Secreted aspartic protease 2 (SAP2) stands as one of the most pivotal virulence factors in Candida albicans (C. albicans). Consequently, the development of potent small-molecule inhibitors targeting SAP2 represents a critical stride toward the treatment of invasive candidiasis. In our previous studies, the lead compound SAP2-IN-1 was successfully identified and synthesized via integrated strategies of virtual screening and scaffold hopping. Preliminary structure-activity relationship (SAR) investigation was performed through rational design, synthesis, and biological evaluation of 10 novel indolin-2-one derivatives derived from the SAP2-IN-1 scaffold. Enzymatic inhibition and cell-based assays confirmed that compound A1 possesses favorable SAP2 inhibitory activity, with an IC₅₀ of 0.87 μmol·L^-1. Notably, when combined with fluconazole (FLC), compound A1 effectively suppressed the growth of fluconazole-resistant C. albicans 0304103, yielding fractional inhibitory concentration index (FICI) of 0.047. Furthermore, preliminary mechanistic studies revealed that A1 significantly impeded biofilm formation and hyphal transition in drug-resistant C. albicans. It possesses great potential as a novel antifungal lead compound and provides a new theoretical basis and research strategy for the development of virulence factor-targeted inhibitors to overcome the drug resistance of C. albicans.