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