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Backgound: Alzheimer disease (AD) is a disastrous disease characterized by accretion of amyloid-beta plaques, neurofibrillary tangles inducing oxidative stress, loss of neuronal functions and continuous progression of cognitive impairment leading to severe dementia. Material and Methods: The newly synthesized benzimidazole derivative 4-chloro-3-(2-phenyl-1H-benzimidazole-1-sulfonyl) benzoic acid (CB) was evaluated for its anti-Alzheimer activity using in silico, in vivo, in vitro and molecular techniques (ELISA, WB & IHC). Results:In-silico studies revealed that CB has atomic contact energy values of −3.9 to −8.9 kcal/mol against selected targets. In vitro assay showed that CB caused acetylcholinesterase (AChE) and diphenyl-1-picrylhydrazyl inhibition. In-vivo findings revealed improvement in dementia as observed in the morris water maze test and Ymaze test. Amyloid-beta disaggregation, increased level of anti-oxidants, decreased expressions of inflammatory markers and enhanced cellular architecture were found in the cortex and hippocampus of treated rats in the histopathological examination, immunohistochemistry analysis, enzyme-linked immunosorbent assay and western blot analysis. Conclusions: This study revealed that CB possess different binding affinities with the Alzheimer-related targets and it possess anti-Alzheimer activity, mediated via AChE and amyloid-beta inhibition, anti-oxidant and anti-inflammatory pathways.

Additional file 1: Figure S1. (A) and (B) represents 2D-interactions of 2E,2′E) dibutylstannanediyl bis(4-(4-nitrophenyl)amino)-4-oxobut-2-enoate (DTN) and omeprazole with hydrogen potassium atipase pump (H+/K+-ATPase) evaluated through Biovia Discovery Studio Visualizer (DSV) 2016. Figure S2. (A) and (B) represents 2D-interactions of 2E,2′E) dibutylstannanediyl bis(4-(4-nitrophenyl)amino)-4-oxobut-2-enoate (DTN) and phenoxy benzamine with muscarinic receptor (M1) respectively, evaluated through Biovia Discovery Studio Visualizer (DSV) 2016. Figure S3. (A) and (B) represents 2D-interactions of 2E,2′E) dibutylstannanediyl bis(4-(4- nitrophenyl)amino)-4-oxobut-2-enoate (DTN) and ranitidine with histamine receptor (H2) respectively, evaluated through Biovia Discovery Studio Visualizer (DSV) 2016. Figure S4. (A) and (B) represents 2D-interactions of 2E,2′E) dibutylstannanediyl bis(4-(4- nitrophenyl)amino)-4-oxobut-2-enoate (DTN) and aspirin with cyclooxiginase-1 (COX1) respectively, evaluated through Biovia Discovery Studio Visualizer (DSV) 2016. Figure S5. (A) and (B) represents 2D-interactions of 2E,2′E) dibutylstannanediyl bis(4-(4-nitrophenyl)amino)-4-oxobut-2-enoate (DTN) and meclofenamate with cyclooxiginase-2 (COX2) respectively, evaluated through Biovia Discovery Studio Visualizer (DSV) 2016. Figure S6. (A) and (B) represents 2D-interactions of 2E,2′E) dibutylstannanediyl bis(4-(4-nitrophenyl)amino)-4-oxobut-2-enoate (DTN) and dinopristone with prostaglandin-E2 (PGE2) respectively, evaluated through Biovia Discovery Studio Visualizer (DSV) 2016. Figure S7. (A) and (B) represents 2D-interactions of 2E,2′E) dibutylstannanediyl bis(4-(4- nitrophenyl)amino)-4-oxobut-2-enoate (DTN) and curcumin with nuclear factor kappa B (NFĸB) respectively, evaluated through Biovia Discovery Studio Visualizer (DSV) 2016. Figure S8. (A) and (B) represents 2D-interactions of 2E,2′E) dibutylstannanediyl bis(4-(4-nitrophenyl)amino)-4-oxobut-2-enoate (DTN) and aspirin with tumor necrosis factor alpha (TNF- α) respectively, evaluated through Biovia Discovery Studio Visualizer (DSV) 2016. Figure S1A. (A) and (B) represents 2D-interactions of 2E,2′E) dibutylstannanediyl bis(4-(4-nitrophenyl)amino)-4-oxobut-2-enoate (DTN) and Omeprazole with hydrogen potassium ATPase (H+/K+-ATPase) evaluated through Biovia Discovery Studio Visualizer (DSV) 2016. Figure S2A. (A) and (B) represents 2D-interactions of 2E,2′E) dibutylstannanediyl bis(4-(4-nitrophenyl)amino)-4-oxobut-2-enoate (DTN) and Phenoxy-benzamine with Muscarinic receptor (M1) evaluated through Biovia Discovery Studio Visualizer (DSV) 2016. Figure S3A. (A) and (B) represents 2D-interactions of 2E,2′E) dibutylstannanediyl bis(4-(4-nitrophenyl)amino)-4-oxobut-2-enoate (DTN) and Ranitidine with histaminergic receptor (H2), evaluated through Biovia Discovery Studio Visualizer (DSV) 2016. Figure S4A. (A) and (B) represents 2D-interactions of 2E,2′E) dibutylstannanediyl bis(4-(4-nitrophenyl)amino)-4-oxobut-2-enoate (DTN) and Aspirin with cyclooxygenase-1 (COX1), evaluated through Biovia Discovery Studio Visualizer (DSV) 2016. Figure S5A. (A) and (B) represents 2D-interactions of 2E,2′E) dibutylstannanediyl bis(4-(4-nitrophenyl)amino)-4-oxobut-2-enoate (DTN) and Meclofinamate with cyclooxygenase-2 (COX2) evaluated through Biovia Discovery Studio Visualizer (DSV) 2016. Figure S6A. (A) and (B) represents 2D-interactions of 2E,2′E) dibutylstannanediyl bis(4-(4-nitrophenyl) amino)-4-oxobut-2-enoate (DTN) and Dinopristone with prostaglandin-E2 (PGE2), evaluated through Biovia Discovery Studio Visualizer (DSV) 2016. Figure S7A. (A) and (B) represents 2D-interactions of 2E,2′E) dibutylstannanediyl bis(4-(4-nitrophenyl)amino)-4-oxobut-2-enoate (DTN) and Curcumin with Nuclear Factor kappa-B (NFκB) evaluated through Biovia Discovery Studio Visualizer (DSV) 2016. Figure S8A. (A) and (B) represents 2D-interactions of 2E,2′E) dibutylstannanediyl bis(4-(4-nitrophenyl) amino)-4-oxobut-2-enoate (DTN) and aspirin with Tumor necrosis factor alpha (TNF-α) evaluated through Biovia Discovery Studio Visualizer (DSV) 2016.

Lina T Al Kury,1 Alam Zeb,2 Zain Ul Abidin,2 Nadeem Irshad,3 Imran Malik,2 Arooj Mohsin Alvi,2 Atif Ali Khan Khalil,4 Sareer Ahmad,4 Muhammad Faheem,2 Arif-Ullah Khan,2 Fawad Ali Shah,2 Shupeng Li51College of Natural and Health Sciences, Zayed University, Abu Dhabi, United Arab Emirates; 2Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan; 3Department of Pharmacy, Quaid-I-Azam University, Islamabad, Pakistan; 4Rehman Medical Institute, Peshawar, Pakistan; 5State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, People’s Republic of ChinaPurpose: Melatonin and celecoxib are antioxidants and anti-inflammatory agents that exert protective effects in different experimental models. In this study, the neuroprotective effects of melatonin and celecoxib were demonstrated against ethanol-induced neuronal injury by in silico, morphological, and biochemical approaches.Methods: For the in silico study, 3-D structures were constructed and docking analysis performed. For in vivo studies, rats were treated with ethanol, melatonin, and celecoxib. Brain samples were collected for biochemical and morphological analysis.Results: Homology modeling was performed to build 3-D structures for IL1β), TNFα, TLR4, and inducible nitric oxide synthase. Structural refinement was achieved via molecular dynamic simulation and processed for docking and postdocking analysis. Further in vivo experiments showed that ethanol induced marked neuronal injury characterized by downregulated glutathione, glutathione S-transferase, and upregulated inducible nitric oxide synthase. Additionally, ethanol increased the expression of TNFα and IL1β. Finally, neuronal apoptosis was demonstrated in ethanol-intoxicated animals using caspase 3 and activated JNK staining. On the other hand, melatonin and celecoxib treatment ameliorated the biochemical and immunohistochemical alterations induced by ethanol.Conclusion: These results demonstrated that ethanol induced neurodegeneration by activating inflammatory and apoptotic proteins in rat brain, while melatonin and celecoxib may protect rat brain by downregulating inflammatory and apoptotic markers.Keywords: simulation, docking, cortex, hippocampus, ethanol, neurodegeneration