Design, Synthesis, and Biological Evaluation of Novel Tetrazole-Containing Tetrahydroisoquinoline Derivatives as Putative CYP51 Inhibitors against Candida Species.

To address the need for structurally diverse tetrazole-based CYP51 inhibitors with reduced CYP inhibition liability, we designed and synthesized a series of tetrazole-tetrahydroisoquinoline derivatives. Starting from the metabolically unstable lead A33 (t1/2 = 2.89 min), an integrated optimization strategy involving bioisosteric replacement, scaffold modification, and metabolic blocking was applied to improve metabolic stability and pharmacological properties. Compound LH23 emerged as a potent anti-Candida agent with improved metabolic stability and reduced CYP inhibition liability compared with the parent lead A33. Mechanistic studies, including sterol profiling and transcriptomic analysis, revealed that LH23 disrupts ergosterol biosynthesis and biofilm-associated pathways. LH23 demonstrated a favorable preliminary safety profile and significant in vivo antifungal efficacy in a murine candidiasis model, although its limited oral bioavailability highlights the need for further optimization. This work provides a new chemical scaffold and valuable starting point for the development of tetrazole-based antifungal agents.