ArticleOrganic letters2026
Pharmacophore Directed Retrosynthesis Applied to Waixenicin A: Synthesis and Bioactivity of Derivatives Bearing a Minimal Proposed Pharmacophore.
Matthew R Parris, Sayuri Suzuki, Sigrid A Kiledal, Xi B Gong, Xinyang Zhang, Reinhold Penner, Hong-Shuo Sun, Zhong-Ping Feng, F David Horgen, Andrea Fleig and 2 more
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In one paragraphArticle in Organic letters, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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5 · Who and what moneyAuthors and funding
12 authors.
Matthew R ParrisDepartment of Chemistry & Biochemistry & Baylor Synthesis and Drug-Lead Discovery Laboratory, Baylor University, Waco, Texas 76798-7348, United States.
Sayuri SuzukiLaboratory of Cell and Molecular Signaling, Center for Biomedical Research, The Queen's Medical Center, Honolulu, Hawaii 96813, United States.
Sigrid A KiledalDepartment of Chemistry & Biochemistry & Baylor Synthesis and Drug-Lead Discovery Laboratory, Baylor University, Waco, Texas 76798-7348, United States.
Xi B GongDepartment of Chemistry & Biochemistry & Baylor Synthesis and Drug-Lead Discovery Laboratory, Baylor University, Waco, Texas 76798-7348, United States.
Xinyang ZhangDepartment of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Reinhold PennerLaboratory of Cell and Molecular Signaling, Center for Biomedical Research, The Queen's Medical Center, Honolulu, Hawaii 96813, United States.ORCID 0000-0002-5366-1537 Hong-Shuo SunDepartment of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Zhong-Ping FengDepartment of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.ORCID 0000-0002-2454-4462 F David HorgenChemistry and Biochemistry, Hawaii Pacific University, Honolulu, Hawaii 96813, United States.ORCID 0000-0001-9409-3030 Andrea FleigLaboratory of Cell and Molecular Signaling, Center for Biomedical Research, The Queen's Medical Center, Honolulu, Hawaii 96813, United States.
Kenneth G HullDepartment of Chemistry & Biochemistry & Baylor Synthesis and Drug-Lead Discovery Laboratory, Baylor University, Waco, Texas 76798-7348, United States.ORCID 0000-0002-3697-9551 Daniel RomoDepartment of Chemistry & Biochemistry & Baylor Synthesis and Drug-Lead Discovery Laboratory, Baylor University, Waco, Texas 76798-7348, United States.ORCID 0000-0003-3805-092X Funding
Pharmacophore-Directed Retrosynthesis Applied to Bioactive Natural Products Informing Mechanism of Action StudiesR35GM134910 · NIGMS · BAYLOR UNIVERSITY · PI DANIEL ROMO · 2020 to 2026
$2.7MDevelopment of the waixenicin A pharmacophore as a therapeutic intervention for neonatal hypoxic brain injuryR61NS124922 · NINDS · BAYLOR UNIVERSITY · PI FENG, ZHONG-PING, FLEIG, ANDREA · 2023 to 2024
$692kNIGMS NIH HHS R35 GM134910NINDS NIH HHS R61 NS124922
6 · The paper itselfAbstract
Waixenicin A (WaixA) is a marine natural product that has emerged as a potential drug lead for the treatment of hypoxic ischemic brain injury. WaixA specifically blocks the divalent ion channel transient receptor potential melastatin 7 (TRPM7), preventing the influx of calcium into the cell and triggering apoptotic pathways. We applied pharmacophore-directed retrosynthesis to this natural product, leading us to prepare a series of highly simplified derivatives bearing our proposed minimal pharmacophore, namely, the pyranyl vinylogous acetal. The synthesis of these derivatives and their ability to inhibit TRPM7 is described. Inhibition in the 9-57% range was found for these simplified structures in patch-clamp experiments; however, the ability of these highly simplified derivatives to exhibit inhibition provides information regarding minimal structural requirements for bioactivity.
Indexed as
Biological ProductsTRPM Cation ChannelsHumansMolecular StructurePharmacophoreStructure-Activity RelationshipBiological ProductsTRPM Cation Channels
Identifiers
PMID42276815
PMCPMC13316981
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