Síntese de novos derivados de 3-aril-5-adamantano-1,2,4-oxadiazol e N’-hidróxi-carboximidamida-2-amino-1,4-naftoquinonas com potencial atividade citotóxica e antitumoral

Abstract

Heterocyclic compounds are present in numerous drugs. Heterocycles such as oxadiazole and imidazole have contributed to the development of new drugs with possible applications such as antiviral, antitumoral, anti-inflammatory and antimicrobial. In this work we propose the synthesis of a molecular diversity of 1,2,4-oxadiazoles and imidazol-naphthoquinones and evaluate their cytotoxic and antitumor potential. O-Acylamidoximes (3a-k) were synthesized via reaction of arylamidoximes (1a-k) with 1-adamantanecarbonyl chloride. Then, cyclocondensation of the O-acylamidoximes employing various methodologies provided the 1,2,4-oxadiazoles (4a-k). For the synthesis of N'-hydroxy-carboximidamide-2-amino-1,4-naphthoquinones (7a,c,f) and (8a-j) was used the reaction between 2-bromo-1,4-naphthoquinone (5) or to 2,3-dibromo-1,4-naphthoquinone (6) with the arylamidoximes (1a-j). In vitro cytotoxic assays were performed in Vero cells and murine fibroblasts, and in tumor cell lines: prostate adenocarcinoma, acute promyelocytic leukemia, colorectal carcinoma, glioblastoma, chronic and acute myeloid leukemia. O-Acylamidoximes (3a-k) were obtained in moderate-to-good yields (50-80%). The 1,2,4-oxadiazoles (4a-k) were obtained from 52 to 90% of yields. N'-hydroxy-carboximidamide-2-amino-1,4-naphthoquinones were synthesized in yields from 36 to 72% (7a,c,f) and from 47 to 82% (8a-j). In cytotoxic assays in Vero cells, 1,2,4-oxadiazoles were less toxic than O-acylamidoximes, having the compound 4g CC50 = 1797.0 μM. In assays with tumor cell lines, O-acylamidoximes (3a,d-h) showed a selective activity against leukemic cells. For acute promyelocytic leukemia (HL-60) cells, the tested compounds showed an inhibition above 90% at concentrations of 10 μg/ml and 25 μg/ml, and the compound 3e was the most active with IC50 = 19.50 μM for chronic myeloid cells (K562).