Design, synthesis, and in vitro biological evaluation of dehydroaripiprazole derivatives as antituberculosis agents and molecular docking study

Abstract

In this study, we describe the synthesis of novel piperazine-substituted 7-(4-chlorobutoxy) quinolin-2(1H) derivatives 5a–z, which were designed through specific structural modifications of aripiprazole. Furthermore, the synthesized derivatives were described as potent in vitro inhibitors of Mycobacterium tuberculosis (MTB) H37Rv strain growth. Among these compounds, 5c, 5 h, and 5r were found to be the most active ones with a MIC of 0.78 μg/mL. This activity is better compared to that of ethambutol (MIC = 1.56 μg/mL). These compounds failed to inhibit normal RAW 264.7 macrophages. Moreover, in vitro findings were supported by molecular docking studies with the known anti-TB target (InhA). The molecular docking studies on 5c, 5 h, and 5r hit compounds clearly validated hydrogen bonds interactions with the Enoyl-acp reductase (INHA). Therefore, these results indicate that this class of compounds may provide candidates for future development, and hopefully provide drug alternatives for tuberculosis treatment.

Keywords

• Dehydro-aripiprazole
• Aripiprazole
• Aripiprazole lauroxil
• Brexpiprazole
• Mycobacterium tuberculosis
• Enoyl-acp reductase