Development of indolealkylamine derivatives as potential multi-target agents for COVID-19 treatment.
Eur J Med Chem
; 249: 115152, 2023 Mar 05.
Article
in English
| MEDLINE | ID: covidwho-2210217
ABSTRACT
COVID-19 is a complex disease with short-term and long-term respiratory, inflammatory and neurological symptoms that are triggered by the infection with SARS-CoV-2. As many drugs targeting single targets showed only limited effectiveness against COVID-19, here, we aimed to explore a multi-target strategy. We synthesized a focused compound library based on C2-substituted indolealkylamines (tryptamines and 5-hydroxytryptamines) with activity for three potential COVID-19-related proteins, namely melatonin receptors, calmodulin and human angiotensin converting enzyme 2 (hACE2). Two molecules from the library, 5e and h, exhibit affinities in the high nanomolar range for melatonin receptors, inhibit the calmodulin-dependent calmodulin kinase II activity and the interaction of the SARS-CoV-2 Spike protein with hACE2 at micromolar concentrations. Both compounds inhibit SARS-CoV-2 entry into host cells and 5h decreases SARS-CoV-2 replication and MPro enzyme activity in addition. In conclusion, we provide a proof-of-concept for the successful design of multi-target compounds based on the tryptamine scaffold. Optimization of these preliminary hit compounds could potentially provide drug candidates to treat COVID-19 and other coronavirus diseases.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
COVID-19
Topics:
Long Covid
Limits:
Humans
Language:
English
Journal:
Eur J Med Chem
Year:
2023
Document Type:
Article
Affiliation country:
J.ejmech.2023.115152
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