Hyejin Kim

We report a Rh(III)-catalyzed C-H functionalization/annulation of N-aryl urazoles with internal alkynes for the synthesis of exo-olefinated indolotriazinediones. The reaction is proposed to proceed through LiCl-assisted N-N bond cleavage to generate a nitrenoid species, followed by aminorhodation and β-H elimination. Mechanistic experiments support the proposed pathway, and representative post-transformations underscore the synthetic value of the products.

A rhodium(III)-catalyzed C–H functionalization of azomethine imines with vinyl cyclopropanes (VCPs) is proposed. Mechanistically, VCPs participate in olefin insertion and β-C elimination to produce allylated intermediates, which undergo endotype [3 + 2] dipolar cycloaddition, providing indenopyrazolopyrazolones. Post-transformations of malonate-containing tetracyclic N-heterocycles highlight the synthetic relevance of the proposed method.

Aberrant activation of the stimulator of interferon genes (STING) drives excessive type I interferon and inflammatory responses implicated in autoimmune and inflammatory diseases, including acute kidney injury (AKI). Here, we report the discovery of a tetrahydroquinoline-based STING inhibitor chemotype, represented by KSI-028, that expands the limited scaffold diversity of current small-molecule STING inhibitors. Mechanistic studies suggest that KSI-028 engages STING through a noncanonical, likely allosteric, binding mode with sustained target engagement. KSI-028 potently suppressed STING-dependent signaling and reduced type I interferon and pro-inflammatory cytokine production in both murine and human cells. In a cisplatin-induced AKI mouse model, KSI-028 attenuated renal and hepatic injury and down-regulated STING-associated inflammatory gene expression. These findings establish the tetrahydroquinoline scaffold as a promising foundation for the development of next-generation STING inhibitors with alternative target engagement modes for the treatment of STING-driven inflammatory disorders.

The global rise of multidrug-resistant bacteria has prompted an urgent need for new antibiotics, yet resistance continues to outpace discovery due to Gram-negative barriers, drug permeability issues, and limited industry investment. In this study, we synthesized a series of 1-hydroxypyridin-2-(1H)-one derivatives targeting Pseudomonas aeruginosa for analyses of antibacterial efficacy. Among these, LP07 displayed potent antibacterial activity across multiple strains, enhanced by subinhibitory colistin. Scanning electron microscopy suggested membrane-associated morphological changes, including surface collapse, shrinkage, and irregular cell shape, consistent with bactericidal effects. Safety profiling showed low CYP inhibition, minimal hERG liability, and no mammalian cytotoxicity. Taken together, LP07's whole-cell activity and observed membrane effects support its promise as a lead for further optimization.

This study explores novel isoxazole-based small molecules, identifying compound 7l with potent antiviral activity against Zika virus (ZIKV) and an improved safety profile in vitro, highlighting its potential as a promising candidate for therapeutic development.

Hepatitis B virus (HBV) is the primary contributor to severe liver ailments, encompassing conditions such as cirrhosis and hepatocellular carcinoma. Globally, 257 million people are affected by HBV annually and 887,000 deaths are attributed to it, representing a substantial health burden. Regrettably, none of the existing therapies for chronic hepatitis B (CHB) have achieved satisfactory clinical cure rates. This issue stems from the existence of covalently closed circular DNA (cccDNA), which is difficult to eliminate from the nucleus of infected hepatocytes. HBV genetic material is composed of partially double-stranded DNA that forms complexes with viral polymerase inside an icosahedral capsid composed of a dimeric core protein. The HBV core protein, consisting of 183 to 185 amino acids, plays integral roles in multiple essential functions within the HBV replication process. In this review, we describe the effects of sulfamoyl-based carboxamide capsid assembly modulators (CAMs) on capsid assembly, which can suppress HBV replication and disrupt the production of new cccDNA. We present research on classical, first-generation sulfamoyl benzocarboxamide CAMs, elucidating their structural composition and antiviral efficacy. Additionally, we explore newly identified sulfamoyl-based CAMs, including sulfamoyl bicyclic carboxamides, sulfamoyl aromatic heterocyclic carboxamides, sulfamoyl aliphatic heterocyclic carboxamides, cyclic sulfonamides, and non-carboxamide sulfomoyl-based CAMs. We believe that certain molecules derived from sulfamoyl groups have the potential to be developed into essential components of a well-suited combination therapy, ultimately yielding superior clinical efficacy outcomes in the future.

Stimulator of interferon genes (STING) is an endoplasmic reticulum-membrane protein that plays important roles in cancer immunotherapy by activating innate immune responses. We designed and synthesized STING modulators and characterized compounds 4a and 4c that share a crucial amidobenzimidazole moiety. In vitro STING binding and cell-based activity assays demonstrated the potency and efficacy of the compounds that function as direct STING agonists by stimulating STING downstream signaling and promoting type I interferon immune responses. In vitro metabolic studies and the pharmacokinetic properties of the compounds led us to investigate their anticancer activity in an in vivo syngeneic model. Intravenous injection of compounds 4a and 4c significantly decreased tumor volume in a CT26 murine colorectal carcinoma model, and the immunological memory-derived cancer inhibition was observed in 4c-treated mouse models. The present results suggest the therapeutic potential of the compounds for cancer immunotherapy via STING-mediated immune activation.