Search for Non-Protein Protease Inhibitors Constituted with an Indole and Acetylene Core

Abstract

A possible inhibitor of proteases, which contains an indole core and an aromatic polar acetylene, was designed and synthesized. This indole derivative has a molecular architecture kindred to biologically relevant species and was obtained through five synthetic steps with an overall yield of 37% from the 2,2′-(phenylazanediyl)di(ethan-1-ol). The indole derivative was evaluated through docking assays using the main protease (SARS-CoV-2-Mpro) as a molecular target, which plays a key role in the replication process of this virus. Additionally, the indole derivative was evaluated as an inhibitor of the enzyme kallikrein 5 (KLK5), which is a serine protease that can be considered as an anticancer drug target.

Synthesis of bis-furyl-pyrrolo[3,4-b]pyridin-5-ones via Ugi–Zhu reaction and in vitro activity assays against human SARS-CoV-2 and in silico studies on its main proteins

“…8A shows the hydrophobic interactions between 1e and the SARS-CoV-2-M Pro , highlighting the arrangement of the two-ring fragment of 1e with the studied protein's hydrophobic surface the main interactions to promote better possesses in this kind of protein. 31…”

“…8A shows the hydrophobic interactions between 1e and the SARS-CoV-2-M Pro , highlighting the arrangement of the two-ring fragment of 1e with the studied protein's hydrophobic surface the main interactions to promote better possesses in this kind of protein. 31 On the other hand, the interaction between 1e and the spike-glycoprotein is more important than the first mentioned protein, due to this is the first contact protein from SARS-CoV-2 with a possible inhibitory molecule. In this order, Fig.…”

From Repurposing to Redesign: Optimization of Boceprevir to Highly Potent Inhibitors of the SARS-CoV-2 Main Protease

“…The main protease (M pro ) of SARS-CoV-2 is a prime target for antiviral drug discovery and development [1][2][3][4][5][6][7][8]. Previously, we have described peptidomimetic α-ketoamides as nearly equipotent inhibitors of the M pro of betacoronaviruses (such as SARS-CoV and MERS-CoV) as well as the 3C pro of enteroviruses [9].…”

Grammatical evolution-based design of SARS-CoV-2 main protease inhibitors

“…29 At the same time, some non-protein inhibitors have been tested in silico against the above-mentioned molecular target of the virus, promoting the steric lock of SARS-CoV-2-M pro . 30 In addition, Zhang research group worked in the design of α-ketoamide SARS-CoV-2-M pro inhibitors, 31 and they reported a compound, named 13b , as a possible broad-spectrum antiviral drug against beta coronavirus, alpha coronavirus and 3C enterovirus proteases. In such studies, a co-crystalized 13b –SARS-CoV-2-M pro structure and a molecular coupling experiment (docking) are presented.…”