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

Francis E Umesiri

doi:10.4172/2161-0444.1000297

Abstract

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.

Highlights

Caused by Mycobacterium tuberculosis (MTB), tuberculosis (TB) has continued to pose major health challenges worldwide
We report on the design, synthesis, and biological evaluation of anti-tubercular activity of new boronic aurones against M. smegmatis, using a structure-based approach targeting antigen 85 (Ag85) and Enoyl-[acyl-carrier-protein] reductase (InhA)
To minimize the probability of a single mutation leading to resistance, we have argued elsewhere [4] that it may be beneficial to target multiple enzymes representing metabolic “hubs” which are essential for multiple biosynthetic pathways involved in mycobacterium cell wall synthesis

Summary

Introduction

Caused by Mycobacterium tuberculosis (MTB), tuberculosis (TB) has continued to pose major health challenges worldwide. Increasing incidence of drug resistance and co-infection with HIV/AIDS are making clinical management of the disease more difficult. An estimated 1.4 million people are reported to die annually from the disease across the globe [1]. About one-third of the world population is believed to be infected with latent form of MTB [2,3]. 13% (1.1 million) of the 8.6 million people who developed TB in 2012 were HIV positive. Of the 1.3 million deaths attributable to TB in 2012, 320 000 deaths were from people living with HIV/AIDS [2]. TB continues to be a major cause of death for people living with HIV/ AIDS

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Discussion

Conclusion