Designing Novel Antitrypanosomal Agents from a Mixed Graph-Theoretical Substructural Approach

Chagas disease is nowadays the most serious parasitic health problem. This disease is caused by Trypanosoma cruzi. The great number of deaths and the insufficient effectiveness of drugs against this parasite have alarmed the scientific community worldwide. In an attempt to overcome this problem, a model for the design and prediction of new antitrypanosomal agents was obtained. This used a mixed approach, containing simple descriptors based on fragments and topological substructural molecular design descriptors. A data set was made up of 188 compounds, 99 of them characterized an antitrypanosomal activity and 88 compounds that belong to other pharmaceutical categories. The model showed sensitivity, specificity and accuracy values above 85%. Quantitative fragmental contributions were also calculated. Then, and to confirm the quality of the model, 15 structures of molecules tested as antitrypanosomal compounds (that we did not include in this study) were predicted, taking into account the information on the abovementioned calculated fragmental contributions. The model showed an accuracy of 100% which means that the ""in silico"" methodology developed by our team is promising for the rational design of new antitrypanosomal drugs. (C) 2009 Wiley Periodicals, Inc. J Comput Chem 31: 882-894. 2010

Natural chromens and chromene derivatives as potential anti-trypanosomal agents

The aim of the study was to investigate the anti-trypanocidal activities of natural chromene and chromene derivatives. Five chromenes were isolated from Piper gaudichaudianum and P. aduncum, and a further seven derivatives were prepared using standard reduction, methylation and acetylation procedures. These compounds were assayed in vitro against epimastigote forms of Trypanosoma cruzi, the causative agent of Chagas disease. The results showed that the most of the compounds, especially those possessing electron-donating groups as substituents on the aromatic ring, showed potent trypanocidal activity. The most active compound, [(2S)-methyl-2-methyl-8-(3 ``-methylbut-2 ``-enyl)-2-(4`-methylpent-3`-enyl)-2H-chromene-6-carboxylate], was almost four times more potent than benznidazole (the positive control) and showed an IC50 of 2.82 mu M. The results reveal that chromenes exhibit significant anti-trypanocidal activities and indicate that this class of natural product should be considered further in the development of new and more potent drugs for use in the treatment of Chagas disease.

Alkaloids from the Bark of Guatteria hispida and Their Evaluation as Antioxidant and Antimicrobial Agents

Phytochemical investigation of the bark of Guatteria hispida afforded three new alkaloids, 9-methoxy-O-methylmoschatoline (1), 9-methoxyisomoschatoline (2), and isocerasonine (3), along with 10 known alkaloids, 8-oxopseudopalmatine (4), O-methylmoschatoline (5), lysicamine (6), liriodenine (7), 10-methoxyliriodenine (8), nornuciferine (9), anonaine (10), xylopine (11), coreximine (12), and isocoreximine (13). The major compounds, 2, 6, 12, and 13, showed significant antioxidant capacity in the ORAC(FL), assay. Compounds 5, 6, and 7 were active against S. epidermidis and C. dubliniensis, with MIC values in the range 12.5-100 mu g mL(-1).

Biosurfactants as Agents to Reduce Adhesion of Pathogenic Bacteria to Polystyrene Surfaces: Effect of Temperature and Hydrophobicity

Polystyrene surfaces were conditioned with surfactin and rhamnolipid biosurfactants and then assessed regarding the attachment of Staphylococcus aureus, Listeria monocytogenes, and Micrococcus lute us. The effect of different temperatures (35, 25, and 4 degrees C) on the anti-adhesive activity was also studied. Microbial adhesion to solvents and contact angle measurements were performed to characterize bacteria and material surfaces. The results showed that surfactin was able to inhibit bacterial adhesion in all the conditions analyzed, giving a 63-66% adhesion reduction in the bacterial strains at 4 degrees C. Rhamnolipid promoted a slight decrease in the attachment of S. aureus. The anti-adhesive activity of surfactin increased with the decrease in temperature, showing that this is an important parameter to be considered in surface conditioning tests. Surfactin showed good potential as an anti-adhesive compound that can be explored to protect surfaces from microbial contamination.

Ruthenium (II) phosphine/picolinate complexes as antimycobacterial agents

The synthesis, characterization and the anti-Mycobacterium tuberculosis (MTB) activities of three ruthenium complexes containing the 2-pyridinecarboxylic acid anion (picolinate), with formulae cis-[Ru(pic)(dppm)(2)]PF(6) (1), Cis- [Ru(pic)(dppe)(2)]PF(6) (2) and [Ru(pic)(2)(PPh(3))(2)] (3) [pic = 2-pyridinecarboxylate; dppm = bis(diphenylphosphino)methane: dppe = 1,2-bis(diphenylphosphino)ethane; PPh(3) = triphenylphosphine] are reported in this article. The complexes were characterized by elemental analysis, spectroscopic and electrochemical techniques. Their in vitro anti mycobacterial activity was determinated as the Minimum Inhibitory Concentration (MIC) for MTB cell growth, measured by the REMA method. The best MICs were found for complexes (1) and (2), with values of 0.78 and 0.26 mu g/mL, respectively. The results are comparable to or better than ""first line"" or ""second line"" drugs commonly used in the treatment of TB. (C) 2009 Elsevier Masson SAS. All rights reserved.

Studies toward the structural optimization of novel thiazolylhydrazone-based potent antitrypanosomal agents

In previous studies, we identified promising anti-Trypanosoma cruzi cruzain inhibitors based on thiazolylhydrazones. To optimize this series, a number of medicinal chemistry directions were explored and new thiazolylhydrazones and thiosemicarbazones were thus synthesized. Potent cruzain inhibitors were identified, such as thiazolylhydrazones 3b and 3j, which exhibited IC(50) of 200-400 nM. Furthermore, molecular docking studies showed concordance with experimentally derived structure-activity relationships (SAR) data. In the course of this work, lead compounds exhibiting in vitro activity against both the epimastigote and trypomastigote forms of T. cruzi were identified and in vivo general toxicity analysis was subsequently performed. Novel SAR were documented, including the importance of the thiocarbonyl carbon attached to the thiazolyl ring and the direct comparison between thiosemicarbazones and thiazolylhydrazones. (C) 2010 Elsevier Ltd. All rights reserved.

Developing a Communication link between Agents and cross Platform IDE

The main objective of this thesis work is to develop communication link between Runrev Revolution (IDE) and JADE (Multi-Agent System) through Socket programming using TCP/IP layer. These two independent platforms are connected using socket programming technique. Socket programming is considered to be newly emerging technology among these two platforms, the work done in this thesis work is considered to be a prototype.A Graphical simulation model is developed by salixphere (Company in Hedemora) to simulate logistic problems using Runrev Revolution (IDE). The simulation software/program is called “BIOSIM”. The logistic problems are complex, and conventional optimization techniques are unlikely very successful. “BIOSIM” can demonstrate the graphical representation of logistic problems depending upon the problem domains. As this simulation model is developed in revolution programming language (Transcript) which is dynamically typed and English-like language, it is quite slow compared to other high level programming languages. The object of this thesis work is to add intelligent behaviour in graphical objects and develop communication link between Runrev revolution (IDE) and JADE (Multi-Agent System) using TCP/IP layers.The test shows the intelligent behaviour in the graphical objects and successful communication between Runrev Revolution (IDE) and JADE (Multi-Agent System).

Simulation of Sawmill Yard Operations Using Software Agents

Bergkvist insjön AB is a sawmill yard which is capable of producing 350,000 cubic meter of timber every year this requires lot of internal resources. Sawmill operations can be classified as unloading, sorting, storage and production of timber. In the company we have trucks arriving at random they have to be unloaded and sent back at the earliest to avoid queuing up of trucks creating a problem for truck owners. The sawmill yard has to operate with two log stackers that does several tasks including transporting the logs from trucks to measurement station where the logs will be sorted into classes and dropped into pockets from pockets to the sorted timber yard where they are stored and finally from there to sawmill for final processing. The main issue that needs to be answered here is the lining up trucks that are waiting to be unload, creating a problem for both sawmill as well as the truck owners and given huge production volume, it is certain that handling of resources is top priority. A key challenge in handling of resources would be unloading of trucks and finding a way to optimize internal resources.To address this problem i have experimented on different ways of using internal resources, i have designed different cases, in case 1 we have both the log stackers working on sawmill and measurement station. The main objective of having this case is to make sawmill and measurement station to work all the time. Then in case 2, i have divided the work between both the log stackers, one log stacker will be working on sawmill and pocket_control and second log stacker will be working on measurement station and truck. Then in case 3 we have only one log stacker working on all the agents, this case was designed to reduce cost of production, as the experiment cannot be done in real-time due to operational cost, for this purpose simulation is used, preliminary investigation into simulation results suggested that case 2 is the best option has it reduced waiting time of trucks considerably when compared with other cases and it showed 50% increase in optimizing internal resources.

School leaders as agents of change : a case study on how two head teachers are trying to implement the learning study method in their school

This paper seeks to describe and discuss the impact of inspections of schools in Sweden. It outlines the political context, based on New Public Management (NPM) theory, according to what role the Schools Inspectorate is supposed to play in order to govern and control. Attention is also devoted, referring an on-going case study, to how inspections influence head teachers and their leadership in their everyday work.   Reports from the Schools inspectorate are public. This forces both politicians and head teachers to take measures. In this case, the head teachers perceived that the inspection reports confirmed what they already knew, but it also gave them an alibi and a tool to push their teachers to take part in everyday school development work. During the first year after the inspection the head teachers mainly strived to adjust formal deficiencies in local steering documents. However, some of the deviations reported from the Schools inspectorate are regarding pedagogical problems that are complicated and difficult to handle. As interventions in many cases will show up much later the results are, for example as increased goal fulfilment, in this case, still an open question. Nevertheless, it seems obvious that the Schools Inspectorate must be seen as a result of the governing philosophy that denotes New Public Management NPM).

Agents and the Grid: Service Discovery

The Grid is a large-scale computer system that is capable of coordinating resources that are not subject to centralised control, whilst using standard, open, general-purpose protocols and interfaces, and delivering non-trivial qualities of service. In this chapter, we argue that Grid applications very strongly suggest the use of agent-based computing, and we review key uses of agent technologies in Grids: user agents, able to customize and personalise data; agent communication languages offering a generic and portable communication medium; and negotiation allowing multiple distributed entities to reach service level agreements. In the second part of the chapter, we focus on Grid service discovery, which we have identified as a prime candidate for use of agent technologies: we show that Grid-services need to be located via personalised, semantic-rich discovery processes, which must rely on the storage of arbitrary metadata about services that originates from both service providers and service users. We present UDDI-MT, an extension to the standard UDDI service directory approach that supports the storage of such metadata via a tunnelling technique that ties the metadata store to the original UDDI directory. The outcome is a flexible service registry which is compatible with existing standards and also provides metadata-enhanced service discovery.