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Synthetic mimics of antimicrobial peptides from aryl scaffolds

Hitesh Thaker, University of Massachusetts Amherst


The rise in bacterial resistance and the declining approval rate of novel anti-infective drugs are a major threat to global public health. Antimicrobial peptides (AMPs), found in almost every multicellular organism, have attracted considerable attention as models for the design of new therapeutic agents due to their broad spectrum activity and reduced bacterial resistance development. This dissertation focuses on the development of a new series of synthetic mimics of antimicrobial peptides (SMAMPs) from simple aryl scaffolds using Suzuki Miyaura coupling. This novel design allows easy tuning of the conformation, overall hydrophobicity of the molecule, amphiphilicity, and the number of charges in order to develop a structure-activity relationship. The antimicrobial activities of the SMAMPs against both gram-positive and gram-negative bacteria suggest that improving the selectivity requires fine-tuning of one or more of these parameters, with overall hydrophobicity and charge having a more significant impact than conformational rigidity. Furthermore, comparing the activities of SMAMPS with facially amphiphilic and disrupted amphiphilic topologies confirmed that amphiphilicity is an important design parameter for attaining antimicrobial activity, especially against gram-negative bacteria. This aryl scaffold design has led to the development of several highly active SMAMPs with selectivities >200 against both gram-positive S. aureus and gram-negative E. coli, which is nearly 20 times higher than that of the conventional AMP, MSI-78. One of these SMAMPs also shows a unique immunomodulatory response involving the induction of both cytokines and chemokines, which can have significant therapeutic potential. Similar chemistry was employed in the development of novel lipopeptide mimics (LPMs), where the attachment of pendant aliphatic chains to the tri-aryl backbone structure can be used to modulate the activity. The second project in this dissertation concerns the investigation of the influence of the cobalt density in the phase-separated domains in the ferromagnetic block copolymer materials A series of metal-containing block-random copolymers composed of an alkyl-functionalized homo block (C16 ) and a random block of cobalt complex- (Co) and ferrocene complex-functionalized (Fe) units was synthesized via ring-opening metathesis polymerization (ROMP). Taking advantage of the block-random architecture, the influence of dipolar interactions on the magnetic properties of these nanostructured BCPs was studied by systematically varying the molar ratio of the Co units to the Fe units, while maintaining the cylindrical phase-separated morphology. A decrease in the cobalt density weakens the dipolar interactions between the cobalt nanoparticles, leading to the transition from a room temperature ferromagnetic material to a superparamagnetic material. These results confirm that the dipolar interactions of the cobalt nanoparticles within the phase-separated domains are responsible for the (unexpected) room temperature ferromagnetic properties of the nanostructured BCPs.

Subject Area

Organic chemistry|Polymer chemistry

Recommended Citation

Thaker, Hitesh, "Synthetic mimics of antimicrobial peptides from aryl scaffolds" (2013). Doctoral Dissertations Available from Proquest. AAI3556293.