Synthesis, biological activity and molecular modelling studies of shikimic acid derivatives as inhibitors of the shikimate dehydrogenase enzyme of Escherichia coli

Abstract

Shikimic acid (SA) pathway is the common route used by bacteria, plants, fungi, algae, and certain Apicomplexa parasites for the biosynthesis of aromatic amino acids and other secondary metabolites. As this essential pathway is absent in mammals designing inhibitors against implied enzymes may lead to the development of antimicrobial and herbicidal agents harmless to humans. Shikimate dehydrogenase (SDH) is the fourth enzyme of the SA pathway. In this contribution, a series of SA amide derivatives were synthesised and evaluated for in vitro SDH inhibition and antibacterial activity against Escherichia coli. All tested compounds showed to be mixed type inhibitors; diamide derivatives displayed more inhibitory activity than synthesised monoamides. Among the evaluated compounds, molecules called 4a and 4b were the most active derivatives with IC₅₀ 588 and 589 µM, respectively. Molecular modelling studies suggested two different binding modes of monoamide and diamide derivatives to the SDH enzyme of E. coli.

Keywords: Escherichia coli; Shikimate dehydrogenase; amide derivative synthesis; enzyme inhibition; molecular docking; shikimic acid.

Scheme 1.

Synthesis of monoamides 3a–d.

Scheme 2.

Synthesis of diamides 4a–c.

Figure 1.

Lineweaver–Burk plots for inhibitory activity of mono and di amides against EcSDH. Lineweaver–Burk plots of EcSDH activity in the presence of (A) 3d and (B) 4b. Substrate DHS concentrations were 0.0625, 0.125, 0.25, 0.5, 1.0 and 1.5 mM, respectively. The data represent the average of three experiments.

Figure 2.

Predicted binding modes of mono and di amides to EcSDH. (A, C) Three-dimensional representations of EcSDH in complex with 3d (yellow carbons) and 4b (magenta carbons). The most involved residues are labelled and shown as green carbons. Hydrogen bonds are represented as black dashed lines. (B, D) Surface and stick representations of the proposed binding modes of synthesised amides.