Novel Sulfonamide‐Sydnone Hybrids: Complementary Insight into Anti‐Inflammatory Action, Anti‐SARS‐CoV‐2 Activity, Human Serum Albumin Interaction, and <i>in silico</i> Analysis

Acute lung injury (ALI) is a severe condition often seen in intensive care unit patients. Due to limited treatment options, ALI is linked to high rates of mortality and morbidity. Bacterial and viral infections are significant contributors to ALI. For instance, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection can lead to a strong inflammatory response that may progress to ALI, a leading cause of death in COVID-19 cases. Prior research has demonstrated that sulfonamides and sydnones exhibit anti-inflammatory and antiviral properties, which has led us to develop compounds containing both scaffolds. Most of the new sulfonamide-sydnone hybrids are expected to be orally bioavailable based on in silico ADME predictions. They effectively suppressed the development of ALI in lipopolysaccharide (LPS)-challenged mice and inhibited viral replication in Calu-3 cells, with minimal cytotoxicity in non-infected Calu-3 and Vero E6 cells. Molecular docking investigations indicated some possible viral targets for the action of the sydnones, highlighting the possible interaction with non-structural proteins of SARS-CoV-2. Additionally, combined experimental and theoretical studies indicated that the new compounds can strongly interact with human serum albumin, suggesting a possible extended residence time in the human bloodstream.