Discovery of efficient inhibitors against pyruvate dehydrogenase complex component E1 with bactericidal activity...

Area of Science:

• Medicinal Chemistry
• Agrochemistry
• Computational Chemistry

Background:

• Computer-aided drug design (CADD) is crucial for developing new agrochemicals.
• Optimization of lead compounds accelerates the discovery process.
• Pyruvate dehydrogenase complex component E1 (PDHc-E1) is a potential target for novel bactericides.

Purpose of the Study:

• To rationally design and synthesize novel PDHc-E1 inhibitors using CADD.
• To evaluate the inhibitory activity of designed compounds against bacterial PDHc-E1.
• To assess the potential of these compounds as agrochemical bactericides.

Main Methods:

• Rational design of 2,6-dimethyl-4-aminopyrimidine acylhydrazones using CADD.
• Enzymatic assays to determine inhibitory activity against E. coli and porcine PDHc-E1.
• Molecular docking and site-directed mutagenesis to elucidate binding modes.
• In vitro antibacterial assays against Ralstonia solanacearum.

Main Results:

• A series of 2,6-dimethyl-4-aminopyrimidine acylhydrazones (6) were designed as PDHc-E1 inhibitors.
• Compound 6l exhibited potent inhibition against E. coli PDHc-E1 (IC50 = 95 nM), outperforming the lead compound A2.
• Compounds demonstrated high selectivity, with negligible inhibition against porcine PDHc-E1.
• Several compounds (6a, 6d, 6e, 6g, 6h, 6i, 6m, 6n) showed significant in vitro antibacterial activity against R. solanacearum.

Conclusions:

• CADD is effective for designing selective PDHc-E1 inhibitors.
• The designed acylhydrazones represent a promising lead structure for novel agrochemical bactericides.
• The compounds exhibit potent and selective inhibition of bacterial PDHc-E1, leading to antibacterial effects.