ABSTRACT Malaria and leishmaniasis are potentially lethal protozoan diseases affecting a huge number of people worldwide, especially in underdeveloped countries. The alarming spread of drug resistance concerning both Plasmodium and Leishmania parasites makes the search of novel antimalarial and antileishmanial agents an urgent need. Unfortunately, at the moment even the combination therapies are failing in many regions afflicted by the diseases and alternatives are scarcely found. In addition, the available antileishmanial drugs are quite toxic, expensive and very often need monitoring and hospitalization. In the light of this dramatic situation, the discovery of novel effective, safe and affordable molecules is vital. Thus far, several strategies have been developed to overcome resistance mechanisms; among them, of particular interest are the structural optimization of already known antiprotozoal molecules, the development of hybrid compounds and the search of new chemical scaffolds. Based on these considerations, the aim of the present thesis was the synthesis of different novel sets of molecules, potentially candidates for the treatment of malaria and/or leishmaniasis. On one hand I prepared derivatives of the antiprotozoal agents chloroquine and clofazimine, in order to improve the biological activity and to reduce resistance mechanisms. On the other hand, I explored the potenzialities of new chemical scaffolds, such as indeno[2,1-c]quinolines, to design new antimalarials. Moreover, I evaluated the possibility of creating hybrid molecules, combining moieties with different mechanism of action which could carry out a synergistic effect. In particular, the quinoline nucleus has been combined with different HDACs inhibiting structures to generate antiplasmodial hybrids, whereas aphidicolin (a fungal metabolite with antileishmanial activity) has been condensed with other molecules endowed with antileishmanial activity, such as ethyl 3-chloroacetamidobenzoate and eflornithine. Biological assays were in general quite encouraging and suggested that these new classes of compounds could be considered as potential leads for the synthesis of new effective antiprotozoal drugs that, in some cases, could hopefully overcome resistance mechanisms.
SYNTHESIS OF NEW POLYCYCLIC COMPOUNDS WITH POTENTIAL ANTIMALARIAL AND/OR ANTILEISHMANIAL ACTIVITY / A. Barteselli ; tutor: A. Sparatore ; coordinatore: E. Valoti. - Milano : Università degli studi di Milano. DIPARTIMENTO DI SCIENZE FARMACEUTICHE, 2015 Jan 15. ((27. ciclo, Anno Accademico 2014.
|Titolo:||SYNTHESIS OF NEW POLYCYCLIC COMPOUNDS WITH POTENTIAL ANTIMALARIAL AND/OR ANTILEISHMANIAL ACTIVITY|
|Supervisori e coordinatori interni:||VALOTI, ERMANNO|
|Data di pubblicazione:||15-gen-2015|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
|Citazione:||SYNTHESIS OF NEW POLYCYCLIC COMPOUNDS WITH POTENTIAL ANTIMALARIAL AND/OR ANTILEISHMANIAL ACTIVITY / A. Barteselli ; tutor: A. Sparatore ; coordinatore: E. Valoti. - Milano : Università degli studi di Milano. DIPARTIMENTO DI SCIENZE FARMACEUTICHE, 2015 Jan 15. ((27. ciclo, Anno Accademico 2014.|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.13130/barteselli-anna_phd2015-01-15|
|Appare nelle tipologie:||Tesi di dottorato|