Total Synthesis and Antibacterial Evaluation of (-)- and (+)-epi-Perrottetinene.

Authors

Vijay Kumar, Anjali Gangwar, Sunandhani Khajuria, Sapna Saini, Muzamil Samad, Varun Pratap Singh, Rashmi Sharma, Parvinder Pal Singh

Published in

ACS infectious diseases. Jul 14, 2026. Epub Jul 14, 2026.

Abstract

Antimicrobial resistance (AMR) is a critical threat to global public health, with emerging resistance to Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), often referred to as a silent pandemic. Despite ongoing efforts in the fight against AMR, the drug discovery pipeline remains underdeveloped, highlighting the urgent need to explore natural and synthetic approaches. Cannabinoid-inspired natural products represent an underexplored chemical space with antimicrobial potential. Herein, we report an efficient, scalable, and enantioselective synthesis and antimicrobial evaluation of epi-perrottetinene (epi-PET), an unnatural bibenzyl-based cannabinoid analog of liverwort-derived perrottetinene. The synthetic strategy employs inexpensive starting materials and a Lewis acid-mediated Friedel-Crafts cyclization to enable regioselective access to both Δ⁸- and Δ⁹-epi-PET isomers. Biological evaluation revealed potent antibacterial activity against Gram-positive pathogens, with particularly strong efficacy against drug-sensitive and drug-resistant S. aureus strains, including MRSA clinical isolates. Notably, the lead compound E exhibited remarkable activity, with MIC values ≤ 1.2 μg/mL. Compound E remained effective against efflux pump-overexpressing strains and bacterial biofilms and eradicated intracellular bacteria, while displaying low hemolytic activity (3.4% of rabbit erythrocytes) and minimal cytotoxicity toward mammalian cell lines (N2a and RAW). Mechanistic studies indicate that bacterial membrane disruption is a key contributor to the observed bactericidal activity, consistent with rapid killing and a low propensity for resistance development. The work establishes epi-perrottetinene as a promising cannabinoid-inspired antibacterial scaffold and highlights the potential of nonclassical cannabinoids as a source of new chemical matter for addressing antimicrobial resistance.

PMID:
42444438
Bibliographic data and abstract were imported from PubMed on 14 Jul 2026.

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