Meisoindigo

Indigo (IND) and its natural derivatives, including Tyrian purple and indirubin (INR), are examples of mols. with a history of millions of years.They also illustrate mol. evolution and longevity, linked to their extraordinary mol. stability associated with excited state decay mechanisms.In the excited state, these mols. efficiently undergo a radiationless deactivation process resulting in negligible fluorescence and triplet state formation (less than 0.1% of the quantum loss in indigo for both processes).Here, we demonstrate that in isoindigo (ISO) this process is even more efficient than in IND, resulting in nearly 100% of the excited state deactivation.In IND, the mol. mechanism behind this decay process involves intramol. proton transfer (ESPT).In the case of INR, ESPT efficiently competes with the formation of a conformational species -the syn-rotamer- for deactivation to the ground state.With ISO, the ESPT process is absent.Instead, the deactivation mechanism involves a rotation of a few degrees around the central C-C bond, aRotational Isomerization (RI).This rotation leads to a sloped conical intersection (CI), making the radiationless deactivation process more efficient than the ESPT found with IND.

The progressive emergence of SARS-CoV-2 variants has necessitated the urgent exploration of novel therapeutic strategies to combat the COVID-19 pandemic. The SARS-CoV-2 main protease (M^pro) represents an evolutionarily conserved therapeutic target for drug discovery. This study highlights the discovery of meisoindigo (Mei), derived from the traditional Chinese medicine (TCM) Indigo naturalis, as a novel non-covalent and nonpeptidic M^pro inhibitor. Substantial optimizations and structure-activity relationship (SAR) studies, guided by a structure-based drug design approach, led to the identification of several Mei derivatives, including S5-27 and S5-28, exhibiting low micromolar inhibition against SARS-CoV-2 M^pro with high binding affinity. Notably, S5-28 provided significant protection against wild-type SARS-CoV-2 in HeLa-hACE2 cells, with EC₅₀ up to 2.66 μM. Furthermore, it displayed favorable physiochemical properties and remarkable gastrointestinal and metabolic stability, demonstrating its potential as an orally bioavailable drug for anti-COVID-19 therapy. This research presents a promising avenue for the development of new antiviral agents, offering hope in the ongoing battle against COVID-19.