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Updated: Jan 8, 2026

Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Discovery, Design, and Synthesis of Novel 2-Benzyl-2,7-diazaspiro[3.5]nonane Benzothiazinones with Broad-Spectrum
Jizhou Wu1, Chao Ma1, Meng Wei1
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Abstract:
Despite their nanomolar potency against M. tuberculosis (MTB), benzothiazinone (BTZs) DprE1 inhibitors like PBTZ169 are ineffective against nontuberculous mycobacteria (NTM) due to a Cys387Ala mutation in the NTM DprE1 target. Here, 529 BTZs in our lab were screened againstM. abscessus, and two hits with the 2-benzyl-2,7-diazaspiro[3.5]nonane scaffold showed enhanced activity. Subsequent optimization led to the discovery of lead compound B2 with potent activity against MTB (MIC: < 0.01 μg/mL) and NTM strains (MIC: < 0.03125-2.5 μg/mL). Notably, B2 also has good safety and oral pharmacokinetic (PK) profiles. Further chiral resolution revealed its R-enantiomer (B2-1) as a more active form. Mechanistic investigations showed that B2-1 establishes a stable electrostatic interaction with Asp326 ofM. abscessusDprE1. As this residue is highly conserved among mycobacterial species, such an interaction likely underpins its broad-spectrum activity. Therefore, our findings provide a blueprint for developing next-generation BTZs with broad-spectrum activity against mycobacteria.
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