Investigation on the effect of alkyl chain linked mono-thioureas as Jack bean urease inhibitors,SAR, pharmacokinetics ADMET parameters and molecular docking studies

The increasing resistance of pathogens to common antibiotics, as well as the need to control urease activity to improve the yield of soil nitrogen fertilization in agricultural applications, has stimulated the development of novel classes of molecules that target urease as an enzyme. In this context, the newly developed compounds on the basis of 1-heptanoyl-3-arylthiourea family were evaluated for Jack bean urease enzyme inhibition activity to validate their role as potent inhibitors of this enzyme. 1-Heptanoyl-3-arylthioureas were obtained in excellent yield and characterized through spectral and elemental analysis. All the compounds displayed remarkable potency against urease inhibition as compared to thiourea standard. It was found that novel compounds fulfill the criteria of drug-likeness by obeying Lipinski’s rule of five. Particularly compound 4a and 4c can serve as lead molecules in 4D (drug designing discovery and development). Kinetic mechanism and molecular docking studies also carried out to delineate the mode of inhibition and binding affinity of the molecules.     

Can the problem of hybridization in threatened species be evaluated using a fieldwork research? A case study in snapdragons

Hybridization, natural or artificial, is considered disadvantageous for species biodiversity when it threatens the population integrity of endangered species. Frequently, studies investigating whether hybridization poses a legitimate risk to rare species are based on genetic data obtained in molecular biology laboratories. In this study, we used field research to approach the problem that hybridization could cause for the viability of a population of a rare species and to be able to propose the most appropriate initial conservation strategy. Specifically, using the model genus Antirrhinum, the reproductive barriers between the rare A. pulverulentum and its common congener A. litigiosum have been analysed under the reproductive isolation index (RI). A. pulverulentum had a high value of total RI, indicating that there are barriers to gene flow from A. litigiosum towards this species, and also had a high value for the intrinsic RI, reflecting a low inherent capacity for production of hybrid plants; in addition, the possibility of successful backcrosses between this species with hybrids produced from A. litigiosum ovules were low, given the high intrinsic RI of A. litigiosum. These data indicate the current existence of strong and permanent barriers to hybridization between the two species, suggesting that hybridization does not seem to be a serious problem for the conservation of A. pulverulentum in the studied population, nor for the near future. This study shows how the RI index can provide useful information for conservation purposes and proposes different management recommendations.     

Liquid chromatographic separation of chiral diarylcarbinols

The direct HPLC separation of three chiral carbinols of general formula Mesityl-CH(OH)-Aryl has been achieved using Pirkle (R)-DNBPG ionic or covalent columns and, for Aryl = o-tolyl, on a Chiralpak OP(+) phase. It is apparent that steric hindrance and hydrogen bonding play important roles in chiral recognition. Two compounds structurally very similar but lacking the hydroxyl group were not resolved in their enantiomeric pairs. © 1992 Wiley-Liss, Inc.     

Substrate-enzyme interactions and catalytic mechanism in phospholipase C: a molecular modeling study using the GRID program.

Based on the high-resolution X-ray crystallographic structure of phospholipase C from Bacillus cereus, the orientation of the phosphatidylcholine substrate in the active site of the enzyme is proposed. The proposal is based on extensive calculations using the GRID program and molecular mechanics geometry relaxations. The substrate model has been constructed by successively placing phosphate, choline and diacylglycerol moieties in the positions indicated from GRID calculations. On the basis of the resulting orientation of a complete phosphatidylcholine molecule, we propose a mechanism for the hydrolysis of the substrate.     

Insight towards the conserved water mediated recognition of catalytic and structural Zn+2 ions in human Matrix Metalloproteinase-8 enzyme: A study by MD-simulation methods

Human matrix metalloproteinase-8 (hMMP-8) plays a important role in the progression of colorectal cancer, metastasis, multiple sclerosis and rheumetoid arthritis. Extensive MD-simulation of the PDB and solvated structures of hMMP-8 has revealed the presence of few conserved water molecules around the catalytic and structural zinc (ZnC and ZnS) ions. The coordination of two conserved water molecules (W and WS) to ZnS and the H-bonding interaction of WS to S151 have indicated the plausible involvement of that metal ion in the catalytic process. Beside this the coupling of ZnC and ZnS metal ions (ZnC – W_H (W₁)…..W₂ ….H₁₆₂ - ZnS) through two conserved hydrophilic centers (occupied by water molecules) may also provide some rational on the recognition of two zinc ions which were separated by ~13 Å in their X-ray structures. This unique recognition of both the Zn⁺² ions in the enzyme through conserved water molecules may be implemented/ exploited for the design of antiproteolytic agent using water mimic drug design protocol.     

Microwave effect on diffusion: a possible mechanism for non-thermal effect

Abstract

In this study, we assume that microwave radiation affects hydrogen bonding between dipolar water molecules and through that diffusion in water at constant temperature. The experimental study was performed on the setup of two identical reservoirs filled with pure water and 0.9% NaCl solution and connected by a thin tube. Alterations of NaCl concentration in the reservoir initially filled with pure water were measured using the resistance of the solution as an indicator. The applied 450?MHz continuous-wave microwave field had the maximal specific absorption rate of 0.4?W/kg on the connecting tube. The standard deviation of water temperature in the setup was 0.02?°C during an experiment. Our experimental data demonstrated that microwave exposure makes faster the process of diffusion in water. The time required for reduction of initial resistance of the solution by 10% was 1.7 times shorter with microwave. This result is consistent with the proposed mechanism of low-level microwave effect: microwave radiation, rotating dipolar water molecules, causes high-frequency alterations of hydrogen bonds between water molecules, thereby affects its viscosity and makes faster diffusion.     

From obesity to cancer: a review on proposed mechanisms

Nowadays, obesity is considered as a serious and growing global health problem. It is documented that the overweight and obesity are major risk factors for a series of noncommunicable diseases, and in recent years, the obesity‐cancer link has received much attention. Numerous epidemiological studies have shown that obesity is associated with increased risk of several cancer types, including colon, breast, endometrium, liver, kidney, esophagus, gastric, pancreatic, gallbladder, and leukemia, and can also lead to poorer treatment. We review here the epidemiological and experimental evidences for the association between obesity and cancer. Specifically, we discuss potential mechanisms focusing how dysfunctional angiogenesis, chronic inflammation, interaction of proinflammatory cytokines, endocrine hormones, and adipokines including leptin, adiponectin insulin, growth factors, estrogen, and progesterone and strikingly, cell metabolism alteration in obesity participate in tumor development and progression, resistance to chemotherapy, and targeted therapies such as antiangiogenic and immune therapies.     

Rapid preflexes in smooth adhesive pads of insects prevent sudden detachment

Many insects possess adhesive organs that can produce extreme attachment forces of more than 100 times body weight but they can rapidly release adhesion to allow locomotion. During walking, weaver ants (Oecophylla smaragdina) use only a fraction of their maximally available contact area, even upside-down on a smooth surface. To test whether the reduced contact area makes the ants more susceptible to sudden and unexpected detachment forces, for example, by rain or wind gusts, we investigated the reaction of untethered ants to rapid horizontal displacements of the substrate. High-speed video recordings revealed that the pad''s contact area could more than double within the first millisecond after the perturbation. This contact area expansion is much faster than any neuromuscular reflex and therefore represents a passive ‘preflex’, resulting from the mechanical properties and geometrical arrangement of the (pre-)tarsus. This preflex reaction protects ants effectively against unexpected detachment, and allows them to use less contact area during locomotion. Contact area expanded most strongly when the substrate displacement generated a pull along the axis of the tarsus, showing that the ants'' preflex is direction-dependent. The preflex may be based on the ability of Hymenopteran adhesive pads to unfold when pulled towards the body. We tested Indian stick insects (Carausius morosus), which have smooth pads that lack this motility. Similar to the ants, they showed a rapid and direction-dependent expansion of the contact area mainly in the lateral direction. We propose that the preflex reaction in stick insects is based on the reorientation of internal cuticle fibrils in a constant-volume system, whereas the ants'' pad cuticle is probably not a hydrostat, and pad extension is achieved by the arcus, an endoscelerite of the arolium.