation of Benzimidazole Derivatives as Potential Neuroprotective Agents in an Ethanol-Induced Rodent Model

New Dual PDE1B and PDE10A Inhibitors Identified via Ligand-Based Pharmacophore Modelling and Virtual Screening

Effects of ortho-eugenol on anxiety, working memory and oxidative stress in mice

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