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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. [ABSTRACT FROM AUTHOR]

Hyperlipidemia is worth‐mentioning risk factor in quickly expanding atherosclerosis, myocardial infarction, and stroke. This study attempted to determine effectiveness of selected pyrimidine derivatives: 5‐(3‐Hydroxybenzylidene)‐2, 4, 6(1H, 3H, 5H)‐pyrimidinetrione (SR‐5), 5‐(4‐Hydroxybenzylidene)‐2, 4, 6(1H, 3H, 5H)‐pyrimidinetrione (SR‐8), 5‐(3‐Chlorobenzylidene)‐2, 4, 6(1H, 3H, 5H)‐pyrimidinetrione (SR‐9), and 5‐(4‐Chlorobenzylidene)‐2, 4, 6(1H, 3H, 5H)‐pyrimidinetrione (SR‐10) against hyperlipidemia. Insilico results revealed that SR‐5, SR‐8, SR‐9, and SR‐10 exhibited high affinity with 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMGCoA) possessing binding energy values of −8.2, −8.4, −8.6, and −9.5 Kcal/mol, respectively, and moderate (<−8 Kcal/mol) against other selected targets. Invivo findings showed that test drugs (25 and 50 mg/Kg) significantly decreased HFD rat total cholesterol, triglycerides, low‐density lipoprotein, very‐low‐density lipoprotein, atherogenic index, coronary risk index, alkaline phosphatase, aspartate transaminase, alanine transaminase, and bilirubin and increased high‐density lipoprotein (p < 0.05, p < 0.01, p < 0.001 vs HFD group). In animal liver tissues, SR‐5, SR‐8, SR‐9, and SR‐10 inhibited HMGCoA reductase enzyme, enhanced glutathione‐s‐transferase, reduced glutathione, catalase levels, improved cellular architecture in histopathological examination, and decreased expression of inflammatory markers: cyclo‐oxygenase 2, tumor necrosis factor alpha, phosphorylated c‐Jun N‐terminal kinase, and phosphorylated‐nuclear factor kappa B, evidenced in immunohistochemistry and enzyme‐linked immunosorbent assay molecular investigations. This study indicates that SR‐5, SR‐8, SR‐9, and SR‐10 exhibit antihyperlipidemic action, mediated possibly through HMGCoA inhibition, hepatoprotection, antioxidant, and anti‐inflammatory pathways. [ABSTRACT FROM AUTHOR]

This study was designed to determine the effectiveness of 5-(3-Hydroxybenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-5), 5-(4-Hydroxybenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-8), 5-(3-Chlorobenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-9) and 5-(4-Chlorobenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-10) against hypertension. In deoxycorticosterone acetate-salt rats, SR-5, SR-8, SR-9, and SR-10 reduced blood pressure and normalized renal functions. In isolated rat aortic rings, SR-5, SR-8, SR-9, and SR-10 relaxed phenylephrine (PE) and K+-induced contractions. The vasodilator effect was endothelium-independent. Test compounds caused a rightward shift of Ca++ and PE concentration-response curves with a reduction of maximum response. SR-5, SR-8, SR-9, and SR-10 inhibited PE peak contractions in a Ca++ free medium. In guinea-pig atria, SR5, SR-8, SR-9, and SR-10 caused a mild-to-moderate inhibition of force and rate of contractions. In the aorta and heart tissues, the test compounds enhanced glutathione-s-transferase, reduced glutathione and catalase levels, improved cellular architecture, and decreased lipid peroxidation and expression of inflammatory markers: cyclooxygenase 2, tumor necrosis factor alpha, phosphorylated c-Jun N-terminal kinase, and phosphorylated-nuclear factor kappa B, evidenced in the immunohistochemistry, enzyme-linked immunosorbent assay, western blot molecular investigations and a decreased mRNA expression of calcium channel in RT-PCR analysis. SR-5, SR-8, SR-9, and SR-10 increased the urinary output in rats and inhibited the human platelet aggregation. This study revealed that SR-5, SR-8, SR-9, and SR-10 possess BP lowering, reno-protective, vasodilatory (mediated via Ca++ antagonist, antioxidant and anti-inflammatory pathways), partial cardio-suppressant, diuretic, and antiplatelet effects, demonstrating their therapeutic potential in hypertension management. [Display omitted] • SR-5, SR-8, SR-9 and SR-10 exhibits L-type calcium channel blockade activity. • SR-5, SR-8, SR-9 and SR-10 improved histological parameters compared to DOCA-salt group. • SR-5, SR-8, SR-9 and SR-10 showed significant reduction in oxidative stress and enhanced the anti-oxidants enzymes. • The SR-5, SR-8, SR-9 and SR-10 markedly attenuated COX 2 , p-JNK, p-NFkB and TNF-α proteins expression. [ABSTRACT FROM AUTHOR]