Optimal Supervisory Control of Hybrid Vehicles

Hybrid vehicles (HV), comprising a conventional ICE-based powertrain and a secondary energy source, to be converted into mechanical power as well, represent a well-established alternative to substantially reduce both fuel consumption and tailpipe emissions of passenger cars. Several HV architectures are either being studied or already available on market, e.g. Mechanical, Electric, Hydraulic and Pneumatic Hybrid Vehicles. Among the others, Electric (HEV) and Mechanical (HSF-HV) parallel Hybrid configurations are examined throughout this Thesis. To fully exploit the HVs potential, an optimal choice of the hybrid components to be installed must be properly designed, while an effective Supervisory Control must be adopted to coordinate the way the different power sources are managed and how they interact. Real-time controllers can be derived starting from the obtained optimal benchmark results. However, the application of these powerful instruments require a simplified and yet reliable and accurate model of the hybrid vehicle system. This can be a complex task, especially when the complexity of the system grows, i.e. a HSF-HV system assessed in this Thesis. The first task of the following dissertation is to establish the optimal modeling approach for an innovative and promising mechanical hybrid vehicle architecture. It will be shown how the chosen modeling paradigm can affect the goodness and the amount of computational effort of the solution, using an optimization technique based on Dynamic Programming. The second goal concerns the control of pollutant emissions in a parallel Diesel-HEV. The emissions level obtained under real world driving conditions is substantially higher than the usual result obtained in a homologation cycle. For this reason, an on-line control strategy capable of guaranteeing the respect of the desired emissions level, while minimizing fuel consumption and avoiding excessive battery depletion is the target of the corresponding section of the Thesis.

Architectures and design patterns for functional design of logic control and diagnostics in industrial automation

Recently in most of the industrial automation process an ever increasing degree of automation has been observed. This increasing is motivated by the higher requirement of systems with great performance in terms of quality of products/services generated, productivity, efficiency and low costs in the design, realization and maintenance. This trend in the growth of complex automation systems is rapidly spreading over automated manufacturing systems (AMS), where the integration of the mechanical and electronic technology, typical of the Mechatronics, is merging with other technologies such as Informatics and the communication networks. An AMS is a very complex system that can be thought constituted by a set of flexible working stations, one or more transportation systems. To understand how this machine are important in our society let considerate that every day most of us use bottles of water or soda, buy product in box like food or cigarets and so on. Another important consideration from its complexity derive from the fact that the the consortium of machine producers has estimated around 350 types of manufacturing machine. A large number of manufacturing machine industry are presented in Italy and notably packaging machine industry,in particular a great concentration of this kind of industry is located in Bologna area; for this reason the Bologna area is called “packaging valley”. Usually, the various parts of the AMS interact among them in a concurrent and asynchronous way, and coordinate the parts of the machine to obtain a desiderated overall behaviour is an hard task. Often, this is the case in large scale systems, organized in a modular and distributed manner. Even if the success of a modern AMS from a functional and behavioural point of view is still to attribute to the design choices operated in the definition of the mechanical structure and electrical electronic architecture, the system that governs the control of the plant is becoming crucial, because of the large number of duties associated to it. Apart from the activity inherent to the automation of themachine cycles, the supervisory system is called to perform other main functions such as: emulating the behaviour of traditional mechanical members thus allowing a drastic constructive simplification of the machine and a crucial functional flexibility; dynamically adapting the control strategies according to the different productive needs and to the different operational scenarios; obtaining a high quality of the final product through the verification of the correctness of the processing; addressing the operator devoted to themachine to promptly and carefully take the actions devoted to establish or restore the optimal operating conditions; managing in real time information on diagnostics, as a support of the maintenance operations of the machine. The kind of facilities that designers can directly find on themarket, in terms of software component libraries provides in fact an adequate support as regard the implementation of either top-level or bottom-level functionalities, typically pertaining to the domains of user-friendly HMIs, closed-loop regulation and motion control, fieldbus-based interconnection of remote smart devices. What is still lacking is a reference framework comprising a comprehensive set of highly reusable logic control components that, focussing on the cross-cutting functionalities characterizing the automation domain, may help the designers in the process of modelling and structuring their applications according to the specific needs. Historically, the design and verification process for complex automated industrial systems is performed in empirical way, without a clear distinction between functional and technological-implementation concepts and without a systematic method to organically deal with the complete system. Traditionally, in the field of analog and digital control design and verification through formal and simulation tools have been adopted since a long time ago, at least for multivariable and/or nonlinear controllers for complex time-driven dynamics as in the fields of vehicles, aircrafts, robots, electric drives and complex power electronics equipments. Moving to the field of logic control, typical for industrial manufacturing automation, the design and verification process is approached in a completely different way, usually very “unstructured”. No clear distinction between functions and implementations, between functional architectures and technological architectures and platforms is considered. Probably this difference is due to the different “dynamical framework”of logic control with respect to analog/digital control. As a matter of facts, in logic control discrete-events dynamics replace time-driven dynamics; hence most of the formal and mathematical tools of analog/digital control cannot be directly migrated to logic control to enlighten the distinction between functions and implementations. In addition, in the common view of application technicians, logic control design is strictly connected to the adopted implementation technology (relays in the past, software nowadays), leading again to a deep confusion among functional view and technological view. In Industrial automation software engineering, concepts as modularity, encapsulation, composability and reusability are strongly emphasized and profitably realized in the so-calledobject-oriented methodologies. Industrial automation is receiving lately this approach, as testified by some IEC standards IEC 611313, IEC 61499 which have been considered in commercial products only recently. On the other hand, in the scientific and technical literature many contributions have been already proposed to establish a suitable modelling framework for industrial automation. During last years it was possible to note a considerable growth in the exploitation of innovative concepts and technologies from ICT world in industrial automation systems. For what concerns the logic control design, Model Based Design (MBD) is being imported in industrial automation from software engineering field. Another key-point in industrial automated systems is the growth of requirements in terms of availability, reliability and safety for technological systems. In other words, the control system should not only deal with the nominal behaviour, but should also deal with other important duties, such as diagnosis and faults isolations, recovery and safety management. Indeed, together with high performance, in complex systems fault occurrences increase. This is a consequence of the fact that, as it typically occurs in reliable mechatronic systems, in complex systems such as AMS, together with reliable mechanical elements, an increasing number of electronic devices are also present, that are more vulnerable by their own nature. The diagnosis problem and the faults isolation in a generic dynamical system consists in the design of an elaboration unit that, appropriately processing the inputs and outputs of the dynamical system, is also capable of detecting incipient faults on the plant devices, reconfiguring the control system so as to guarantee satisfactory performance. The designer should be able to formally verify the product, certifying that, in its final implementation, it will perform itsrequired function guarantying the desired level of reliability and safety; the next step is that of preventing faults and eventually reconfiguring the control system so that faults are tolerated. On this topic an important improvement to formal verification of logic control, fault diagnosis and fault tolerant control results derive from Discrete Event Systems theory. The aimof this work is to define a design pattern and a control architecture to help the designer of control logic in industrial automated systems. The work starts with a brief discussion on main characteristics and description of industrial automated systems on Chapter 1. In Chapter 2 a survey on the state of the software engineering paradigm applied to industrial automation is discussed. Chapter 3 presentes a architecture for industrial automated systems based on the new concept of Generalized Actuator showing its benefits, while in Chapter 4 this architecture is refined using a novel entity, the Generalized Device in order to have a better reusability and modularity of the control logic. In Chapter 5 a new approach will be present based on Discrete Event Systems for the problemof software formal verification and an active fault tolerant control architecture using online diagnostic. Finally conclusive remarks and some ideas on new directions to explore are given. In Appendix A are briefly reported some concepts and results about Discrete Event Systems which should help the reader in understanding some crucial points in chapter 5; while in Appendix B an overview on the experimental testbed of the Laboratory of Automation of University of Bologna, is reported to validated the approach presented in chapter 3, chapter 4 and chapter 5. In Appendix C some components model used in chapter 5 for formal verification are reported.

Model predictive control in thermal management of multiprocessor systems-on-chip

MultiProcessor Systems-on-Chip (MPSoC) are the core of nowadays and next generation computing platforms. Their relevance in the global market continuously increase, occupying an important role both in everydaylife products (e.g. smartphones, tablets, laptops, cars) and in strategical market sectors as aviation, defense, robotics, medicine. Despite of the incredible performance improvements in the recent years processors manufacturers have had to deal with issues, commonly called “Walls”, that have hindered the processors development. After the famous “Power Wall”, that limited the maximum frequency of a single core and marked the birth of the modern multiprocessors system-on-chip, the “Thermal Wall” and the “Utilization Wall” are the actual key limiter for performance improvements. The former concerns the damaging effects of the high temperature on the chip caused by the large power densities dissipation, whereas the second refers to the impossibility of fully exploiting the computing power of the processor due to the limitations on power and temperature budgets. In this thesis we faced these challenges by developing efficient and reliable solutions able to maximize performance while limiting the maximum temperature below a fixed critical threshold and saving energy. This has been possible by exploiting the Model Predictive Controller (MPC) paradigm that solves an optimization problem subject to constraints in order to find the optimal control decisions for the future interval. A fully-distributedMPC-based thermal controller with a far lower complexity respect to a centralized one has been developed. The control feasibility and interesting properties for the simplification of the control design has been proved by studying a partial differential equation thermal model. Finally, the controller has been efficiently included in more complex control schemes able to minimize energy consumption and deal with mixed-criticalities tasks

Spectrum reconstruction from a scattering measurement using the adjoint Boltzmann transport equation for photons

Quality control of medical radiological systems is of fundamental importance, and requires efficient methods for accurately determine the X-ray source spectrum. Straightforward measurements of X-ray spectra in standard operating require the limitation of the high photon flux, and therefore the measure has to be performed in a laboratory. However, the optimal quality control requires frequent in situ measurements which can be only performed using a portable system. To reduce the photon flux by 3 magnitude orders an indirect technique based on the scattering of the X-ray source beam by a solid target is used. The measured spectrum presents a lack of information because of transport and detection effects. The solution is then unfolded by solving the matrix equation that represents formally the scattering problem. However, the algebraic system is ill-conditioned and, therefore, it is not possible to obtain a satisfactory solution. Special strategies are necessary to circumvent the ill-conditioning. Numerous attempts have been done to solve this problem by using purely mathematical methods. In this thesis, a more physical point of view is adopted. The proposed method uses both the forward and the adjoint solutions of the Boltzmann transport equation to generate a better conditioned linear algebraic system. The procedure has been tested first on numerical experiments, giving excellent results. Then, the method has been verified with experimental measurements performed at the Operational Unit of Health Physics of the University of Bologna. The reconstructed spectra have been compared with the ones obtained with straightforward measurements, showing very good agreement.

Nonlinear Approaches to Attitude Control Using Magnetic and Mechanical Actuation

This thesis argues the attitude control problem of nanosatellites, which has been a challenging issue over the years for the scientific community and still constitutes an active area of research. The interest is increasing as more than 70% of future satellite launches are nanosatellites. Therefore, new challenges appear with the miniaturisation of the subsystems and improvements must be reached. In this framework, the aim of this thesis is to develop novel control approaches for three-axis stabilisation of nanosatellites equipped with magnetorquers and reaction wheels, to improve the performance of the existent control strategies and demonstrate the stability of the system. In particular, this thesis is focused on the development of non-linear control techniques to stabilise full-actuated nanosatellites, and in the case of underactuation, in which the number of control variables is less than the degrees of freedom of the system. The main contributions are, for the first control strategy proposed, to demonstrate global asymptotic stability derived from control laws that stabilise the system in a target frame, a fixed direction of the orbit frame. Simulation results show good performance, also in presence of disturbances, and a theoretical selection of the magnetic control gain is given. The second control approach presents instead, a novel stable control methodology for three-axis stabilisation in underactuated conditions. The control scheme consists of the dynamical implementation of an attitude manoeuvre planning by means of a switching control logic. A detailed numerical analysis of the control law gains and the effect on the convergence time, total integrated and maximum torque is presented demonstrating the good performance and robustness also in the presence of disturbances.

Path planning for image based visual servoing

This thesis deals with Visual Servoing and its strictly connected disciplines like projective geometry, image processing, robotics and non-linear control. More specifically the work addresses the problem to control a robotic manipulator through one of the largely used Visual Servoing techniques: the Image Based Visual Servoing (IBVS). In Image Based Visual Servoing the robot is driven by on-line performing a feedback control loop that is closed directly in the 2D space of the camera sensor. The work considers the case of a monocular system with the only camera mounted on the robot end effector (eye in hand configuration). Through IBVS the system can be positioned with respect to a 3D fixed target by minimizing the differences between its initial view and its goal view, corresponding respectively to the initial and the goal system configurations: the robot Cartesian Motion is thus generated only by means of visual informations. However, the execution of a positioning control task by IBVS is not straightforward because singularity problems may occur and local minima may be reached where the reached image is very close to the target one but the 3D positioning task is far from being fulfilled: this happens in particular for large camera displacements, when the the initial and the goal target views are noticeably different. To overcame singularity and local minima drawbacks, maintaining the good properties of IBVS robustness with respect to modeling and camera calibration errors, an opportune image path planning can be exploited. This work deals with the problem of generating opportune image plane trajectories for tracked points of the servoing control scheme (a trajectory is made of a path plus a time law). The generated image plane paths must be feasible i.e. they must be compliant with rigid body motion of the camera with respect to the object so as to avoid image jacobian singularities and local minima problems. In addition, the image planned trajectories must generate camera velocity screws which are smooth and within the allowed bounds of the robot. We will show that a scaled 3D motion planning algorithm can be devised in order to generate feasible image plane trajectories. Since the paths in the image are off-line generated it is also possible to tune the planning parameters so as to maintain the target inside the camera field of view even if, in some unfortunate cases, the feature target points would leave the camera images due to 3D robot motions. To test the validity of the proposed approach some both experiments and simulations results have been reported taking also into account the influence of noise in the path planning strategy. The experiments have been realized with a 6DOF anthropomorphic manipulator with a fire-wire camera installed on its end effector: the results demonstrate the good performances and the feasibility of the proposed approach.

New target tracking and monitoring guidance laws for UAV

A pursuer UAV tracking and loitering around a target is the problem analyzed in this thesis. The UAV is assumed to be a fixed-wing vehicle and constant airspeed together with bounded lateral accelerations are the main constraints of the problem. Three different guidance laws are designed for ensuring a continuos overfly on the target. Different proofs are presented to demonstrate the stability properties of the laws. All the algorithms are tested on a 6DoF Pioneer software simulator. Classic control design methods have been adopted to develop autopilots for implementig the simulation platform used for testing the guidance laws.

Non-Linear Analysis and Design of Synchronous Bearingless Multiphase Permanent Magnet Machines and Drives

A two-dimensional model to analyze the distribution of magnetic fields in the airgap of a PM electrical machines is studied. A numerical algorithm for non-linear magnetic analysis of multiphase surface-mounted PM machines with semi-closed slots is developed, based on the equivalent magnetic circuit method. By using a modular structure geometry, whose the basic element can be duplicated, it allows to design whatever typology of windings distribution. In comparison to a FEA, permits a reduction in computing time and to directly changing the values of the parameters in a user interface, without re-designing the model. Output torque and radial forces acting on the moving part of the machine can be calculated. In addition, an analytical model for radial forces calculation in multiphase bearingless Surface-Mounted Permanent Magnet Synchronous Motors (SPMSM) is presented. It allows to predict amplitude and direction of the force, depending on the values of torque current, of levitation current and of rotor position. It is based on the space vectors method, letting the analysis of the machine also during transients. The calculations are conducted by developing the analytical functions in Fourier series, taking all the possible interactions between stator and rotor mmf harmonic components into account and allowing to analyze the effects of electrical and geometrical quantities of the machine, being parametrized. The model is implemented in the design of a control system for bearingless machines, as an accurate electromagnetic model integrated in a three-dimensional mechanical model, where one end of the motor shaft is constrained to simulate the presence of a mechanical bearing, while the other is free, only supported by the radial forces developed in the interactions between magnetic fields, to realize a bearingless system with three degrees of freedom. The complete model represents the design of the experimental system to be realized in the laboratory.

Design and control techniques of optical networks

The world of communication has changed quickly in the last decade resulting in the the rapid increase in the pace of peoples’ lives. This is due to the explosion of mobile communication and the internet which has now reached all levels of society. With such pressure for access to communication there is increased demand for bandwidth. Photonic technology is the right solution for high speed networks that have to supply wide bandwidth to new communication service providers. In particular this Ph.D. dissertation deals with DWDM optical packet-switched networks. The issue introduces a huge quantity of problems from physical layer up to transport layer. Here this subject is tackled from the network level perspective. The long term solution represented by optical packet switching has been fully explored in this years together with the Network Research Group at the department of Electronics, Computer Science and System of the University of Bologna. Some national as well as international projects supported this research like the Network of Excellence (NoE) e-Photon/ONe, funded by the European Commission in the Sixth Framework Programme and INTREPIDO project (End-to-end Traffic Engineering and Protection for IP over DWDM Optical Networks) funded by the Italian Ministry of Education, University and Scientific Research. Optical packet switching for DWDM networks is studied at single node level as well as at network level. In particular the techniques discussed are thought to be implemented for a long-haul transport network that connects local and metropolitan networks around the world. The main issues faced are contention resolution in a asynchronous variable packet length environment, adaptive routing, wavelength conversion and node architecture. Characteristics that a network must assure as quality of service and resilience are also explored at both node and network level. Results are mainly evaluated via simulation and through analysis.

Tools and methods for the quality assurance of force platforms in human movement analysis

The human movement analysis (HMA) aims to measure the abilities of a subject to stand or to walk. In the field of HMA, tests are daily performed in research laboratories, hospitals and clinics, aiming to diagnose a disease, distinguish between disease entities, monitor the progress of a treatment and predict the outcome of an intervention [Brand and Crowninshield, 1981; Brand, 1987; Baker, 2006]. To achieve these purposes, clinicians and researchers use measurement devices, like force platforms, stereophotogrammetric systems, accelerometers, baropodometric insoles, etc. This thesis focus on the force platform (FP) and in particular on the quality assessment of the FP data. The principal objective of our work was the design and the experimental validation of a portable system for the in situ calibration of FPs. The thesis is structured as follows: Chapter 1. Description of the physical principles used for the functioning of a FP: how these principles are used to create force transducers, such as strain gauges and piezoelectrics transducers. Then, description of the two category of FPs, three- and six-component, the signals acquisition (hardware structure), and the signals calibration. Finally, a brief description of the use of FPs in HMA, for balance or gait analysis. Chapter 2. Description of the inverse dynamics, the most common method used in the field of HMA. This method uses the signals measured by a FP to estimate kinetic quantities, such as joint forces and moments. The measures of these variables can not be taken directly, unless very invasive techniques; consequently these variables can only be estimated using indirect techniques, as the inverse dynamics. Finally, a brief description of the sources of error, present in the gait analysis. Chapter 3. State of the art in the FP calibration. The selected literature is divided in sections, each section describes: systems for the periodic control of the FP accuracy; systems for the error reduction in the FP signals; systems and procedures for the construction of a FP. In particular is detailed described a calibration system designed by our group, based on the theoretical method proposed by ?. This system was the “starting point” for the new system presented in this thesis. Chapter 4. Description of the new system, divided in its parts: 1) the algorithm; 2) the device; and 3) the calibration procedure, for the correct performing of the calibration process. The algorithm characteristics were optimized by a simulation approach, the results are here presented. In addiction, the different versions of the device are described. Chapter 5. Experimental validation of the new system, achieved by testing it on 4 commercial FPs. The effectiveness of the calibration was verified by measuring, before and after calibration, the accuracy of the FPs in measuring the center of pressure of an applied force. The new system can estimate local and global calibration matrices; by local and global calibration matrices, the non–linearity of the FPs was quantified and locally compensated. Further, a non–linear calibration is proposed. This calibration compensates the non– linear effect in the FP functioning, due to the bending of its upper plate. The experimental results are presented. Chapter 6. Influence of the FP calibration on the estimation of kinetic quantities, with the inverse dynamics approach. Chapter 7. The conclusions of this thesis are presented: need of a calibration of FPs and consequential enhancement in the kinetic data quality. Appendix: Calibration of the LC used in the presented system. Different calibration set–up of a 3D force transducer are presented, and is proposed the optimal set–up, with particular attention to the compensation of non–linearities. The optimal set–up is verified by experimental results.

Creazione e sviluppo di un sistema di controllo in tempo reale per un sistema fuel cell

The control of a proton exchange membrane fuel cell system (PEM FC) for domestic heat and power supply requires extensive control measures to handle the complicated process. Highly dynamic and non linear behavior, increase drastically the difficulties to find the optimal design and control strategies. The objective is to design, implement and commission a controller for the entire fuel cell system. The fuel cell process and the control system are engineered simultaneously; therefore there is no access to the process hardware during the control system development. Therefore the method of choice was a model based design approach, following the rapid control prototyping (RCP) methodology. The fuel cell system is simulated using a fuel cell library which allowed thermodynamic calculations. In the course of the development the process model is continuously adapted to the real system. The controller application is designed and developed in parallel and thereby tested and verified against the process model. Furthermore, after the commissioning of the real system, the process model can be also better identified and parameterized utilizing measurement data to perform optimization procedures. The process model and the controller application are implemented in Simulink using Mathworks` Real Time Workshop (RTW) and the xPC development suite for MiL (model-in-theloop) and HiL (hardware-in-the-loop) testing. It is possible to completely develop, verify and validate the controller application without depending on the real fuel cell system, which is not available for testing during the development process. The fuel cell system can be immediately taken into operation after connecting the controller to the process.

De Novo Design of secondary structures: Synthesis and conformational studies

Chemists have long sought to extrapolate the power of biological catalysis and recognition to synthetic systems. These efforts have focused largely on low molecular weight catalysts and receptors; however, biological systems themselves rely almost exclusively on polymers, proteins and RNA, to perform complex chemical functions. Proteins and RNA are unique in their ability to adopt compact, well-ordered conformations, and specific folding provides precise spatial orientation of the functional groups that comprise the “active site”. These features suggest that identification of new polymer backbones with discrete and predictable folding propensities (“foldamers”) will provide a basis for design of molecular machines with unique capabilities. The foldamer approach complements current efforts to design unnatural properties into polypeptides and polynucleotides. The aim of this thesis is the synthesis and conformational studies of new classes of foldamers, using a peptidomimetic approach. Moreover their attitude to be utilized as ionophores, catalysts, and nanobiomaterials were analyzed in solution and in the solid state. This thesis is divided in thematically chapters that are reported below. It begins with a very general introduction (page 4) which is useful, but not strictly necessary, to the expert reader. It is worth mentioning that paragraph I.3 (page 22) is the starting point of this work and paragraph I.5 (page 32) isrequired to better understand the results of chapters 4 and 5. In chapter 1 (page 39) is reported the synthesis and conformational analysis of a novel class of foldamers containing (S)-β3-homophenylglycine [(S)-β3-hPhg] and D- 4-carboxy-oxazolidin-2-one (D-Oxd) residues in alternate order is reported. The experimental conformational analysis performed in solution by IR, 1HNMR, and CD spectroscopy unambiguously proved that these oligomers fold into ordered structures with increasing sequence length. Theoretical calculations employing ab initio MO theory suggest a helix with 11-membered hydrogenbonded rings as the preferred secondary structure type. The novel structures enrich the field of peptidic foldamers and might be useful in the mimicry of native peptides. In chapter 2 cyclo-(L-Ala-D-Oxd)3 and cyclo-(L-Ala-DOxd) 4 were prepared in the liquid phase with good overall yields and were utilized for bivalent ions chelation (Ca2+, Mg2+, Cu2+, Zn2+ and Hg2+); their chelation skill was analyzed with ESI-MS, CD and 1HNMR techniques and the best results were obtained with cyclo-(L-Ala-D-Oxd)3 and Mg2+ or Ca2+. Chapter 3 describes an application of oligopeptides as catalysts for aldol reactions. Paragraph 3.1 concerns the use of prolinamides as catalysts of the cross aldol addition of hydroxyacetone to aromatic aldeydes, whereas paragraphs 3.2 and 3.3 are about the catalyzed aldol addition of acetone to isatins. By means of DFT and AIM calculations, the steric and stereoelectronic effects that control the enantioselectivity in the cross-aldol addition of acetone to isatin catalysed by L-proline have been studied, also in the presence of small quantities of water. In chapter 4 is reported the synthesis and the analysis of a new fiber-like material, obtained from the selfaggregation of the dipeptide Boc-L-Phe-D-Oxd-OBn, which spontaneously forms uniform fibers consisting of parallel infinite linear chains arising from singleintermolecular N-H···O=C hydrogen bonds. This is the absolute borderline case of a parallel β-sheet structure. Longer oligomers of the same series with general formula Boc-(L-Phe-D-Oxd)n-OBn (where n = 2-5), are described in chapter 5. Their properties in solution and in the solid state were analyzed, in correlation with their attitude to form intramolecular hydrogen bond. In chapter 6 is reported the synthesis of imidazolidin-2- one-4-carboxylate and (tetrahydro)-pyrimidin-2-one-5- carboxylate, via an efficient modification of the Hofmann rearrangement. The reaction affords the desired compounds from protected asparagine or glutamine in good to high yield, using PhI(OAc)2 as source of iodine(III).

Design and synthesis of novel non peptidomimtic beta-secretase inhibitors in the treatment of Alzheimer's disease

The aspartic protease BACE1 (β-amyloid precursor protein cleaving enzyme, β-secretase) is recognized as one of the most promising targets in the treatment of Alzheimer's disease (AD). The accumulation of β-amyloid peptide (Aβ) in the brain is a major factor in the pathogenesis of AD. Aβ is formed by initial cleavage of β-amyloid precursor protein (APP) by β-secretase, therefore BACE1 inhibition represents one of the therapeutic approaches to control progression of AD, by preventing the abnormal generation of Aβ. For this reason, in the last decade, many research efforts have focused at the identification of new BACE1 inhibitors as drug candidates. Generally, BACE1 inhibitors are grouped into two families: substrate-based inhibitors, designed as peptidomimetic inhibitors, and non-peptidomimetic ones. The research on non-peptidomimetic small molecules BACE1 inhibitors remains the most interesting approach, since these compounds hold an improved bioavailability after systemic administration, due to a good blood-brain barrier permeability in comparison to peptidomimetic inhibitors. Very recently, our research group discovered a new promising lead compound for the treatment of AD, named lipocrine, a hybrid derivative between lipoic acid and the AChE inhibitor (AChEI) tacrine, characterized by a tetrahydroacridinic moiety. Lipocrine is one of the first compounds able to inhibit the catalytic activity of AChE and AChE-induced amyloid-β aggregation and to protect against reactive oxygen species. Due to this interesting profile, lipocrine was also evaluated for BACE1 inhibitory activity, resulting in a potent lead compound for BACE1 inhibition. Starting from this interesting profile, a series of tetrahydroacridine analogues were synthesised varying the chain length between the two fragments. Moreover, following the approach of combining in a single molecule two different pharmacophores, we designed and synthesised different compounds bearing the moieties of known AChEIs (rivastigmine and caproctamine) coupled with lipoic acid, since it was shown that dithiolane group is an important structural feature of lipocrine for the optimal inhibition of BACE1. All the tetrahydroacridines, rivastigmine and caproctamine-based compounds, were evaluated for BACE1 inhibitory activity in a FRET (fluorescence resonance energy transfer) enzymatic assay (test A). With the aim to enhancing the biological activity of the lead compound, we applied the molecular simplification approach to design and synthesize novel heterocyclic compounds related to lipocrine, in which the tetrahydroacridine moiety was replaced by 4-amino-quinoline or 4-amino-quinazoline rings. All the synthesized compounds were also evaluated in a modified FRET enzymatic assay (test B), changing the fluorescent substrate for enzymatic BACE1 cleavage. This test method guided deep structure-activity relationships for BACE1 inhibition on the most promising quinazoline-based derivatives. By varying the substituent on the 2-position of the quinazoline ring and by replacing the lipoic acid residue in lateral chain with different moieties (i.e. trans-ferulic acid, a known antioxidant molecule), a series of quinazoline derivatives were obtained. In order to confirm inhibitory activity of the most active compounds, they were evaluated with a third FRET assay (test C) which, surprisingly, did not confirm the previous good activity profiles. An evaluation study of kinetic parameters of the three assays revealed that method C is endowed with the best specificity and enzymatic efficiency. Biological evaluation of the modified 2,4-diamino-quinazoline derivatives measured through the method C, allow to obtain a new lead compound bearing the trans-ferulic acid residue coupled to 2,4-diamino-quinazoline core endowed with a good BACE1 inhibitory activity (IC50 = 0.8 mM). We reported on the variability of the results in the three different FRET assays that are known to have some disadvantages in term of interference rates that are strongly dependent on compound properties. The observed results variability could be also ascribed to different enzyme origin, varied substrate and different fluorescent groups. The inhibitors should be tested on a parallel screening in order to have a more reliable data prior to be tested into cellular assay. With this aim, preliminary cellular BACE1 inhibition assay carried out on lipocrine confirmed a good cellular activity profile (EC50 = 3.7 mM) strengthening the idea to find a small molecule non-peptidomimetic compound as BACE1 inhibitor. In conclusion, the present study allowed to identify a new lead compound endowed with BACE1 inhibitory activity in submicromolar range. Further lead optimization to the obtained derivative is needed in order to obtain a more potent and a selective BACE1 inhibitor based on 2,4-diamino-quinazoline scaffold. A side project related to the synthesis of novel enzymatic inhibitors of BACE1 in order to explore the pseudopeptidic transition-state isosteres chemistry was carried out during research stage at Università de Montrèal (Canada) in Hanessian's group. The aim of this work has been the synthesis of the δ-aminocyclohexane carboxylic acid motif with stereochemically defined substitution to incorporating such a constrained core in potential BACE1 inhibitors. This fragment, endowed with reduced peptidic character, is not known in the context of peptidomimetic design. In particular, we envisioned an alternative route based on an organocatalytic asymmetric conjugate addition of nitroalkanes to cyclohexenone in presence of D-proline and trans-2,5-dimethylpiperazine. The enantioenriched obtained 3-(α-nitroalkyl)-cyclohexanones were further functionalized to give the corresponding δ-nitroalkyl cyclohexane carboxylic acids. These intermediates were elaborated to the target structures 3-(α-aminoalkyl)-1-cyclohexane carboxylic acids in a new readily accessible way.