Molecular modeling and antimycobacterial studies of Mannich bases: 5-hydroxy-2-methyl-4H-pyran-4-ones

摘要

The World Health Organization lists tuberculosis among thetop 3 leading causes of death from a single infectious agent, andreported cases of multidrug-resistant tuberculosis (MDR-TB) are on therise.In an attempt to improve MDR-TB drug-directed therapy, we synthesized 11 4-substituted piperazine derivatives of 3-hydroxy-6-methyl-4H-pyran-4-one pharmacophore by reacting 5-hydroxy-2-methyl-4H-pyran-4-one with suitable piperazine derivatives under Mannich reaction conditions.Inhibitory effects of the 11 compounds on Escherichia coli DNA gyrasewere evaluated via DNA gyrase supercoiling assay. The minimuminhibitory concentrations (MIC) of the 11 compounds and 41 compoundsfrom our previous studies against Mycobacterium tuberculosis H37RVwere assessed, in vitro, by a broth dilution method. To determine theinteraction pattern between active site amino acids and all 52compounds, homology modeling for the construction of M. tuberculosisDNA gyrase B subunit was performed, followed by a docking study.The data presented here could prove useful in future studies on interaction field analysis and high throughput virtual screening of the derivatives of the 3-hydroxy-6-methyl-4H-pyran-4-one pharmacophore toward the development of more clinically applicable compounds.