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Related Experiment Videos

Relationship between structure and biological activity of novel R106 analogs

M J Rodriguez1, M J Zweifel, J D Farmer

  • 1Infectious Disease Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.

The Journal of Antibiotics
|April 1, 1996
PubMed
Summary

Researchers modified a natural product (R106-1) to create new antifungal analogs. L-isomers showed stronger activity, but hydrogen bonding at residue 8 was crucial for effectiveness against Cryptococcus neoformans.

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Area of Science:

  • Medicinal Chemistry
  • Organic Synthesis
  • Mycology

Background:

  • The natural product R106-1 possesses antifungal properties.
  • Modifications to R106-1 were explored to enhance or alter its activity spectrum.
  • Understanding structure-activity relationships is key to developing new antifungal agents.

Purpose of the Study:

  • To synthesize novel hydroxylated analogs of R106-1 using retro-aldol and alkylation reactions.
  • To evaluate the antifungal activity of these new analogs against various fungal species.
  • To elucidate the structure-activity relationship (SAR) of these analogs, focusing on steric and electronic requirements for receptor binding.

Main Methods:

  • Retro-aldol reaction at residue 8 of R106-1 to introduce a sarcosine residue.

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  • Classical aldol alkylation for further chemical modification.
  • In vitro antifungal assays to determine the potency of synthesized analogs.
  • Comparative analysis of activity against Candida spp. and Cryptococcus neoformans.

    • Main Results:

    • Synthesized analogs with a sarcosine residue amenable to alkylation.
    • L-isomers of hydroxylated analogs demonstrated greater antifungal potency than D-isomers.
    • All analogs showed reduced activity against Cryptococcus neoformans compared to R106-1.
    • Some structural modifications were tolerated by Candida spp., but with diminished potency.

    Conclusions:

    • The stereochemistry (L-isomers) and specific structural features, particularly hydrogen bonding at residue 8, are critical for potent antifungal activity against Cryptococcus neoformans.
    • The SAR studies provide insights into the binding requirements of antifungal targets.
    • Further optimization is needed to develop analogs effective against Cryptococcus neoformans.