{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:15:09Z","timestamp":1760112909505,"version":"build-2065373602"},"reference-count":46,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T00:00:00Z","timestamp":1722470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Australian Postgraduate Award (APA)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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\u201356) 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\u201356 were examined for their potential bioactivities against the Parkinson\u2019s Disease amyloid protein alpha synuclein (\u03b1-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 \u03b1-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.<\/jats:p>","DOI":"10.3390\/molecules29153648","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T11:34:20Z","timestamp":1722512060000},"page":"3648","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cheminformatics-Guided Exploration of Synthetic Marine Natural Product-Inspired Brominated Indole-3-Glyoxylamides and Their Potentials for Drug Discovery"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2498-6084","authenticated-orcid":false,"given":"Darren C.","family":"Holland","sequence":"first","affiliation":[{"name":"School of Environment and Science, Griffith University, Southport, QLD 4222, Australia"},{"name":"Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD 4111, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7084-8299","authenticated-orcid":false,"given":"Dale W.","family":"Prebble","sequence":"additional","affiliation":[{"name":"School of Environment and Science, Griffith University, Southport, QLD 4222, Australia"},{"name":"Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD 4111, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7736-8095","authenticated-orcid":false,"given":"Mark J.","family":"Calcott","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Victoria University of Wellington, Wellington 6102, New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wayne A.","family":"Schroder","sequence":"additional","affiliation":[{"name":"School of Environment and Science, Griffith University, Nathan, QLD 4111, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Ferretti","sequence":"additional","affiliation":[{"name":"School of Environment and Science, Griffith University, Southport, QLD 4222, Australia"},{"name":"Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD 4111, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaron","family":"Lock","sequence":"additional","affiliation":[{"name":"School of Environment and Science, Griffith University, Nathan, QLD 4111, Australia"},{"name":"Discovery Biology, Griffith University, Nathan, QLD 4111, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4914-2299","authenticated-orcid":false,"given":"Vicky M.","family":"Avery","sequence":"additional","affiliation":[{"name":"School of Environment and Science, Griffith University, Nathan, QLD 4111, Australia"},{"name":"Discovery Biology, Griffith University, Nathan, QLD 4111, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milton J.","family":"Kiefel","sequence":"additional","affiliation":[{"name":"School of Environment and Science, Griffith University, Southport, QLD 4222, Australia"},{"name":"Institute for Glycomics, Griffith University, Southport, QLD 4221, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7695-8301","authenticated-orcid":false,"given":"Anthony R.","family":"Carroll","sequence":"additional","affiliation":[{"name":"School of Environment and Science, Griffith University, Southport, QLD 4222, Australia"},{"name":"Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD 4111, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,1]]},"reference":[{"key":"ref_1","unstructured":"(2024, May 11). Marine Pharmacology. Available online: https:\/\/www.marinepharmacology.org\/approved."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1146\/annurev-pharmtox-010716-105029","article-title":"Harnessing the Properties of Natural Products","volume":"58","author":"Boufridi","year":"2018","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1039\/D2NP00085G","article-title":"Marine indole alkaloid diversity and bioactivity. What do we know and what are we missing?","volume":"40","author":"Holland","year":"2023","journal-title":"Nat. Prod. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"20130690","DOI":"10.1098\/rspa.2013.0690","article-title":"Organic Synthesis: The Art and Science of Replicating the Molecules of Living Nature and Creating Others like Them in the Laboratory","volume":"470","author":"Nicolaou","year":"2014","journal-title":"Proc. R. Soc. A"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2000171","DOI":"10.1002\/minf.202000171","article-title":"Cheminformatics in Natural Product-Based Drug Discovery","volume":"39","author":"Chen","year":"2020","journal-title":"Mol. Inform."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Medina-Franco, J.L., and Sald\u00edvar-Gonz\u00e1lez, F.I. (2020). Cheminformatics to Characterize Pharmacologically Active Natural Products. Biomolecules, 10.","DOI":"10.3390\/biom10111566"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9275","DOI":"10.1039\/C7OB02193C","article-title":"Harnessing the Potential of Natural Products in Drug Discovery from a Cheminformatics Vantage Point","volume":"15","author":"Rodrigues","year":"2017","journal-title":"Org. Biomol. Chem."},{"key":"ref_8","unstructured":"(2024, May 11). MarinLit. Available online: http:\/\/pubs.rsc.org\/marinlit\/."},{"key":"ref_9","unstructured":"(2024, May 02). SuperNatural 3.0. Available online: https:\/\/bioinf-applied.charite.de\/supernatural_3\/subpages\/compounds.php."},{"key":"ref_10","unstructured":"(2024, May 02). COCONUT. Available online: https:\/\/coconut.naturalproducts.net\/."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Holland, D.C., Hayton, J.B., Kiefel, M.J., and Carroll, A.R. (2024). Synthesis and Cheminformatics-Directed Antibacterial Evaluation of Echinosulfonic Acid-Inspired Bis-Indole Alkaloids. Molecules, 29.","DOI":"10.3390\/molecules29122806"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: A Major Update to the DrugBank Database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Barresi, E., Robello, M., Baglini, E., Poggetti, V., Viviano, M., Salerno, S., da Settimo, F., and Taliani, S. (2023). Indol-3-ylglyoxylamide as Privileged Scaffold in Medicinal Chemistry. Pharmaceuticals, 16.","DOI":"10.3390\/ph16070997"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1021\/ci500588j","article-title":"DataWarrior: An Open-Source Program for Chemistry Aware Data Visualization and Analysis","volume":"55","author":"Sander","year":"2015","journal-title":"J. Chem. Inf. Model"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12978","DOI":"10.1021\/acs.jmedchem.0c01271","article-title":"Identification, Structure-Activity Relationships of Marine-Derived Indolocarbazoles, and a Dual PKC\u03b8\/\u0394Inhibitor with Potent Antipancreatic Cancer Efficacy","volume":"63","author":"Wang","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1021\/np800831z","article-title":"Leptoclinidamines A-C, Indole Alkaloids from the Australian Ascidian Leptoclinides durus","volume":"72","author":"Carroll","year":"2009","journal-title":"J. Nat. Prod."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1021\/np1008619","article-title":"Didemnidines A and B, Indole Spermidine Alkaloids from the New Zealand Ascidian Didemnum sp.","volume":"74","author":"Finlayson","year":"2011","journal-title":"J. Nat. Prod."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6305","DOI":"10.1016\/S0040-4039(00)01062-5","article-title":"Coscinamides A, B and C, Three New Bis Indole Alkaloids from the Marine Sponge Coscinoderma sp.","volume":"41","author":"Bokesch","year":"2000","journal-title":"Tetrahedron Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1021\/np300401g","article-title":"PPAR-\u03b3 Agonistic Metabolites from the Ascidian Herdmania momus","volume":"75","author":"Li","year":"2012","journal-title":"J. Nat. Prod."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"525","DOI":"10.4155\/fmc-2018-0246","article-title":"Indole-3-Glyoxyl Tyrosine: Synthesis and Antimalarial Activity against Plasmodium falciparum","volume":"11","author":"Vasconcelos","year":"2019","journal-title":"Future Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5821","DOI":"10.1016\/j.tetlet.2013.08.064","article-title":"One-Pot Three-Component Synthesis of Indole-3-Glyoxyl Derivatives and Indole-3-Glyoxyl Triazoles","volume":"54","author":"Stefani","year":"2013","journal-title":"Tetrahedron Lett."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Pujols, J., Pe\u00f1a-D\u00edaz, S., Conde-Gim\u00e9nez, M., Pinheiro, F., Navarro, S., Sancho, J., and Ventura, S. (2017). High-Throughput Screening Methodology to Identify Alpha-Synuclein Aggregation Inhibitors. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18030478"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/nchem.2129","article-title":"Screening and Classifying Small-Molecule Inhibitors of Amyloid Formation Using Ion Mobility Spectrometry-Mass Spectrometry","volume":"7","author":"Young","year":"2015","journal-title":"Nat. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.bcp.2017.04.004","article-title":"Natural Product-Based Amyloid Inhibitors","volume":"139","author":"Velander","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1080\/19336896.2018.1513315","article-title":"Yeast-based screening of natural product extracts results in the identification of prion inhibitors from a marine sponge","volume":"12","author":"Jennings","year":"2018","journal-title":"Prion"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1021\/acs.jnatprod.2c01140","article-title":"\u03b1-Synuclein Aggregation Inhibitory Procerolides and Diphenylalkanes from the Ascidian Polycarpa procera","volume":"86","author":"Prebble","year":"2023","journal-title":"J. Nat. Prod."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"100472","DOI":"10.1016\/j.rechem.2022.100472","article-title":"\u03b1-Synuclein Aggregation Inhibitory Activity of the Bromotyrosine Derivatives Aerothionin and Aerophobin-2 from the Subtropical Marine Sponge Aplysinella sp.","volume":"4","author":"Prebble","year":"2022","journal-title":"Results Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1039\/D1NP00075F","article-title":"Trends of Antimalarial Marine Natural Products: Progresses, Challenges and Opportunities","volume":"39","author":"Hai","year":"2022","journal-title":"Nat. Prod. Rep."},{"key":"ref_29","unstructured":"WHO (2021). World Malaria Report 2021, WHO."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/s41589-020-00689-z","article-title":"SARS-CoV-2 Mpro Inhibitors and Activity-Based Probes for Patient-Sample Imaging","volume":"17","author":"Rut","year":"2021","journal-title":"Nat. Chem. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Brown, A.S., Ackerley, D.F., and Calcott, M.J. (2020). High-Throughput Screening for Inhibitors of the SARS-CoV-2 Protease Using a FRET-Biosensor. Molecules, 25.","DOI":"10.3390\/molecules25204666"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1021\/acsptsci.0c00130","article-title":"Ebselen, Disulfiram, Carmofur, PX-12, Tideglusib, and Shikonin Are Nonspecific Promiscuous SARS-CoV-2 Main Protease Inhibitors","volume":"3","author":"Ma","year":"2020","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1126\/science.abb4489","article-title":"Structure-Based Design of Antiviral Drug Candidates Targeting the SARS-CoV-2 Main Protease","volume":"368","author":"Dai","year":"2020","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1039\/D0MD00288G","article-title":"Indole-a Promising Pharmacophore in Recent Antiviral Drug Discovery","volume":"11","author":"Dorababu","year":"2020","journal-title":"RSC Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1016\/j.bmcl.2019.03.018","article-title":"A Survey of Core Replacements in Indole-Based HIV-1 Attachment Inhibitors","volume":"29","author":"Wang","year":"2019","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2216","DOI":"10.1021\/acs.jnatprod.3c00633","article-title":"Cyclotheonellazoles D-I, Potent Elastase Inhibitory Thiazole-Containing Cyclic Peptides from Theonella sp.","volume":"86","author":"Holland","year":"2023","journal-title":"J. Nat. Prod."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"12619","DOI":"10.1021\/ja00079a065","article-title":"Atomic Structure of the Trypsin-Cyclotheonamide A Complex: Lessons for the Design of Serine Protease Inhibitors","volume":"115","author":"Lee","year":"1993","journal-title":"J. Am. Chem. Soc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1021\/acs.jnatprod.7b00028","article-title":"Cyclotheonellazoles A-C, Potent Protease Inhibitors from the Marine Sponge Theonella aff","volume":"80","author":"Issac","year":"2017","journal-title":"swinhoei. J. Nat. Prod."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1016\/j.bmc.2007.11.015","article-title":"Inhibitors of Proteases and Amide Hydrolases That Employ an \u03b1-Ketoheterocycle as a Key Enabling Functionality","volume":"16","author":"Maryanoff","year":"2008","journal-title":"Bioorganic Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.4155\/fmc-2020-0163","article-title":"Recent Advances in the Development of Elastase Inhibitors","volume":"12","author":"Donarska","year":"2020","journal-title":"Future Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.1021\/acs.jmedchem.1c01583","article-title":"Elastase Inhibitor Cyclotheonellazole A: Total Synthesis and in Vivo Biological Evaluation for Acute Lung Injury","volume":"65","author":"Cui","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/s41576-018-0011-4","article-title":"Prions, prionoids and protein misfolding disorders","volume":"19","author":"Scheckel","year":"2018","journal-title":"Nat. Reviews. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7503","DOI":"10.1021\/jm900920x","article-title":"Design, Synthesis, and Structure\u2212Activity Relationship of Indole-3-glyoxylamide Libraries Possessing Highly Potent Activity in a Cell Line Model of Prion Disease","volume":"52","author":"Thompson","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6191","DOI":"10.1016\/j.bmcl.2010.08.119","article-title":"Synthesis and biological evaluation of indolyl glyoxylamides as a new class of antileishmanial agents","volume":"20","author":"Chauhan","year":"2010","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1186\/1475-2875-12-408","article-title":"Identification of Inhibitors of Plasmodium falciparum Gametocyte Development","volume":"12","author":"Duffy","year":"2013","journal-title":"Malar. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1038\/nprot.2006.77","article-title":"A Detergent-Based Assay for the Detection of Promiscuous Inhibitors","volume":"1","author":"Feng","year":"2006","journal-title":"Nat. Protoc."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/15\/3648\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:28:04Z","timestamp":1760110084000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/15\/3648"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,1]]},"references-count":46,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["molecules29153648"],"URL":"https:\/\/doi.org\/10.3390\/molecules29153648","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2024,8,1]]}}}