Title page for ETD etd-02032007-143323


Type of Document Dissertation
Author Sugandhi, Eko Winny
URN etd-02032007-143323
Title Synthesis, Characterization, and Antimicrobial Activity of Water-soluble, Tri-carboxylato Amphiphiles
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Gandour, Richard D. Committee Chair
Carlier, Paul R. Committee Member
Hanson, Brian E. Committee Member
Kingston, David G. I. Committee Member
Tanko, James M. Committee Member
Keywords
  • multi-tailed
  • multi-headed
  • tri-carboxylato
  • dendritic
  • amphiphile
  • solubility
  • microorganism
  • biological and intrinsic activity
Date of Defense 2007-01-31
Availability unrestricted
Abstract
Many previous studies of biological activity in a homologous series of amphiphiles have shown a cut-off effect, where the biological activity increases with an increase in chain length, after which the activity plateaus or weakens. One factor suspected to cause this problem is solubility issues. We have designed several series of very hydrophobic, water-soluble amphiphiles to overcome this problem. Three homologous series containing mobile hydrophobic moieties and two series of epimers containing rigid cholestane moieties have been synthesized; the hydrophobic moiety is connected to the first-generation, Newkome-type dendron via a ureido linker. We have demonstrated that as tris(triethanolammonium) salts, these amphiphiles show excellent solubility in water. The solubilities in aqueous triethanolamine solution of the three series containing mobile hydrophobic moieties are 19,500 to 25,700 μM depending on the formula weight of the homolog, while those containing rigid cholestane moieties are 18,900 and 17,400 μM.

Having eliminated the solubility issue, the antimicrobial activity against a broad spectrum of microorganisms has been screened. We have demonstrated that the antimicrobial activity depends on the amphiphile-series, species, chain-length, or epimer specificities, as well as hydrophobicity. The one-tailed, tri-carboxylato amphiphiles are generally better than the other series, with two exceptions. First, the two-tailed tri-carboxylato amphiphiles, 3CUr1(11)2 and 3CUr1(12)2, are more active against Cryptococcus neoformans; in fact, both amphiphiles (MICs are 6.9 and 7.2 μM, respectively) are considered to display good antifungal activity. Second, amphiphile 3CUr-β-cholestane, whose MIC is 27 μM, is more active against Staphylococcus aureus. Overall, these new tri-carboxylato amphiphiles only exhibit moderate activity with two promising leads.

Furthermore, we have demonstrated the intrinsic activity (MIC0) of the one-tailed, tri-carboxylato amphiphile series (3CUrn) against Mycobacterium smegmatis. All the MIC0s observed are at least 8-fold lower than the corresponding CMCs. Amphiphile 3CUr16 is the most active; the MIC0 is 100-fold smaller than the CMC. With this consideration, we have suggested that the mechanism of action of the antimycobacterial activity in amphiphile 3CUr16 is not related to detergency.

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