PLANEJAMENTO, SÍNTESE E AVALIAÇÃO DA ATIVIDADE ANTILEISHMANIA DE ANÁLOGOS 3,5-DIARIL-1,2,4-OXADIAZÓIS INSPIRADOS NAS NEOLIGNANAS VERAGUESINA, GRANDISINA E MACHILINA G

Abstract

Leishmaniasis is a neglected disease that has made little progress in its eradication, becoming a reemerging disease. Brazil reported more than 54 thousand cases between the years 2001 to 2015 throughout its national territory. The disease has a high mortality, reaching almost 9% and leading to the death of about 90% of untreated patients. The treatments are not ideal, very long, with adverse reactions and still considered costly for the health system, in addition, few efforts have been invested in recent decades in search of new therapeutic schemes. All of this makes the search for new drugs for leishmaniasis necessary. The triazole and isoxazole heterocyclic analogues inspired by neolignans (veraguesine, grandisin and machilin G) have shown good antileishmania results in previous studies. In order to expand the bioispheric exchange studies of the neolignan tetrahydrofuran ring with other rings, 25 1,2,4-oxadiazole analogs were planned and synthesized in this work. The compounds were obtained with yields ranging from 26.7% to 75.4%. Among the new analogs, 6 of them showed good activities against promastigote forms of L. amazonensis, with compound 1.18 being the highlight with IC50 = 0.1  0.7 µM, being about 12 times more active than pentamidine (IC50 = 1.2 ± 0.3). The 1,2,4-oxadiazole analogs with greater activity showed a good pharmacokinetic and toxicological profile in silico evaluations.