Synthesis and Antimicrobial Evaluation of Small Molecule Amphiphiles Derived from Amphiphilic Antimicrobial Natural Products
Doctoral thesis
Permanent lenke
http://hdl.handle.net/11250/2455508Utgivelsesdato
2017Metadata
Vis full innførselSamlinger
- Institutt for kjemi [1431]
Sammendrag
Development of antimicrobial agents that work through novel mechanisms is of importance for combating the steadily increasing proliferation of resistant bacteria. Infections caused by resistant bacteria have become an increasing global problem, where clinicians in the worst case scenarios are left without treatment options against severe bacterial infections. If this trend is left unchecked, the modern society will return to the medicinal dark-ages before the antibiotic era, where bacterial infections were often untreatable life-threatening ailments. Investigations into new antimicrobials are therefore not only important, but vital for the continuation of the current status quo in medicine.
This project has focused on preparation of novel amphiphilic antimicrobials based on a model developed from antimicrobial peptides and marine antimicrobial natural products. The aim was to create a library of cationic amphiphiles for biological evaluation. The current compound library has now reached over 100 compounds, consisting mostly of 1,2,3-triazoles in addition to around 20 compounds based on isoindoline and dihydro pyrrolopyridine. The synthetic workhorses in this project have been the copper-catalyzed azide-alkyne cycloaddition (CuAAC) and transition metal catalyzed [2+2+2] cycloaddition reactions.
After scaffold synthesis and N-functionalization, the target amphiphiles were evaluated against five strains of clinically important bacteria: Staphylococcus aureus, Enterococcus faecalis, Streptococcus agalacticae, Pseudomonas aeruginosa, and Escheria coli. In addition to antimicrobial evaluations, the most active target compounds in the antimicrobial assays were evaluated for mammalian toxicity against HepG2-cells (human hepatic cells). All biological testing was performed at Marbio at UiT - The arctic university of Norway.
The biological evaluations were used to evaluate the relative potencies and toxicities of different functional groups. Some functional groups have therefore become more prevalent in the later substrates and future work, whereas some functional groups have been excluded due to low antimicrobial potency or high level of cytotoxicity against HepG2. On basis of these evaluations, the "current lead" compounds in the library were chosen. The compounds were coined "current leads", as they still have some selectivity issues that needs to be addressed in order to make them more suitable as lead structures.
Består av
Paper 1: Bakka, Thomas Aleksander; Gautun, Odd Reidar. "Simple generalized reaction conditions for the conversion of primary aliphatic amines to surfactant-like guanidine salts with 1H-pyrazole carboxamidine hydrochloride." Synthetic Communications 2017 ;Volum 47.(2) Suppl. 1 s. 169-172 - Is not included due to copyright available at http://dx.doi.org/10.1080/00397911.2016.1257724Paper 2: Bakka, Thomas Aleksander; Strøm, Morten B.; Andersen, Jeanette hammer; Gautun, Odd Reidar. "Synthesis and antimicrobial evaluation of cationic low molecular weight amphipathic 1,2,3-triazoles." Bioorganic & Medicinal Chemistry Letters 2017 ;Volum 27.(5) s. 1119-1123 https://doi.org/10.1016/j.bmcl.2017.01.092
Paper 3: Bakka, Thomas Aleksander; Strøm, Morten B.; Andersen, Jeanette hammer; Gautun, Odd Reidar. "Methyl propiolate and 3-butynone: starting points for synthesis of amphiphilic 1,2,3-triazole peptidomimetics for antimicrobial evaluation." Bioorganic & Medicinal Chemistry 2017 https://doi.org/10.1016/j.bmc.2017.07.060 © 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
Paper 4: Bakka, Thomas A.; Myreng, Kristian N.; Lea, Kristoffer L.; Brondz, Anton C; Strøm, Morten B.; Andersen, Jeanette H.; Gautun, Odd R. "Synthesis and antimicrobial evaluation of fused pyridine and isoindoline amphiphiles"