Investigação do uso de bentonita e solventes eutéticos profundos na síntese de N´-(2-oxoindolin-3-ilideno) hidrazidas assistida por micro-ondas com potencial atividade biológica

Abstract

N-(2-oxoindolin-3-ylidene) hydrazides are imines derived from isatin, which contains the indoline core, found in various structures of bioactive molecules. However, the most used protocols to obtain it use solvents that are toxic, flammable and increase the production of waste. This work presents a Green Chemistry proposal for the synthesis of these compounds, aiming to exclude or to minimize the use of commonly used solvents in the synthesis of these imines, such as methanol and acetonitrile. The ecological protocols that were investigated in this work involve the use of bentonite or deep eutectic solvents as catalysts, both with desirable properties for Green Chemistry such as low toxicity, accessibility, ease of handling and reuse. The influence of energy source, type and amount of catalyst, absence/presence of solvents, as well as the use of deep eutectic solvents were investigated. The study demonstrated the catalytic application of bentonite under heterogeneous conditions or without solvents, irradiated by microwaves in the synthesis of 12 products derived from isatin and benzhydrazide, six of which are new. The use of bentonite in the absence of solvents promoted yields of 37-96%, using microwaves, in times of 15-60 minutes. Bentonite could be reused for three cycles, without loss of efficiency for the synthesis of Schiff's base, resultant from the reaction between isatin and benzhydrazide. The eutectic solvent derived from the combination of benzalkonium chloride (hydrogen bond acceptor species) and lactic acid (hydrogen bond donor species) provided excellent yield for the molecule that originated from isatin, without substitution in the aromatic ring (99% in 10 minutes). The protocol was extended to N-alkylated molecules, where it was possible to obtain products with yields of 71-73%. However, the use of this eutectic solvent proved to be unsatisfactory for the other isatin derivatives with substitution in the aromatic ring. The methodology using bentonite proved to be more efficient and in most cases, the results were superior to those found in the literature, with the advantage of promoting a chemistry that comes close to meeting some aspects of Green Chemistry. Additional investigations regarding potential biological activity were performed through preliminary in silico evaluation of molecular docking and pharmacokinetic properties. Molecular docking results pointed to affinities of all synthesized compounds with DNA-gyrase, a bacterial target previously recognized by analogous compounds, with the nitrated hydrazide containing the N-allylated portion (2l) having the best binding energy value. Furthermore, all molecules showed a tendency towards good oral bioavailability, proving to be a promising class for future investigations.