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

Autor(es)

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

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: CURRENT TOPICS IN MEDICINAL CHEMISTRY; v. 21, n. 13, p. 1186-1197, 2021.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 13/15947-3 - Candidatos a novos agentes tuberculostáticos: planejamento e síntese de inibidores da fosfopanteteína adenililtransferase
• Beneficiário: Marina Candido Primi
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 15/21470-0 - Ensaios in vitro de inibidores da fosfopanteteína adenililtransferase potencialmente ativos contra tuberculose e planejamento de novos inibidores potenciais
• Beneficiário: Marina Candido Primi
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado