Journal of Medicinal Chemistry· 2026Q1
Design, Synthesis, and Biological Evaluation of Novel Tetrazole-Containing Tetrahydroisoquinoline Derivatives as Putative CYP51 Inhibitors against Candida Species
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- Q1SCImago
- 2026year
Short summary
A new tetrazole-tetrahydroisoquinoline derivative, LH23, demonstrates potent anti-Candida activity by disrupting ergosterol biosynthesis and biofilm formation, with improved metabolic stability and reduced CYP inhibition compared to lead compound A33.
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Key points
- Compound LH23, a novel tetrazole-tetrahydroisoquinoline derivative, exhibits potent antifungal activity against Candida species.
- LH23 disrupts ergosterol biosynthesis and biofilm-associated pathways, as confirmed by sterol profiling and transcriptomic analysis.
- LH23 demonstrates improved metabolic stability (t1/2 not specified, but better than A33's 2.89 min) and reduced CYP inhibition compared to the lead compound A33.
- LH23 showed significant efficacy in a murine candidiasis model, with a favorable preliminary safety profile.
AI-generated from the title and abstract; the full text is not read.
Abstract
Abstract 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.
The authors' abstract, as published at the source. Journal of Medicinal Chemistry, 2026 · DOI ↗
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Field: Organic Chemistry
Organic ChemistryChemistry