Phenothiazine-linked glutamic acid dendrons: an easy access and a new class of SARS-CoV-2 main protease inhibitors.

In this report, a structurally unique phenothiazine (PTZ) core is linked with glutamic acid-based dendrons through a solid-phase peptide synthesis approach to access a variety of PTZ-linked dendrons conveniently. Inferior cytotoxicity of anionic surface-linked second-generation glutamic acid-based dendrons would be more desirable for various applications than respective lysine-based dendrons. Solid-phase synthesis of PTZ-linked glutamic acid-based dendrons would be a novel approach to access this class of molecules. These newly synthesized dendrons were screened as an inhibitor against the main protease (M) enzyme, proposed to be the best target against SARS-CoV-2. The preliminary assay studies designated a moderate response for the M inhibition, specifically by tryptophan (Trp)-enriched dendron, among other analogues, which play a vital role in combating COVID-19. Further, the experimental studies realize the essential contribution of the PTZ core in interacting with the M enzyme. Molecular dynamics (MD) simulations revealed that the active dendrons formed stable complexes with M, and the binding affinity of the Trp-based PTZ-linked dendrons was higher than that of the decoy dendron analogue.