Hybridization-based design of novel anticholinesterase indanone-carbamates for Alzheimer's disease: Synthesis, biological evaluation, and docking studies.

Inspired by the structures of donepezil and rivastigmine, a novel series of indanone-carbamate hybrids was synthesized using the pharmacophore hybridization-based design strategy, and their biological activities toward acetylcholinesterase (AChE) and butyrylcholinesterase were evaluated. Among the synthesized compounds, 4d and 4b showed the highest AChE inhibitory activities with IC50 values in the micromolar range (compound 4d: IC50 = 3.04 µM; compound 4b: IC50 = 4.64 µM). Moreover, the results of the Aß1-40 aggregation assay revealed that compound 4b is a potent Aß1-40 aggregation inhibitor. The kinetics of AChE enzymatic activity in the presence of 4b was investigated, and the results were indicative of a reversible partial noncompetitive type of inhibition. A molecular docking study was conducted to determine the possible allosteric binding mode of 4b with the enzyme. The allosteric nature of AChE inhibition by these compounds provides the opportunity for the design of subtype-selective enzyme inhibitors. The presented indanone-carbamate scaffold can be structurally modified and optimized through medicinal chemistry-based approaches for designing novel multitargeted anti-Alzheimer agents.

Overdrive suppression of postoperative sustained ventricular tachycardia by atrial pacing and its hemodynamic effect.

Sustained ventricular tachycardia (VT) in the early postoperative period following intracardiac repair for tetralogy of Fallot is rare. In stable VT, amiodarone forms the mainstay of management. However, where amiodarone and other antiarrhythmic drugs are contraindicated, suppressive overdrive atrial pacing can be used as a safe and efficient alternative to maintain cardiac output. We present a case of 1-year 5-month-old child who developed VT with low cardiac output syndrome with deranged hepatic function, who was managed efficiently using suppressive atrial pacing to ameliorate the effects of sustained VT.

Differential responses of one hundred tomato genotypes grown under cadmium stress.

Due to increased global concern over the deleterious effects of toxic heavy metals in the environment, it has become necessary to develop plant genotypes that limit the uptake of heavy metals to aerial edible parts. To address this concern, we performed a glasshouse experiment to assess variations within tomato germplasm for cadmium (Cd) tolerance under control conditions and under simulated stress conditions. Significant differences (P < 0.01) were observed among all genotypes at both Cd levels (3 ppm and 6 ppm). Our analyses showed that the genotypes 9086, Roma, Sitara TS-01, pak0010990, CLN-2123A, Picdeneato, 0.006231, and 7035 gave the best yields with minimum Cd content in their fruit, whereas the genotypes 42-07, 17883, BL-1176-Riostone-1-1, Marmande, and 17882 had relatively low yields with higher metal contents. The heavy metal was found to accumulate first in the shoot, then fruit, leaf, and finally root in tolerant genotypes; in susceptible genotypes, the order was fruit, shoot, leaf, and root. The inter-genotype differences in Cd uptake indicated the possibility of manipulating tomato genotypes to develop Cd tolerant tomato varieties or hybrids that allow safe use of a tomato crop grown on Cd contaminated soils.

Health problems and stress in Information Technology and Business Process Outsourcing employees.

Stress is high in software profession because of their nature of work, target, achievements, night shift, over work load. 1. To study the demographic profile of the employees. 2. To access the level of job stress and quality of life of the respondents. 3. To study in detail the health problems of the employees. All employees working in IT and BPO industry for more than two years were included into the study. A detailed questionnaire of around 1000 IT and BPO employees including their personal details, stress score by Holmes and Rahe to assess the level of stress and master health checkup profile were taken and the results were analysed. Around 56% had musculoskeletal symptoms. 22% had newly diagnosed hypertension,10% had diabetes, 36% had dyslipidemia, 54% had depression, anxiety and insomnia, 40% had obesity. The stress score was higher in employees who developed diabetes, hypertension and depression. Early diagnosis of stress induced health problems can be made out by stress scores, intense lifestyle modification, diet advice along with psychological counselling would reduce the incidence of health problems in IT sector and improve the quality of work force.

A national house-staff audit of medical prophylaxis in medical patients for the PREVENTion of Venous ThromboEmbolism (PREVENT-VTE).

We established a national audit to assess the thromboprophylaxis rate for venous thromoembolism (VTE) in at risk medical patients in acute hospitals in the Republic of Ireland and to determine whether the use of stickers to alert physicians regarding thromboprophylaxis would double the rate prophylaxis in a follow-up audit. 651 acute medical admission patients in the first audit and 524 in the second re-audit were recruited. The mean age was 66.5 yrs with similar numbers of male and female patients and 265 (22.6%) patients were active smokers. The first and second audits identified 549 (84%) and 487 (93%) of patients at-risk for VTE respectively. Of the at-risk patients, 163 (29.7%) and 132 (27.1%) received LMWH in the first and second audit respectively. Mechanical thromboprophylaxis was instigated in 75 (13.6%) patients in the first and 86 (17.7%) patients in the second audit. The placement of stickers in patient charts didn't produce a significant increase in the number of at risk patients treated in the second audit. There is unacceptably low adherence to the ACCP guidelines in Ireland and more complex intervention than chart reminders are required to improve compliance.

Preparation of glucosamine from exoskeleton of shrimp and predicting production yield by response surface methodology.

Chitin was prepared from Persian Gulf shrimp (Metapenaeus monoceros), and then, the obtained chitin was hydrolyzed by hydrochloric acid solutions. The production yield of glucosamine hydrochloride from chitin was optimized, and the effect of three factors (acid concentration, acid to chitin ratio, and reaction time) was investigated. A Box-Behnken design by Minitab software created 12 reactions with different conditions. Each reaction was performed in two replicates. Response surface methodology was used for predicting the glucosamine preparation. The optimum conditions for glucosamine hydrochloride preparation were 30 and 37% hydrochloric acid, 9:1 (v/w) acid solution to solid ratio, and 4 h of reaction time. Time ratio and time acid concentrations were the effective factors on the yield.

Design and synthesis of alkyl 7,7-dihalo-3-methyl-5-(nitrophenyl)-2-azabicyclo[4.1.0]hept-3-ene-4-carboxylates with calcium channel antagonist activity.

A group of alkyl 7,7-dihalo-3-methyl-5-(2- or 3-nitrophenyl)-2-azabicyclo[4.1.0]hept-3-ene-4-carboxylates were prepared by reaction of dihalocarbenes (:CX(2), X=Br, Cl) with alkyl 2-methyl-4-(2- or 3-nitrophenyl)-1,4-dihydropyridine-3-carboxylates. In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. The title compounds exhibited weaker CC antagonist activity (10(-5) to 10(-7)M range) than the reference drug nifedipine (1.4 x 10(-8)M). Structure-activity relationships showed that the position (ortho or meta) of the nitro-substituent on the C-5 phenyl ring, the size (van der Waal's radius for Br and Cl are 1.95 and 1.80A, respectively) and/or electronegativity (Cl>Br) of the C-7 geminal halogen atoms do not appear to have a significant effect on CC antagonist activity. In contrast, the effect of the alkyl ester substituent was more pronounced where compounds having a Me or Et alkyl ester group showed superior potency (IC(50) in the 10(-7)M range) relative to the reference drug nifedipine (IC(50)=1.40 x 10(-8)M). Replacement of a 2-methyl-3-methoxycarbonylvinyl moiety present in nifedipine by a bioisosteric geminal-dihalocyclopropyl moiety provided a novel class of calcium channel antagonists that do not exhibit any inotropic effect on guinea pig atria.

Design and synthesis of methyl 2-methyl-7,7-dihalo-5-phenyl-2-azabicyclo[4.1.0]hept-3-ene-4-carboxylates with calcium channel antagonist activity.

A group of methyl 2-methyl-7,7-dihalo-5-(substituted-phenyl)-2-azabicyclo[4.1.0]hept-3-ene-4-carboxylates were prepared by reaction of dihalocarbenes (:CX2, X = Br, Cl) with methyl 1-methyl-4-(substituted-phenyl)-1,4-dihydropyridine-3-carboxylates. In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. The title compounds exhibited weaker CC antagonist activity (10(-5)-10(-6)M range) than the reference drug nifedipine (1.4 x 10(-8)M). Structure-activity relationship studies showed that the position of a nitro substituent on the C-5 phenyl ring where the relative potency order was ortho > meta > para, and the size and/or electronegativity of the C-7 geminal-dihalo substituents (Br > Cl), were determinants of calcium channel antagonist activity. This class of compounds did not exhibit any inotropic effect on guinea pig left atria. A dihalocyclopropyl moiety is a potential bioisostere for the 2-methyl-3-methoxycarbonylvinyl moiety present in the calcium channel antagonist nifedipine.