Síntese de dipeptídeos miméticos com potencial uso na terapia da osteoporose e desenvolvimento de nova metodologia para obtenção de 2-amino-1,3,4-oxadiazois

Abstract

This work is divided into two chapters. In chapter I, new nitrile dipeptides and amino-1,3,4-oxadiazole derivatives were synthesized and their potential for the management of osteoporosis disease was evaluated. Chapter II approach the development of a new methodology for the synthesis of the amino-1,3,4-oxadiazole core. Osteoporosis is a metabolic bone disease, characterized by decreasing bone mass and increase of fractures risks. The currently treatment used for this disease cause several side effects in patients, so research for new anti-osteoporosis therapies is an important challenge in many knowledge fields. Promising targets for the development of new anti-osteoporosis therapies include selective cathepsin K inhibitors (a cysteine protease expressed mainly in osteoclast cells, which are involved in degradation of bone matrix). In this work, 16 new dipeptides compounds and 7 amino-1,3,4-oxadiazole derivatives, whose molecular structures are based on scaffolds of cathepsin K inhibitors, were synthesized. The new derivatives were evaluated as cathepsin K inhibitors, and the compound 38a containing the amino-1,3,4-oxadiazole core display an excellent inhibitory activity, with Ki = 2.13 μM. In vitro tests with osteoblast and osteoclast cells and human mesenchymal stem cells were performed, and the results have shown that the compounds can able stimulated the osteoblast activity, and not acting negatively in osteoclast activity, in addition, these compounds showed an osteogenic potential in stem cells human mesenchymal. The results suggested that amino-1,3,4-oxadiazole core display a remarkable potential as a building block for new drugs for anti-osteoporosis therapies. In view that compounds containing amino-1,3,4-oxadiazole core have a broad range spectrum of biological activities and considerable applications in several areas, a new synthetic methodology was developed for the construction of this heterocycle using an electrophilic nitrile source less toxic and accessible. The new protocol was employed for the synthesis of the amino-1,3,4-oxadiazole derivatives 47a-g achieved yields range 42 to 70%.