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

## TL;DR

This paper introduces a new class of SARS-CoV-2 protease inhibitors made from phenothiazine-linked glutamic acid dendrons, showing moderate inhibition potential.

## Contribution

A novel solid-phase synthesis method for phenothiazine-linked glutamic acid dendrons as SARS-CoV-2 Mpro inhibitors.

## Key findings

- PTZ-linked glutamic acid dendrons showed moderate Mpro inhibition, especially Trp-enriched analogues.
- Molecular dynamics simulations confirmed stable Mpro-dendron complexes with higher binding affinity for Trp-based dendrons.
- The PTZ core was found to play a key role in Mpro enzyme interactions.

## Abstract

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