Among infectious diseases, two large groups have great clinical relevance: parasitic and bacterial infections. Belonging to the first category is malaria, caused by the parasite Plasmodium falciparum. Transmission of Plasmodium parasites between humans and Anopheles mosquitoes is one of the most important contributors to the global impact of malaria and to the difficulties encountered in eliminating this parasite1 . Gametocytogenesis, the process by which merozoites switch from asexual replication to produce male and female gametocytes, represents a critical step in malaria transmission and Plasmodium genetic diversity. Still too little is known about the biochemical events that regulate gametocytogenesis and there are few existing drugs able of inhibiting the gametocytes development and block malaria transmission2 . To encourage drug discovery and research, the non-profit foundation Medicines for Malaria Venture (MMV) has provided a library of 400 compounds that present antimalarial activity in the micromolar range, but their molecular targets and mode of action are not necessarily known3 . Here we describe the medchem investigation of one of the most promising hit compound included in this library, MMV019918. MMV019918 has been highlighted in several in vitro studies for its promising antigametocyte activity coupled to activity against schizonts. On the basis of its structure, the synthesis of a new series of compounds with transmission-blocking activity has been designed. It has been found very interesting the activity of one derivative NF2350 which resulted active also in the standard membrane feeding assay (SMFA), to measure subsequent mosquito infection, and which has an improved toxicological profile compared to MMV019918. A further investigation of NF2350 will allow us to optimize the transmission-blocking activity and to indentify its putative target. Regarding bacterial infections, a critical issue to be addressed is bacterial resistance to antibiotics and in particular to β-lactams. Metallo-β-lactamases (MBL) are a family of enzymes involved in the widespread mechanisms of resistance to beta-lactam antibiotics, The diffusion of MBL-producing isolates of Pseudomonas aeruginosa, a bacterial pathogen of primary relevance for both nosocomial and chronic infections of the respiratory tracts in cystic fibrosis patients, is notably increasing in some specific settings. No clinically useful MBLs inhibitors are currently available in therapy3 Here we will present the design, synthesis, and biological investigation of a series of functionalized 2-arylfuran compounds with sub-micromolar antiplasmodial activity, against both asexual and sexual stages. Furthermore, appropriate decoration of this molecular scaffold allowed to obtain activity against some isoforms of MBL (including IMP-1and NDM-1).
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|Titolo:||INVESTIGATION OF NOVEL THERAPEUTIC TOOLS AGAINST INFECTIOUS DISEASES Part 1. Medicinal Chemistry Investigation of MMV019918 Derivatives as Dual Schizonticide And Gametocytocidal Agents Against Plasmodium falciparum Part 2. Investigation of 5-Aryl-Heterocycles As Potential Inhibitors of Metallo beta-Lactamase Enzymes|
|Appare nelle tipologie:||8.1 Tesi Dottorato|
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