Development of indolealkylamine derivatives as potential multi-target agents for COVID-19 treatment

Eur J Med Chem. 2023 Mar 5:249:115152. doi: 10.1016/j.ejmech.2023.115152. Epub 2023 Jan 27.


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: COVID-19; Calmodulin; Indolealkylamine; Melatonin receptors; SARS-CoV-2; hACE2.

MeSH terms

  • COVID-19 Drug Treatment
  • COVID-19*
  • Calmodulin
  • Humans
  • Receptors, Melatonin
  • SARS-CoV-2


  • spike protein, SARS-CoV-2
  • Calmodulin
  • Receptors, Melatonin