Synthesis and antibacterial evaluation of novel psoralen derivatives against methicillin-resistant Staphylococcus aureus (MRSA).

Today, the bacterial infections caused by multidrug-resistant pathogens seriously threaten human health. Thereby, there is an urgent need to discover antibacterial drugs with novel mechanism. Here, novel psoralen derivatives had been designed and synthesized by a scaffold hopping strategy. Among these targeted twenty-five compounds, compound ZM631 showed the best antibacterial activity against methicillin-resistant S. aureus (MRSA) with the low MIC of 1 µg/mL which is 2-fold more active than that of the positive drug gepotidacin. Molecular docking study revealed that compound ZM631 fitted well in the active pockets of bacterial S. aureus DNA gyrase and formed a key hydrogen bond binding with the residue ASP-1083. These findings demonstrated that the psoralen scaffold could serve as an antibacterial lead compound for further drug development against multidrug-resistant bacterial infections.

Discovery of novel oridonin sulfamide derivatives as potent NLRP3 inhibitors by a visible-light photocatalysis-enabled peripheral editing.

The progress of organicsyntheticmethod can promote late-stage lead compound modification and novel active compound discovery. Molecular editing technology in the field of organic synthesis, including peripheral and skeletal editing, facilitates rapid access to molecular diversity of a lead compound. Peripheral editing of CH bond activation is gradually used in lead optimization to afford novel active scaffolds and chemical space exploitation. To develop oridonin derivatives with high anti-inflammatory potency, novel oridonin sulfamides had been designed and synthesized by a scaffoldhopping strategy based on a visible-light photocatalysis peripheral editing. All novel compounds revealed measurable inhibition of IL-1ß and low cytotoxicity in THP-1 cells. The docking study indicated that the best active compound ZM640 was accommodated in thebinding site of NLRP3 with two hydrogen bond interaction. These preliminary results confirm that α, ß-unsaturated carbonyl of oridonin is not essential for NLRP3 inhibitory effect. This new oridonin scaffold has its potential to be further developed as a promising class of NLRP3 inhibitors.