Design, synthesis, structural optimization, and biological activity research of quinazolinone alkaloid isaindigotone.

Abstract

BACKGROUND Plant viruses, which are among the most devastating pathogens, cause enormous losses to agricultural industries worldwide and continue to threaten global food security. Current antivirals like ribavirin and ningnanmycin show limited efficacy against plant viruses, underscoring the need for more potent agents. Quinazolinone alkaloids play a vital role in drug discovery. RESULT After an extensive literature survey, we explored a highly efficient and straightforward synthetic route to access isaindigotone. Starting from commercially available deoxyvasicinone, a two-step sequence delivered the target isaindigotone in an overall yield of 60%. A series of isaindigotone derivatives were designed, synthesized, and evaluated for their bioactivities. We found that these compounds have good to excellent antiviral activities against tobacco mosaic virus (TMV). Most of these compounds exhibited higher anti-TMV activities than ribavirin. Alkaloid isaindigotone and its derivatives 2b and 2f displayed significantly higher inhibitory effects (half-maximal inhibitory concentration (IC50): 120-195 μg mL-1) than ningnanmycin (IC50: 220 μg mL-1), thus emerged as novel antiviral candidates. We selected 2f for further antiviral mechanism studies and found that 2f can inhibit viral assembly by interacting with the TMV coat protein (CP). Molecular docking results further confirmed that these compounds can interact with CP through hydrogen bonds. These compounds also demonstrated broad-spectrum antifungal activities. In particular, compound 4a displayed significant antifungal activity (IC50: 1.14 μg mL-1) against Pyricularia grisea. The preliminary action mechanism research proved that 4a can destroy the cell membrane of pathogens. CONCLUSION The natural product isaindigotone and its derivatives were synthesized and evaluated for their anti-TMV and fungicidal activities. Some compounds with good activities emerged as new antiviral and anti-fungal candidates. This study provides a reference for the application of isaindigotone alkaloids as new pesticides. © 2025 Society of Chemical Industry.