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^pro) enzyme, proposed to be the best target against SARS-CoV-2. The preliminary assay studies designated a moderate response for the M^pro 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^pro enzyme. Molecular dynamics (MD) simulations revealed that the active dendrons formed stable complexes with M^pro, and the binding affinity of the Trp-based PTZ-linked dendrons was higher than that of the decoy dendron analogue.