Synthesis, antimicrobial, anti-biofilm evaluation, and molecular modelling study of new chalcone linked amines derivatives

Abstract

A series of amide chalcones conjugated with different secondary amines were synthesised and characterised by different spectroscopic techniques ¹H NMR, ¹³C NMR, and ESI-MS. They were screened for in vitro antibacterial activity. Compounds 36, 37, 38, 42, and 44 are the most active among the synthesised series exhibiting MIC value of 2.0-10.0 µg/ml against different bacterial strains. Compound 36 was equipotent to the standard drug Ampicillin displaying MBC value of 2.0 µg/ml against the bacterial strain Staphylococcus aureus. The products were screened for anti-biofilm activity. Compounds 36, 37, and 38 exhibited promising anti-biofilm activity with IC₅₀ value ranges from 2.4 to 8.6 µg. Molecular modelling was performed suggesting parameters of signalling anti-biofilm mechanism. AspB327 HisB340 (arene-arene interaction) and IleB328 amino acid residues seemed of higher importance to inhibit c-di-GMP. Hydrophobicity may be crucial for activity. ADME calculations suggested that compounds 36, 37, and 38 could be used as good orally absorbed anti-biofilm agents.

Keywords: Chalcones linked amines; antimicrobial/anti-biofilm activity; c-di-GMP inhibition; molecular modelling.

Graphical abstract

Chart 1.

The rational design of our synthesised compounds.

Scheme 1.

Synthesis of the target compounds 20–51.

Figure 1.

Lowest energy conformers of compound (a) 36, (b) 38, and (c) 37 with balls and cylinders.

Figure 2.

2D binding mode and residues involved in the recognition of reference ligand at active site (c-di-GMP) Arg 386, Arg 390, Asp 362 Thr 379, Asp 383, and Arg 359 via hydrogen bonding interaction.

Figure 3.

2D binding mode and residues involved in the recognition of active biofilm inhibitors (a) Compound A, (b) Compound B, ligands as references at active site (c-di-GMP).

Figure 4.

3D binding mode and residues involved in the recognition of active compound 36 at active site (c-di-GMP).

Figure 5.

3D binding mode and residues involved in the recognition of active compound 37 at active site (c-di-GMP).

Figure 6.

The aligned conformation of compound 37 (ball and stick) occupying pocket (space filled).

Figure 7.

3D binding mode and residues involved in the recognition of active compound 38 at active site (c-di-GMP).

Figure 8.

The aligned conformation of compound 38 (space filled cyan) occupying pocket c-di-GMP.

Figure 9.

Close-up view of ligand binding pocket crystal structure of the response regulator, within a bound dimer of c-di-GMP which make specific contacts to the ligand in the crystal structure.

Figure 10.

Surface map for (a) compound 36, (b) compound 37 and (c) compound 38, Pink, hydrogen bond, blue: mild polar, green hydrophobic.