Cannabidiol-Derived Compounds Show Potent Effects Against SARS-CoV-2

Researchers in Brazil have identified two novel synthetic compounds derived from cannabidiol (CBD) that demonstrate striking antiviral and anti-inflammatory effects against SARS-CoV-2. The findings, published in Pharmaceuticals in October 2025, offer promising leads for a new class of orally administered COVID-19 therapeutics that could act on multiple disease mechanisms simultaneously.

Developed at the Federal University of Alfenas, the compounds—named PQM-243 and PQM-249—belong to a new generation of terpene-based N-acyl-aryl-hydrazones structurally inspired by CBD. They were rationally designed to retain the beneficial immunomodulatory and antioxidant effects observed in natural cannabinoids while improving antiviral potency through targeted structural modifications.

In a series of in vitro experiments, both compounds showed potent direct activity against SARS-CoV-2. PQM-243 demonstrated an IC₅₀ of 0.0648 µM, while PQM-249 achieved an IC₅₀ of 0.2860 µM—both outperforming the FDA-approved antiviral nirmatrelvir in terms of selectivity index, a key safety marker. Neither compound exhibited significant cytotoxicity, and PQM-243, in particular, reduced viral load by six-fold in virucidal assays.

Further mechanistic investigations revealed that both compounds effectively inhibit the interaction between the viral spike protein's receptor-binding domain (RBD) and the host ACE2 receptor, a critical step in viral cell entry. Notably, PQM-243 and PQM-249 demonstrated low nanomolar inhibitory activity against ACE2, significantly more potent than DX600, a benchmark ACE2 inhibitor.

Computational modeling supported these findings, showing that both molecules bind favorably not only to ACE2 and the spike RBD but also to TMPRSS2 and the viral RNA polymerase (RdRp). PQM-243 exhibited stronger binding affinity across most targets, potentially due to its hydroxyl substituent enhancing hydrogen bonding in the viral active sites.

Importantly, the compounds also showed protective effects in vivo. In a mouse model of virus-induced lung inflammation, oral administration of either PQM-243 or PQM-249 significantly reduced leukocyte infiltration in the lungs and lowered levels of pro-inflammatory cytokines TNF-α, IL-6, and IFN-γ by over 40%.

This dual action—direct antiviral inhibition coupled with immunomodulatory effects—makes PQM-243 and PQM-249 compelling prototypes for further development. Unlike most current antivirals that act on a single target, these compounds appear to disrupt both viral replication and the downstream inflammatory cascade that contributes to COVID-19 severity.

While clinical trials are still needed, the study authors emphasize the accessibility and synthetic simplicity of these molecules, which could facilitate rapid scale-up if efficacy is confirmed in humans. As respiratory viruses evolve and new variants emerge, multifunctional agents like these may be critical tools in the global antiviral arsenal.