Synthesis of quinazolin-4(3H)-ones in natural deep eutectic solvents: Comparison of various synthetic methods and calculation of ADME properties

Abstract

In this work, natural deep eutectic solvents (NADESs) were used as a worthy alternative to organic solvents in combination with microwave-assisted, ultrasound-assisted, and mechanochemical synthesis for the preparation of substituted quinazolin-4(3H)-one derivatives 1–29. Choline chloride-based (ChCl) NADESs were tested in the condensation of 2-methylbenzoxazin-4-ones (f–j) and amines or hydrazides to obtain substituted quinazolin-4(3H)-one derivatives. The reaction conditions were optimized for each method using 2-methylbenzoxazin-4-one and 4-chloroaniline as model substrates. Their structures were also confirmed by 1H- and 13C NMR and mass spectrometry. Prediction of biological activities and drug-like properties of the compounds was performed by in silico methods. Among 20 tested NADESs, choline chloride/urea was proven to be the best solvent and catalyst system for the synthesis of target compounds. Synthesized quinazolin-4(3H)-ones were obtained conventionally with 17–73% yields, by microwave-assisted synthesis (10–41%), ultrasound-assisted synthesis (15–56%), and mechanochemical synthesis (45–87%), respectively. Synthesized quinazolin-4(3H)-ones have the potential to be anticonvulsants, skeletal muscle relaxants, and antifungal drugs. These green procedures provide better methods for the synthesis of substituted quinazolin-4(3H)-ones, because mechanochemical synthesis, among others, shown the best efficiency. Leading compounds for the design of future drugs were pointed out.