A026(Lanzhou University)

Rho-associated coiled-coil containing protein kinase 2 (ROCK2) has been identified as a promising target for the treatment of pulmonary fibrosis (PF). In this study, a series of novel imidazo[1,2-b]pyridazine derivatives were designed as selective ROCK2 inhibitors. Through comprehensive investigation of SARs, compounds A25 and A26 exhibited superior ROCK2 inhibitory potency (IC₅₀ = 7.0 and 8.7 nM, respectively) and excellent isoform selectivity (SI = 200/138). In bleomycin-induced PF mice models, administration of A25 and A26 resulted in a pronounced reduction of collagen deposition and a significant reversal of fibrotic progression. Mechanism study confirmed that A25 exerted antifibrotic effects via the TGF-β/Smad and ROCK2/STAT3 signaling pathways. Furthermore, A25 exhibited a favorable safety profile, showing low hERG channel inhibition and almost no pathological alterations in major organs. Overall, A25 was identified as a promising lead compound for the development of selective ROCK2 inhibitors for PF therapy.

The threats to the safety of humans and the environment and the resistance of agricultural chemicals to plant pathogenic fungi and bacteria highlight an urgent need to find safe and efficient alternatives to chemical fungicides and bactericides. In this study, a series of Berberine (BBR) derivatives were designed, synthesized and evaluated for in vitro and in vivo antimicrobial activity against plant pathogenic fungi and bacteria.

Bioassay results indicated that compounds A11, A14, A20, A21, A22, A25, A26, E1, E2, E3, Z1 and Z2 showed high inhibitory activity against Sclerotinia sclerotiorum and Botrytis cinerea. Especially, A25 showed a broad spectrum and the highest antifungal activity among these compounds. Its EC50 value against Botrytis cinerea was 1.34 μg mL−1. Compound E6 possessed high inhibitory activity against Xanthomonas oryzae and Xanthomonas Campestris, with MIC90 values of 3.12 μg mL−1 and 1.56 μg mL−1. A Topomer CoMFA model was generated for 3D‐QSAR studies based on anti‐B. cinerea effects, with high predictive accuracy, showed that the addition of an appropriate substituent group at the para‐position of benzyl of BBR derivatives could effectively improve the anti‐B. cinerea activity. In addition, compound A25 could significantly inhibit the spore germination of Botrytis cinerea at low concentration, and compound F4 exhibited remarkable curative and protective efficiencies on rice bacterial leaf blight.

This study indicates that the BBR derivatives are hopeful for further exploration as the lead compound with novel antimicrobial agents. © 2024 Society of Chemical Industry.