Chitin synthase (CHS), as crucial antifungal target, plays a pivotal role in the fungal proliferation and invasion processes. This study constructed pharmacophore models based on ligand and receptor features. These models were used to guide the construction of novel CHS inhibitors via the scaffold-growth pathway. The corresponding molecular structures were synthesized, and their biological activities were evaluated. Among them, compounds 9c, 9e, and 9f exhibited significant inhibitory activity against chitin synthesis, achieving high potent antifungal effect. Furthermore, the potential compound 9f, in combination with immune activators, could accelerate the recovery rate of drug-resistant fungal infections in vivo. This study not only successfully established scientific pharmacophore models but also discovered novel CHS inhibitors, opening up a potential new pathway for effectively treating fungal infections by regulating chitin synthesis pathways.