Free radical scavenging behaviour of the plant-beneficial secondary metabolite 2,4-diacetylphloroglucinol derivatives under physiological conditions: A joint experimental and theoretical study

Undoubtedly, natural products (NPs) offer a crucial foundation for crafting novel biologically relevant scaffolds. Among these, 2,4-diacetylphloroglucinol (DAPG) stands out as a polyketide compound produced by Pseudomonads spp, showcasing substantial antimicrobial activity. This study focuses on synthesising derivatives of DAPG and delving into their structural characteristics, tautomerism, and antiradical properties. Through density functional theory (DFT) calculations at the B3LYP/def2-SVP level, we examined the thermodynamic parameters governing the double H+/e(-)radical trapping processes. These investigations encompassed both gas phase and physiological environments (lipid-like and aqueous solution media). Comparative analyses were conducted with its analogue (2,4-diisobutyrylphloroglucinol, DBPG), its parent compound (phloroglucinol, PG), and a commercial antioxidant standard (2-butylated hydroxyanisole, 2-BHA). This study unveils that DAPG exhibits a preference for double-sequential proton loss electron transfer (dSPLET) as the favoured mechanism within physiological environments. Additionally, we computed redox potentials and equilibrium constants to discuss the effectiveness of the overall scavenging process against diverse reactive oxygen, nitrogen, and sulphur species (ROS, RNS, and RSS). Further insights were gained through molecular docking studies, evaluating the potential inhibition against several ROS-generating enzymes such as xanthine oxidase (XO), lipoxygenase (LO), CYP2C9 (CP450), and NADPH-oxidase (NO). Comprehensive discussions regarding the effects of modifications on PG rings were also conducted. In addition, bioinformatic POM (Petra/Osiris/Molinspiration) analyses were reported to aid in clarifying the experimental data and DFT calculations. Ultimately, this study advocates for the development of potent acyl phloroglucinols (ACPLs)-based antiradical agents, shedding light on how structural characteristics influence their radical scavenging potential.