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

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

Volume: 21 Issue: 13

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

Affiliation:

• Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo,Brazil

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

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.

Cite this article as:

Primi C. Marina, Tavares T. Maurício , Klein L. Larry , Izard Tina, Sant'Anna M. R. Carlos , Franzblau G. Scott and Ferreira I. Elizabeth*, Design of Novel Phosphopantetheine Adenylyltransferase Inhibitors: A Potential New Approach to Tackle Mycobacterium tuberculosis, Current Topics in Medicinal Chemistry 2021; 21 (13) . https://dx.doi.org/10.2174/1568026621666210728094804