Design, synthesis, in vitro and in silico biological assays of new quinazolinone-2-thio-metronidazole derivatives

Abstract

• Discovery of quinazolinone-2-thio-metronidazole derivatives as a novel class of metabolic enzyme inhibitors. • The title compounds demonstrated significant inhibitory activities against studied enzymes hCA I, hCA II, AChE, BChE, and α-glucosidase. • The most potent compounds interacted with main residues in the active site of target enzymes. • In silico pharmacokinetic study of the most potent compounds was also performed. A new series of quinazolinone-2-thio-metronidazole derivatives 9a-o was designed, synthesized and assayed for their activities against metabolic enzymes human carbonic anhydrase I and II (hCAs I and II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glucosidase. The results indicated that all the synthesized compounds exhibited excellent inhibitory activities against mentioned enzymes as compared with standard inhibitors. Representatively, the most potent compound against CA enzymes, 4-fluorophenyl derivative 9i , was 4 and 7-times more potent than standard inhibitor acetazolamide against hCA I and II, respectively; 4-fluorobenzyl derivative 9m as the most potent compound against cholinesterase enzymes, was around 11 and 21-times more potent than standard inhibitor tacrine against AChE and BChE, respectively; the most active α-glucosidase inhibitor 9h with 4-methoxyphenyl moiety was 5-times more active that acarbose as standard inhibitor. Furthermore, in order to study interaction modes of the most potent compounds in the active site of their related enzymes, molecular modeling was performed. Druglikeness, ADME, and toxicity profile of the compounds 9i, 9m , and 9h were also predicted.