Synthesis and molecular docking analysis of MBH adducts' derived amides as potential β-lactamase inhibitors

Abstract

Humans suffer from various diseases that require more specific drugs to target them. Among the different potent agents, β-lactamases serve as good antibacterial agents; however, β-lactamases are resistant to such antibiotics. The present study was designed to prepare efficient β-lactamase inhibitor amides (12-15) from inexpensive, easily accessible, and bioactive precursors; Morita Baylis Hillman (MBH) adducts (5-8). The adducts (5-8) were primarily prepared by treating their respective aldehydes with the corresponding acrylate in the presence of an organic Lewis base at ambient temperature. The compounds were characterized using mass spectrometry, FTIR and NMR spectroscopy. Furthermore, in silico studies (using AutoDock Tools and AutoDock Vina programs) on the adduct and corresponding amide product revealed that all MBH adducts (5-8) and their product amides (12-15) are significant inhibitors of β-lactamase. Additionally, among the MBH adducts, adduct 7 showed the highest binding affinity with β-lactamase, whereas amide 15 was identified as a highly potent antibacterial based on its docking score (-8.6). In addition, the absorption, distribution, metabolism, and excretion (ADME) test of the synthesized compounds demonstrated that all compounds showed drug-likeness properties.

Keywords: ADME properties; MBH adducts; Synthesis; antibacterial amides; in silico studies; β-lactamase inhibitors.

Figure 1

Structural formulae of compounds 3-4.

Figure 2

An infographical representation of the current study indicating the synthetic scheme and the most efficient β-lactamase inhibitors.

Figure 3

Structural representation of the synthesized MBH adduct's derived amides 12-15.

Figure 4

IR frequencies variation due to resonance in esters and amides

Figure 5

(A) 2D representation of the docked MBH adducts (6-8), indicating interaction with the active sites of β- lactamase; Figure (B) 3D representation of the docked MBH adducts (6-8), indicating interaction with the active sites of β- lactamase

Figure 6

(A) 2D representation of the docked MBH adducts (12-15), indicating interaction with the active sites of β- lactamase; (B) 3D representation of the docked amides (12-15), indicating interaction with the active sites of β- lactamase. A B