Cheminformatics-Guided Exploration of Synthetic Marine Natural Product-Inspired Brominated Indole-3-Glyoxylamides and Their Potentials for Drug Discovery

Author:

Holland Darren C.12ORCID,Prebble Dale W.12ORCID,Calcott Mark J.3ORCID,Schroder Wayne A.4,Ferretti Francesca12,Lock Aaron45,Avery Vicky M.45ORCID,Kiefel Milton J.16,Carroll Anthony R.12ORCID

Affiliation:

1. School of Environment and Science, Griffith University, Southport, QLD 4222, Australia

2. Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD 4111, Australia

3. School of Biological Sciences, Victoria University of Wellington, Wellington 6102, New Zealand

4. School of Environment and Science, Griffith University, Nathan, QLD 4111, Australia

5. Discovery Biology, Griffith University, Nathan, QLD 4111, Australia

6. Institute for Glycomics, Griffith University, Southport, QLD 4221, Australia

Abstract

Marine natural products (MNPs) continue to be tested primarily in cellular toxicity assays, both mammalian and microbial, despite most being inactive at concentrations relevant to drug discovery. These MNPs become missed opportunities and represent a wasteful use of precious bioresources. The use of cheminformatics aligned with published bioactivity data can provide insights to direct the choice of bioassays for the evaluation of new MNPs. Cheminformatics analysis of MNPs found in MarinLit (n = 39,730) up to the end of 2023 highlighted indol-3-yl-glyoxylamides (IGAs, n = 24) as a group of MNPs with no reported bioactivities. However, a recent review of synthetic IGAs highlighted these scaffolds as privileged structures with several compounds under clinical evaluation. Herein, we report the synthesis of a library of 32 MNP-inspired brominated IGAs (25–56) using a simple one-pot, multistep method affording access to these diverse chemical scaffolds. Directed by a meta-analysis of the biological activities reported for marine indole alkaloids (MIAs) and synthetic IGAs, the brominated IGAs 25–56 were examined for their potential bioactivities against the Parkinson’s Disease amyloid protein alpha synuclein (α-syn), antiplasmodial activities against chloroquine-resistant (3D7) and sensitive (Dd2) parasite strains of Plasmodium falciparum, and inhibition of mammalian (chymotrypsin and elastase) and viral (SARS-CoV-2 3CLpro) proteases. All of the synthetic IGAs tested exhibited binding affinity to the amyloid protein α-syn, while some showed inhibitory activities against P. falciparum, and the proteases, SARS-CoV-2 3CLpro, and chymotrypsin. The cellular safety of the IGAs was examined against cancerous and non-cancerous human cell lines, with all of the compounds tested inactive, thereby validating cheminformatics and meta-analyses results. The findings presented herein expand our knowledge of marine IGA bioactive chemical space and advocate expanding the scope of biological assays routinely used to investigate NP bioactivities, specifically those more suitable for non-toxic compounds. By integrating cheminformatics tools and functional assays into NP biological testing workflows, we can aim to enhance the potential of NPs and their scaffolds for future drug discovery and development.

Funder

Australian Postgraduate Award

Publisher

MDPI AG

Reference46 articles.

1. (2024, May 11). Marine Pharmacology. Available online: https://www.marinepharmacology.org/approved.

2. Harnessing the Properties of Natural Products;Boufridi;Annu. Rev. Pharmacol. Toxicol.,2018

3. Marine indole alkaloid diversity and bioactivity. What do we know and what are we missing?;Holland;Nat. Prod. Rep.,2023

4. Organic Synthesis: The Art and Science of Replicating the Molecules of Living Nature and Creating Others like Them in the Laboratory;Nicolaou;Proc. R. Soc. A,2014

5. Cheminformatics in Natural Product-Based Drug Discovery;Chen;Mol. Inform.,2020

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