Aryl-functionalized mono- and diketone curcumin derivatives inhibit SARS-CoV-2 Spike:ACE2 interactions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initiates viral entry through binding of its spike (S) protein receptor-binding domain (RBD) with the human angiotensin-converting enzyme 2 (ACE2). Curcumin, a turmeric-derived curcuminoid with broad antiviral properties, shows potential as a SARS-CoV-2 S:ACE2 inhibitor. However, its poor bioavailability, which results in low plasma concentrations, limits effective delivery to infected sites. Structural modifications, such as converting the 1,3-diketone backbone to a monoketone and varying the aromatic ring substituents, offer strategies to enhance both bioavailability and inhibitory activity. Here, fifteen (15) aryl-functionalized mono- and diketone curcumin derivatives were synthesized and evaluated for their inhibitory activity against SARS-CoV-2 S:ACE2 binding using an ELISA-type assay. Their absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) profiles were predicted using SwissADME and ProTox 3.0. Four monoketone derivatives showed >50% inhibition and dose-dependent responses (2d, IC50 = 13.45 μM; 3c, IC50 = 23.84 μM; 3d, IC50 = 1.24 μM; 3e, IC50 = 10.15 μM). Active derivatives also exhibited favorable ADME properties and low toxicity, demonstrating their potential as lead candidates for SARS-CoV-2 S:ACE2 inhibitors.