Synthesis of pyrrole-based inhibitors of the macrophage infectivity potentiator proteins

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Supervisors: Prof. Dr. Ulrike Holzgrabe PharmDr. Jaroslav Roh, PhD Candidate: Josef Skoda Title of diploma thesis: Synthesis of pyrrole macrophage infectivity potentiator inhibitors Pathogens Burkholderia pseudomallei and Legionella pneumophila cause severe diseases like Legionnaire's disease and melioidosis. While Legionnaire's disease manifests as acute pneumonia, melioidosis has different clinical features and ends by multi-organ involvement and septic shock. Low sensibility of gram negative bacteria B. pseudomallei and L. pneumophila to antibiotics together with threatening resistance represent a great problem. For these pathogens their virulent factor macrophage infectivity potentiator (MIP) protein is a suitable target. MIP proteins are peptidyl/prolyl cis/trans isomerases, highly important factor of penetration and dissemination for B. pseudomallei a L. pneumophila. MIP protein belongs to FK506 binding protein (FKBPs) superfamily, which forms highly stable complex with its inhibitors tacrolimus and rapamycin. Due their immunosuppressive activity, these drugs are contraindicated for treatment of infection diseases. However inhibition of the protein proves that MIP protein is..