Design of Novel Phosphopantetheine Adenylyltransferase Inhibitors: A Potential New Approach to Tackle Mycobacterium tuberculosis

Author(s): Marina C. Primi, Maurício T. Tavares, Larry L. Klein, Tina Izard, Carlos M. R. Sant'Anna, Scott G. Franzblau, Elizabeth I. Ferreira*

Journal Name: Current Topics in Medicinal Chemistry

Volume 21 , Issue 13 , 2021


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Abstract:

Background: Tuberculosis (TB) has been a challenging disease worldwide, especially for the neglected poor populations. Presently, there are approximately 2 billion people infected with TB worldwide and 10 million people in the world fell ill with active TB, leading to 1.5 million deaths.

Introduction: The classic treatment is extensive and the drug- and multi-drug resistance of Mycobacterium tuberculosis has been a threat to the efficacy of the drugs currently used. Therefore, the rational design of new anti-TB candidates is urgently needed.

Methods: With the aim of contributing to face this challenge, 78 compounds have been proposed based on SBDD (Structure-Based Drug Design) strategies applied to target the M. tuberculosis phosphopantetheine adenylyltransferase (MtPPAT) enzyme. Ligand-Based Drug Design (LBDD) strategies were also used for establishing Structure-Activity Relationships (SAR) and for optimizing the structures. MtPPAT is important for the biosynthesis of coenzyme A (CoA) and it has been studied recently toward the discovery of new inhibitors.

Results: After docking simulations and enthalpy calculations, the interaction of selected compounds with MtPPAT was found to be energetically favorable. The most promising compounds were then synthesized and submitted to anti-M. tuberculosis and MtPPAT inhibition assays.

Conclusion: One of the compounds synthesized (MCP163), showed the highest activity in both of these assays.

Keywords: PPAT, TB, Coenzyme A, Enzyme inhibition, Antibiotics, Chemotherapy, Mycobacteria.

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Article Details

VOLUME: 21
ISSUE: 13
Year: 2021
Published on: 27 July, 2021
Page: [1186 - 1197]
Pages: 12
DOI: 10.2174/1568026621666210728094804
Price: $65

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