Medicinal Chemistry

Boronic-aurone Derivatives as Anti-Tubercular Agents: Design, Synthesis and Biological Evaluation

Abstract

Francis E Umesiri, Ashley Lick, Christine Fricke and Thomas I Nathaniel

Purpose: Current study involved the design, synthesis and biological evaluation of novel boronic-aurones as anti-tubercular agents targeting inhibition of antigen 85, enzymatic complex involved in synthesis of mycobacterial cell wall. To minimize the probability of a single mutation leading to resistance, it is important to target multiple enzymes implicated in mycobacterium cell wall biosynthesis. Hence, new synthetics were virtually screened against both antigen 85 and enoyl-[acyl-carrier-protein] reductase (InhA).
Methods: Using a structure-based approach, new boronic aurone derivatives were designed to target both antigen 85 and InhA, synthesized and screened for anti-tuberculosis activity against Mycobacterium smegmatis. Minimum inhibitory concentration(MIC) was determined using resazurin-based assay.

Results: Compound CF1 was the most active boronic aurone analog, with MIC of 0.083 mg/mL; followed by CF2 with MIC of 0.100 mg/mL. AL10 and AL11 both exhibited the same MIC of 0.125 mg/mL. Although AL10 and AL11 scored higher in terms of binding affinity during molecular docking, CF2 and CF1 both exhibited higher antimycobacterial activity, showing the importance of hydroxyl groups on aurone core.

Conclusion: This study demonstrates, for the first time, that anti-tuberculosis activity of boronic-aurone derivatives is significant enough, compared to isoniazid, to warrant further investigation.