In this thesis, a series of imidazolium salts and gold(I) N-heterocyclic carbene (NHC) complexes coupled to the natural peptide deformylase (PDF) inhibitor actinonin were synthesized and evaluated for their biological activity. Their antibacterial efficacy was assessed against representative gram-positive and gram-negative strains, including Mycobacterium tuberculosis, and their inhibition of human peptide deformylase (HsPDF) was examined. In addition, their anticancer potential was investigated using cell-count and metabolic-activity assays. Complementary in silico studies – including non-covalent and covalent docking, molecular dynamics simulations, and MM/GBSA binding-energy calculations – provided mechanistic insights into the mode of action and selectivity of the gold(I) NHC complexes toward bacterial versus human PDFs. An established total synthesis of actinonin was further optimized and scaled up. Additional, both polymer-supported and solid-phase strategies were explored as alternative routes to key intermediates. Biological evaluation showed that free hydroxamate derivatives retained potent in vitro EcPDF inhibition in the low-nanomolar range. Gold(I) NHC complexes bearing a free hydroxamate group exhibited submicromolar to low-micromolar inhibition of both EcPDF and HsPDF. Unexpectedly, PMB-protected gold(I) NHC complexes displayed submicromolar inhibition of HsPDF while, showing no detectable activity against EcPDF. Several gold(I)–actinonin conjugates also reduced cell numbers and metabolic activity in Hep2G cancer cells, highlighting their potential as anticancer agents. Overall, these findings demonstrate the versatility of the NHC–gold(I) scaffold in modulating metal–ligand cooperativity for selective PDF inhibition and provide a foundation for the further development of gold(I)–actinonin hybrids as promising antimicrobial and anticancer candidates.
Oliver Richard Borzek (Thu,) studied this question.