Síntese de derivados fluoroquinolônicos e estudos visando a obtenção de beta-lactamas, potenciais agentes antibacterianos

Abstract

This work describes the search for new antitubercular drugs and it was divided in two chapters. The chapter 1 describes the synthesis and biological evaluation of 20 new fluoroquinolones derivatives. The modifications were focused in C7 position of quinolone nucleus and it was investigated two different approaches. In the firstone the substitution of the diamine moiety present in gatifloxacin or moxifloxacin structure by N-alkylated 1,2-ethanediamine or 1,3-propanediamine furnished 12 news lipophilic compounds. These compounds were prepared by reaction of difluoride 13 with different N-alkyl-1,2-ethanediamine or N-alkyl-1,3-propanediamine. The in vitro biological evaluation against M. tuberculosis was performed and the results showed that compound 23 was more active than moxifloxacin (currently in phase III of clinical trials against tuberculosis). Aiming to profit from a broad spectrum of activity presented by fluoroquinolones, these 12 N-alkylated derivatives were evaluated against 15 other bacterial strains including Gram-negative and Gram-positive species of clinical and microbiological importance. When compared with gatifloxacin compounds 23 and 22 were 10 and 16 time more active, respectively, against M. lentus. Derivatives 23 and 24 were twice more active against S. aureus. Another approach was based on the synthesis of new analogues of cipro-, gati-, and moxifloxacin having carbohydrate moiety coupled with these fluoroquinolones, either by the free amino group of these compounds or by the condensation of diaminosugars with difluoride 13. In this part the microwave irradiation provided reactions with better yields and shorter times than the conventional heating. The biological activity of these compounds was evaluated and in order to rationalize the observed activity, theoretical calculations were made for cipro-, gati-, moxifloxacin and compounds 35 and 39. The chapter 2 showed the results of the research realized at Institut de Chimie des Substances Naturelles-Centre National de la Recherche Scientifique (ICSN- CNRS)-France as part of a PhD traineeship. This part describes the development of a new synthetic route aiming the β-lactam derivative synthesis. This strategy was based on rhodium catalysis intramolecular aziridination by nitrene transfer of 5-O- sulfamoylbutenolide 57, to furnish the unusual tricyclic compound 58. The aziridine ring opening was performed with various amines and solvents, and the results were optimized, furnishing the products of regioselective aziridine ring opening in good yields. The lactone ring opening was achieved in good yield using just methanol. The protection/activation of sulfamate ring was performed with various protecting groups and good yields were obtained. The sulfamate ring opening was performed with various nucleophiles to furnish the respectives α,β-diamino ester. The β-amino group was unprotected and three trials for lactamization step were performed, but the aimed product was not observed. Other trials are required for this last step. The extremely functionalized α,β-diamino esters obtained could be used as valuable building blocks on organic chemistry including as precursors on β-lactams synthesis.