In vivo anti-inflammatory activity and docking study of newly synthesized benzimidazole derivatives bearing oxadiazole and morpholine rings.

In search of potential therapeutics for inflammatory disease, we report herein the synthesis, characterization and anti-inflammatory activities of a new series of 1-{(5-substituted-1,3,4-oxadiazol-2-yl)methyl}-2-(morpholinomethyl)-1H-benzimidazoles (5a-r). The anti-inflammatory activity of the compounds was evaluated using carrageenan induced rat paw edema test. Some compounds showed excellent anti-inflammatory activity in carrageenan induced rat paw edema test. 1-{(5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl)methyl}-2-(morpholinomethyl)-1H-benzimidazole (5g) showed maximum anti-inflammatory (74.17±1.28% inhibition) with reduced ulcerogenic and lipid peroxidation profile and also showed significant COX-2 inhibition with IC50 values of 8.00µM. Compounds 5o and 5q were also found to exhibit good COX-2 inhibition with IC50 values of 11.4 and 13.7µM concentrations. Molecular docking study showed that morpholine and oxadiazole rings linked to the benzimidazole nucleus play an important role in binding with the COX-2.

Designing, synthesis, and antimicrobial action of oxazoline and thiazoline derivatives of fatty acid esters.

In this study, a novel series of oxazoline and thiazoline were designed as inhibitors of cytochrome P450 14 alpha-sterol demethylase (CYP51) from Candida albicans and peptide deformylase (PDF) of Escherichia coli. The long chain dibromo derivative of fatty acid esters on reaction with urea and thiourea gave their corresponding oxazolines and thiazolines, respectively. All the compounds were characterized by their spectral data (IR, 1H NMR, 13C NMR and MS) and tested for antibacterial and antifungal activity by disk diffusion assay and minimum inhibitory concentration by the broth microdilution method against gram-positive and gram-negative strains of bacteria as well as fungus strains. The investigation into antimicrobial screening revealed that all the compounds were found to be potent antimicrobial agents. After calculating likeness drug properties of the compounds by Prediction of Activity Spectra for Substances software, ADMET-related descriptors were computed to predict the pharmacokinetic properties for the active and bioavailable compounds by discovery studio 2.5. Molecular docking studies have been performed on PDF of E. coli and CYP 450-14DM of C. albicans to understand the mode of binding of the molecules in the active site of the receptor. Compounds (2-amino-5-(carbomethoxyoctyl)-1,3-oxazoline, 2-amino-5-(carbomethoxyoctyl)-1,3-thiazoline and 2-amino-4-pentyl-5-[(8'R)-8' hydroxy (carbomethoxydecyl)-1,3-oxazoline) showed excellent antimicrobial activity nearly equivalent to the control compounds and compounds, 2-amino-4-octyl-5-(carbomethoxyheptyl)-1,3-oxazolin, 2-amino-4-(2'R)(2'-hydroxy octyl)-5-(carbomethoxyheptyl)-1,3-oxazoline and 2-amino-4-pentyl-5-[(8'R)-8'-hydroxy(carbomethoxy decyl)-1,3-oxazolineshowed vasodilation and antihypertensive properties. Furthermore, a computational analysis of physicochemical parameters revealed that the most of the compounds possessed drug-like attributes. Using Bioinformatics approach, we found a correlation between the observed and predicted antimicrobial activities.

Umbelliferone and esculetin protect against N-nitrosodiethylamine-induced hepatotoxicity in rats.

N-nitrosodiethylamine (NDEA), a nitrosamine compound, is known to cause liver damage through the generation of reactive oxygen species (ROS), resulting in oxidative damage to macromolecules such as DNA, and the consequent development of cancer. The present study examines the protective effects of two antioxidant coumarin compounds umbelliferone (Umb) and esculetin (Esc) against NDEA-induced hepatotoxicity when administered in the diet to male Wistar rats. The results show that treatment with Umb (0.5% w/w) and Esc (0.5% w/w) in the diet for 7 days significantly attenuates NDEA-induced liver damage, lowering serum alanine transaminase (ALT) levels, decreasing hepatic lipid peroxidation, and restoring total glutathione levels. To investigate the mechanism for the observed protective effect, the levels of the key protective enzymes NAD(P)H: quinone oxidoreductase 1 (NQO1), heme oxygenase (HO1), and glutathione S-transferase Pi (GSTP1) were measured by Western blotting following Umb and Esc administration. The results showed that Umb and Esc administration significantly increased the expression of NQO1 by 3.6- and 2.7-fold, HO1 by 2.7- and 3.2-fold, and GSTP1 by 2.8- and 3.2-fold, respectively. In conclusion, Umb and Esc are capable of protecting liver from NDEA-induced hepatotoxicity, and this is associated with the induction of protective enzymes.

Region specific mitochondrial impairment in mice with widespread overexpression of alpha-synuclein.

Parkinson's disease (PD) is characterized by the progressive degeneration of nigrostriatal dopaminergic neurons leading to motor deficits. The mechanisms underlying the preferential vulnerability of nigrostriatal dopaminergic neurons in PD remain poorly understood. Recent evidence supports a role for mitochondrial dysfunction and increased oxidative stress in PD pathogenesis. Genetic and pathological studies also point to alpha-synuclein as a critical factor in both familial and sporadic forms of the disease; alpha-synuclein pathology affects mitochondrial function but is widespread in PD brain, raising the question of its role in the greater vulnerability of nigrostriatal neurons in PD. We have examined mitochondrial function and oxidative damage in mice overexpressing human wild type alpha-synuclein broadly throughout the nervous system under the Thy1 promoter (Thy1-aSyn mice) between 4 and 8months of age. Similar levels of alpha-synuclein accumulation in mitochondria were detected in the ventral midbrain, striatum and cortex of Thy1-aSyn mice. However, analysis of mitochondrial respiration using Seahorse XF analyzer showed defects in mitochondrial respiratory complexes I, II, IV and V specifically in the midbrain, and IV and V in the striatum, of Thy1-aSyn mice compared to wild type littermates; mitochondrial complex I activity assay by ELISA confirmed a 40% inhibition specifically in the ventral midbrain. Mitochondrial dysfunction can contribute to oxidative stress and we observed a 40% increase in 4-hydroxynenal and 2-fold increase in malondialdehyde levels, indicative of a high level of lipid peroxidation, specifically in the ventral midbrain of Thy1-aSyn mice. The levels of peroxiredoxin 2, a neuronal antioxidant enzyme that is involved in removal of H2O2 and other toxic peroxides were decreased in the midbrain whereas its oxidized form increased 4-fold, suggesting that antioxidant defenses were compromised in this region. In contrast, peroxiredoxin 2 increased in the striatum and cortex, which may contribute to their protection in the presence of high levels of alpha-synuclein. Thus, in mice over-expressing alpha-synuclein, mitochondrial dysfunction occurred preferentially in nigrostriatal dopaminergic neurons many months before striatal dopamine loss occurs at 14months of age. This may contribute to a higher level of oxidative stress that overwhelms antioxidant defense in these neurons, leading to their increased vulnerability in PD.

Bacterial-induced expression of RAB18 protein in Orzya sativa salinity stress and insights into molecular interaction with GTP ligand.

In the present research, we have studied the inoculation effects of two root-associated plant growth-promoting rhizobacteria (PGPR) in rice and provide the pieces of evidence that the inoculation of the PGPR could potentially result in inducing the expression of the salt stress-related RAB18 plant gene under varying degrees of salinity stress. The sequenced putative gene of RAB18 of Oryza sativa in this study is 740 bp long, has a content of 44.4%, and a molecular weight of 492 102.00 Da. BLAST homology patterns revealed sequence similarity with the previously sequenced RAB in model plant species. We demonstrate the mode of action of this stress-related protein by performing comparative modeling of Q10RT8 (Os03g0146000 protein, homolog of the sequenced RAB18; O. sativa subsp. japonica) using energy minimization, molecular dynamic simulations, and molecular docking of a guanosine triphosphate (GTP) ligand with the protein. The docking results indicated that Ser21, Ala22, Lys25, Asp68, Ala70, Glu73, and Arg74 are important determinant residues for functional interaction with the GTP ligand. The present research contributes to the understanding of the PGPR inoculation in salinity stress. Additionally, it provides the layout of the understanding of the molecular interactions between RAB and GTP ligand.

Mitochondrial dysfunction and oxidative stress in Parkinson's disease.

Parkinson's disease (PD) is a movement disorder that is characterized by the progressive degeneration of dopaminergic neurons in substantia nigra pars compacta resulting in dopamine deficiency in the striatum. Although majority of the PD cases are sporadic several genetic mutations have also been linked to the disease thus providing new opportunities to study the pathology of the illness. Studies in humans and various animal models of PD reveal that mitochondrial dysfunction might be a defect that occurs early in PD pathogenesis and appears to be a widespread feature in both sporadic and monogenic forms of PD. The general mitochondrial abnormalities linked with the disease include mitochondrial electron transport chain impairment, alterations in mitochondrial morphology and dynamics, mitochondrial DNA mutations and anomaly in calcium homeostasis. Mitochondria are vital organelles with multiple functions and their dysfunction can lead to a decline in energy production, generation of reactive oxygen species and induction of stress-induced apoptosis. In this review, we give an outline of mitochondrial functions that are affected in the pathogenesis of sporadic and familial PD, and hence provide insights that might be valuable for focused future research to exploit possible mitochondrial targets for neuroprotective interventions in PD.