Family-level stereoselective synthesis and biological evaluation of pyrrolomorpholine spiroketal natural product antioxidants

The lipoxazolidinone family of marine natural products, with an unusual 4-oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow-up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogs to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4-oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.

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Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A

10.26434/chemrxiv.6103607 ◽

2018 ◽

Author(s):

Jonathan J. Mills ◽

Kaylib R. Robinson ◽

Troy E. Zehnder ◽

Joshua G. Pierce

Keyword(s):

Natural Products ◽

Natural Product ◽

Mechanism Of Action ◽

Marine Natural Products ◽

Biological Evaluation ◽

Lead Compounds ◽

Follow Up Studies ◽

Initial Resistance ◽

Synthesis And Biological Evaluation

The lipoxazolidinone family of marine natural products, with an unusual 4-oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow-up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogs to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4-oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.

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Rational Design, Synthesis and Biological Evaluation of Novel Derivatives Based on in vivo Metabolism of Natural Product β-elemene

Letters in Drug Design & Discovery ◽

10.2174/1570180814666171108093021 ◽

2018 ◽

Vol 15 (8) ◽

pp. 905-912 ◽

Cited By ~ 1

Author(s):

Renren Bai ◽

Xiaokang Jie ◽

Eric Salgado ◽

Jian Sun ◽

Yao Zhu ◽

...

Keyword(s):

Natural Product ◽

Rational Design ◽

Biological Evaluation ◽

In Vivo Metabolism ◽

Design Synthesis ◽

Synthesis And Biological Evaluation

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Natural product fragment combination to performance-diverse pseudo-natural products

Nature Communications ◽

10.1038/s41467-021-22174-4 ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 2

Author(s):

Michael Grigalunas ◽

Annina Burhop ◽

Sarah Zinken ◽

Axel Pahl ◽

José-Manuel Gally ◽

...

Keyword(s):

Natural Products ◽

Product Design ◽

Natural Product ◽

Chemical Space ◽

Biological Evaluation ◽

Product Structure ◽

Biologically Relevant ◽

Biologically Relevant Chemical Space

AbstractNatural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. We describe the synthetic combination of the fragment-sized natural products quinine, quinidine, sinomenine, and griseofulvin with chromanone or indole-containing fragments to provide a 244-member pseudo-natural product collection. Cheminformatic analyses reveal that the resulting eight pseudo-natural product classes are chemically diverse and share both drug- and natural product-like properties. Unbiased biological evaluation by cell painting demonstrates that bioactivity of pseudo-natural products, guiding natural products, and fragments differ and that combination of different fragments dominates establishment of unique bioactivity. Identification of phenotypic fragment dominance enables design of compound classes with correctly predicted bioactivity. The results demonstrate that fusion of natural product fragments in different combinations and arrangements can provide chemically and biologically diverse pseudo-natural product classes for wider exploration of biologically relevant chemical space.

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