SÍNTESE DE ANÁLOGOS ISOXAZÓLICOS HÍBRIDOS COM POTENCIAL ATIVIDADE CONTRA TUBERCULOSE

Abstract

Tuberculosis (TB), a disease caused by the bacterium Mycobacterium tuberculosis, is a serious public health problematic that infects a quarter of the world's population, sickens 10.4 million people, and claims 1.7 million lives. Its treatment is multidrug and presents a series of problems, such as long duration (six months to two years), high complexity, numerous adverse effects, resistant bacterial strains, and lack of interest from the pharmaceutical industries (lack of innovation). Therefore, the discovery of new compounds against TB is vital. In this sense, as candidates, it arises the isoxazoles, natural and synthetic compounds with a broad spectrum of biological activities such as antibacterial activity, including activity against M. tuberculosis. In parallel, some drugs used in the treatment of TB, such as isoniazid, linezolid and fluoroquinolones, exhibit appreciable structural characteristics for the development of new drugs against TB. In planning new candidates for anti-tuberculosis drugs, molecular hybridization has emerged as one of the best tools. Within this context, this work aimed to plan, synthesize and characterize 48 new isoxazole analogues hybridized with pyridine ring of isoniazid and cyclic amines found in fluoroquinolones and in linezolid and 48 analogues of chalcones hybridized with pyridine ring of isoniazid and cyclic and fluorine amines found in fluoroquinolones and linezolid and to evaluate biological activity against M. tuberculosis. The initial synthetic route to obtain these isoxazoles proposed to obtain them from the reaction of hydroxylamine with 48 chalcones. However, 24 of these chalcones turned out to be unstable, 9a-x, that is, 24 isoxazoles, 11a-x, would no longer be obtained from them. A new route was unsuccessfully conducted to obtain 11a-x isoxazoles through 1,3-dipolar cycloaddition. On the other hand, from 24 stable chalcones, 8a-x, 20 isoxazoles 10a-x were obtained with yields between 08 and 99%. However, some were obtained in a mixture of regio-isomers (10a-x and 11a-x). In this way, 20 unpublished 10-a-x isoxazole analogues were obtained using an unpublished methodology. Some analogues were obtained in the form of two regio-isomers. Four could not be synthesized. Therefore, a synthesis methodology was standardized and the 20 unpublished compounds were obtained, all characterized by techniques such as ¹H NMR, ¹³C NMR and EM. In parallel, 24 azachalcones 30a-x, hybridized with the pyridine ring of isoniazid and cyclic amines and fluorine found in fluoroquinolones and linezolid, were successfully obtained with yields between 20% and 99% and adequately characterized by techniques such as ¹H NMR, ¹³C NMR and MS. The 24 chalcones 31a-x could not be obtained, as the synthesis of their precursors presented problems. It is expected to receive the data on the in vitro biological activity against Mycobacterium tuberculosis and cytotoxicity on mammalian cells and carry out a study of the biological structure-activity relationship.