Síntese de derivados da isoniazida, potenciais agentes antimicrobianos e estudo visando a síntese da alloenduracididina via reações de aziridinação intramolecular

Abstract

Tuberculosis occupies a prominent place among the neglected diseases, mainly due to the great number of deaths that it causes all around the world. Isoniazid (INH) is one of the oldest and most common drugs used in the treatment of tuberculosis. However, despite its excellent antimycobacterial activity, INH causes side effects related to its hepatic and neuronal toxicity and cases of isoniazid resistant strains of the bacillus have emerged worldwide. The first chapter of this work describes the synthesis of potential new antitubercular compounds obtained from the condensation of D-galactose or curcumin derivatives with isoniazid. The synthesized compounds were evaluated in vitro against Mycobacterium tuberculosis. The results showed that the citral-derived isoniazid analogue has an activity similar to INH and when it was encapsulated using the system of PLGA nanoparticles (poly-lactic-co-glycolic acid) its activity was increased. INH was also encapsulated in Hp-β-cyclodextrin, Me-β-cyclodextrin, psulphonic acid calixar[4]ene (SO3CX4) and p-sulphonic acid calixar[6]ene (SO3CX6) and the supramolecular system thus obtained were studied using 1H NMR as the major tool. The antitubercular activity (1.6 - 2.6 µmol/L) of these complexes was similar to that of INH (1.5 µmol/L). The second chapter describes the results obtained in the preparation of the amino acid alloenduracididine using synthetic strategy analogous to that used for the preparation of enduracididine. The cyclic guanidine was obtained by the reaction of a isothiourea with 4,5-diamine prepared from an aziridine intermediate. The late one was obtained by a rhodium-catalyzed intramolecular aziridination of (2R)-2-(tertbutoxycarbonyl)-aminopent-4-enyl sulfamate with iodosylbenzene. The application of the methodology developed in the course of the work to appropriate substrates will lead to the preparation of other amino acids containing the guanidinium group.