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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Primi, Marina C. [1, 2, 3] ; Tavares, Mauricio T. [4] ; Klein, Larry L. [1] ; Izard, Tina [3] ; Sant'Anna, Carlos M. R. [5] ; Franzblau, Scott G. [1] ; Ferreira, I, Elizabeth
Total Authors: 7
[1] Univ Illinois, Coll Pharm, Inst TB Res, Chicago, IL - USA
[2] I, Univ Sao Paulo, Fac Pharmaceut Sci, Dept Pharm, Sao Paulo - Brazil
[3] Scripps Res Inst, Dept Integrat Struct & Computat Biol, Jupiter, FL - USA
[4] Scripps Res Inst, Dept Mol Med, Jupiter, FL - USA
[5] Univ Fed Rural Rio de Janeiro, Dept Fundamental Chem, Inst Chem, Seropedica - Brazil
Total Affiliations: 5
Document type: Journal article
Source: CURRENT TOPICS IN MEDICINAL CHEMISTRY; v. 21, n. 13, p. 1186-1197, 2021.
Web of Science Citations: 0

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. (AU)

FAPESP's process: 13/15947-3 - New antituberculosis agents candidates: design and synthesis of phosphopantetheine adenylyltransferase inhibitors
Grantee:Marina Candido Primi
Support Opportunities: Scholarships in Brazil - Doctorate
FAPESP's process: 15/21470-0 - In vitro tests of phosphopantetheine adenililtrasferase inhibitors potentially active against Mycobacterium tuberculosis and design of novel compounds
Grantee:Marina Candido Primi
Support Opportunities: Scholarships abroad - Research Internship - Doctorate