Síntese assistida por micro-ondas de novos espiros 1,3,4-tiadiazóis derivados da isatina com potencial atividade biológica

Abstract

This work was executed aiming the synthesis of 12 spiro-1,3,4-thiadiazoles derived from isatin (3a-3l), including 9 novel ones, using microwave as heating source and investigating the antimicrobial and antitumoral activities. Chlorinated and N-alkylated isatin derivatives were synthetized and used as substrates to the obtainment of thiosemicarbazones (2a-2l) under microwave irradiation. These intermediates were obtained in short reaction times and yields of between 53-88%. The final reaction step consisted on the thiosemicarbazones cyclization (2a-2l) using acetic anhydride and microwave irradiation. The spiro-1,3,4-thiadiazoles (3a-3l) derived from isatin were produced in reaction times between 6 to 18 minutes, presenting yields around 25-90%. All the compounds were characterized by spectroscopic techniques of NMR 13C and NMR 1H. The antimicrobial and anticancer activities of these compounds were evaluated. 5 from 10 evaluated compounds showed antimicrobial activity, highlighting 3d (dichlorinated and N-allylated) and 3g (N-allylated) that presented the minor values of Minimum Inhibitory Concentration (137.5 μg / mL) to all the tested microorganisms, except for P. aureuginosa ATCC – 9027 that was sensitive to the N-allylated 3g at 550 μg/mL. A preliminary assessment of cytotoxic activity in 3 tumour cell lines (HT-29, K562 e HL60) showed only the dichlorinated and N-benzylated spiro-compound 3e as active, obtaining IC50 = 6,8 μM. An in silico investigation demonstrated that the spiro-compounds 3d, 3e and 3g are potential drug candidates with satisfactory oral bioavailability calculated.