Synthesis, in Vitro Cholinesterase Inhibition, Molecular Docking, DFT, and ADME Studies of Novel 1,3,4-Oxadiazole-2-Thiol Derivatives.

A series of 1,3,4-oxadiazole-2-thiol derivatives bearing various alkyl or aryl moieties were designed, synthesized, and characterized using modern spectroscopic methods to yield 17 compounds (6a-6q) that were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes in the search for 'lead' compounds for Alzheimer's disease treatment (AD). The compounds 6q, 6p, 6k, 6o, and 6l showed inhibitory capability against AChE and BChE, with IC50 values ranging from 11.73±0.49 to 27.36±0.29 µM for AChE and 21.83±0.39 to 39.43±0.44 µM for BChE, inhibiting both enzymes within a limited range. The SAR ascertained that the substitution of the aromatic moiety had a profound effect on the AChE and BChE inhibitory potential as compared to the aliphatic substitutions which were supported by the molecular docking studies. The drug-likeness of the most synthesized compounds was confirmed by in silico ADME investigations. These results were additionally supplemented by the molecular orbital analysis (HOMO-LUMO) and electrostatic potential maps got from DFT calculations. ESP maps expose that on all structures, there are two potential binding sites conquered by the most positive and most negative districts.

Antioxidant Supplements and Gastrointestinal Diseases: A Critical Appraisal.

The gastrointestinal tract digests and absorbs dietary nutrients, protects the body against physical and chemical damage from contents in its lumen, provides immunity against external antigens, and keeps an optimum environment for the gut microbiota. These functions cannot be performed normally in several diseases of which the following are discussed here: irritable bowel syndrome and inflammatory bowel disease, which includes Crohn's disease and ulcerative colitis. Because these diseases are associated with oxidative stress, a host of antioxidant supplements are used for maintenance and recovery of the gut functions. However, the benefits of these supplements have not been established. The available 80 human trials were rated for levels of confidence and for benefits of the antioxidant supplements. For Crohn's disease, the supplements for which clear benefits occurred in at least 2 studies were allopurinol, Boswellia serrata (frankincense or shallaki), Artemesia species (wormwood), Tripterygium wilfordii (léi gong téng), and omega-3 fatty acids. Similar beneficial supplements for ulcerative colitis were allopurinol, Matricaria chamomilla (chamomile), Curcuma longa (curcumin in turmeric), and omega-3 fatty acids. There was also a clear benefit for ulcerative colitis in 2 studies where a multiherbal Chinese medicine preparation and an Ayurvedic medicine preparation were used. For irritable bowel syndrome, there was only a marginal benefit of some of the antioxidant supplements. Thus, some antioxidant supplements may be beneficial at certain stages of specific diseases. This is consistent with the current concept that antioxidants act by inhibiting oxidative stress pathways in a tissue- and environment-specific manner and not by simply acting as scavengers.

SENSITIVITY PATTERNS OF PSEUDOMONAS AERUGINOSA ISOLATES OBTAINED FROM CLINICAL SPECIMENS IN PESHAWAR.

BACKGROUND: Pseudomonas aeruginosa (P. aeruginosa) is a highly virulent opportunistic pathogen and a leading cause of nosocomial infections. Affected patients are often hospitalized in an intensive care unit, and are immuno-compromised as a result of disease and treatment. Suspected P. aeruginosa require timely, adequate and empirical antibiotic therapy to ensure improved outcomes. The purpose of the study was to find the sensitivity and resistance pattern of P. aeruginosa to various groups of drugs, in clinical isolates collected from two major tertiary care hospitals of Peshawar. METHODS: Different clinical isolate were taken from patients admitted in various wards of Khyber Teaching Hospital and Lady Reading Hospital Peshawar. RESULTS: A total of 258 clinical isolates were positive for P. aeruginosa out of 2058 clinical isolates. Pseudomonas showed high degree of resistance to third generation Cephalosporins (Ceftazidime, and Ceftriaxone) and moderate degree of resistance to Quinolones and Aminoglycosides (Ofloxacin, Ciprofloxacin, Levofloxacin and Amikacin). Low resistance was observed to different combinations (Cefoperazone+Sulbactum, Piperacillin+Tazobactum). Meropenem and Imipenem had negligible resistance. CONCLUSION: There is growing resistance to different classes of antibiotics. Combination drugs are useful approach for empirical treatment in suspected Pseudomonas infection. Imipenem and Meropenem are extremely effective but should be in reserve.

Suppression of Na+/H+ exchanger isoform-3 in human inflammatory bowel disease: lack of reversal by 5'-aminosalicylate treatment.

OBJECTIVE: Na+/H+ exchanger isoform 3 (NHE-3) is responsible for net uptake of NaCl and water from the gastrointestinal (GI) tract. However, its status in human inflammatory bowel diseases (IBDs) such as ulcerative colitis(UC) and Crohn's disease (CD) remains poorly understood. The aim of this study was to investigate the underlying mechanism of NHE-3 isoform expression and its modulation by 5'-aminosalicylate in human CD and UC. MATERIAL AND METHODS: Subjects were divided into three groups: 1) controls; 2) untreated/new IBD cases (n = 13) and 3) 5'-aminosalicylate-treated IBD patients (n = 13). Subjects presenting with abdominal pain but with endoscopically normal colons served as normal controls. Inflammation was confirmed by the level of myeloperoxidase (MPO) activity, malondialdehyde (MDA) concentrations and by histologic evaluation. Expressions of NHE-3 protein and mRNA, sodium pump activity and IL-1beta and TNF-alpha mRNA were estimated in the colonic biopsies using ECL-Western blot analysis,reverse transcription-polymerase chain reaction (RT-PCR) and enzyme assays. RESULTS: The level of NHE-3 protein and sodium pump activity was reduced (p < 0.05) in both the untreated and treated CD and UC patients. NHE-3 mRNA was reduced only in CD patients but not in those with UC. The treatment reversed the symptoms, but levels of MPO activity, MDA concentration, IL-1beta, TNF-alpha and infiltration of inflammatory cells remained high with the exception of IL-1beta mRNA in the treated patients. CONCLUSIONS: NHE-3 suppression is regulated differentially in CD and UC, which together with suppression of sodium pump activity will reduce NaCl and water uptake from the colonic lumen. These findings suggest a role of TNF-a in the regulation of NHE-3 expression in IBD.