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    Studies in organic and medicinal chemistry: (i) Synthesis, antimicrobial evaluation, and photophysical studies of novel conjugated systems; (ii) Antimicrobial evaluation of pyrazolopyrimidinone heterocycles.

    Doyle, Amanda (2020) Studies in organic and medicinal chemistry: (i) Synthesis, antimicrobial evaluation, and photophysical studies of novel conjugated systems; (ii) Antimicrobial evaluation of pyrazolopyrimidinone heterocycles. PhD thesis, National University of Ireland Maynooth.

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    This thesis is divided into three distinct chapters. The first chapter highlights the synthesis of a family of trans-cinnamaldehydes using a Wittig methodology, and their evaluation as antibacterial agents against Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli) in vitro. Cinnamaldehydes are known electrophiles, with some literature reports suggesting a Michael acceptor role as part of their antibacterial mode of action. The electrophilicities of our family of transcinnamaldehydes were calculated, and a relationship between electrophilicity and observed antibacterial activity was considered. Here, the more electrophilic cinnamaldehydes appeared to be more active in our antibacterial assays. An in vivo toxicity assessment of a selection of these trans-cinnamaldehydes was undertaken using Galleria mellonella larvae, and an initial mechanism of action study was performed using protein and amino acid leakage as an indication of the effect the trans-cinnamaldehydes might have on the integrity of the bacterial cell wall and/or membrane. The transcinnamaldehydes studied were non-toxic and did show some protein and amino acid leakage, although the results were such that the cell wall/membrane disruption may not be the primary or only mechanism of action. Overall, the antibacterial activity of the trans-cinnamaldehydes was modest to low. They were non-toxic and displayed both an interesting relationship to electrophilicity and an ability to disrupt the cell wall/membrane. However, they are not strong candidates for further development as antibacterial agents and would require further structural modification to improve efficacy. A second antimicrobial study was undertaken with the aim of identifying novel potent antimicrobial agents. An initial screen of novel structures, which was available in the Stephens group, identified a pyrazolo[1,5-a]pyrimidin-7-one family of compounds with antibacterial potential. This family of pyrazolo[1,5-a]pyrimidin-7-ones were synthesized by other group members and I carried out the antimicrobial activity study. One member of this family, 2-butyl-5-(3,5-bis(trifluoromethyl))phenylpyrazolo[1,5-a]pyrimidin- 7(4H)-one, was identified as a leading hit compound against S. aureus in the preliminary study. The family of thirty-five pyrazolo[1,5-a]pyrimidin-7-ones was divided into groups based on their structure as part of a structure activity relationship (SAR) study, and each member was tested in vitro against S. aureus (Gram-positive bacteria), E. coli (Gramnegative bacteria), and Candida albicans (representative fungus). The pyrazolo[1,5- a]pyrimidin-7-ones showed more potent antibacterial activity than antifungal activity. The SAR studies resulted in the identification of a leading hit pyrazolo[1,5-a]pyrimidin- 7-one, 2-isopropyl-5-(3,5-bis(trifluoromethyl))phenylpyrazolo[1,5-a]pyrimidin-7(4H)- one, which showed the highest activity against S. aureus, MIC50 of 1.2 μM. The activity of 2-isopropyl-5-(3,5-bis(trifluoromethyl))phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one was superior to that of the commercial antibiotics tested against S. aureus, in that, a MIC50 of 21.8 μM, 11.03 μM, and 5.22 μM was obtained for ampicillin trihydrate, tetracycline, and streptomycin sulfate, respectively. A selection of pyrazolo[1,5-a]pyrimidin-7-ones, including our most active candidates, were then evaluated against more clinicallyrelevant bacterial strains, namely methicillin-resistant S. aureus (MRSA, Gram-positive), and Pseudomonas aeruginosa (Gram-negative). The most active compound was 2-(4- trifluoromethylphenyl)-5-(3,5-bis(trifluoromethyl))phenylpyrazolo[1,5-a]pyrimidin- 7(4H)-one, with an MIC50 of 1.88 μM against MRSA, and compares favourably to the MIC50 of 2.33 mM and 291.72 μM for the commercial antibiotics ampicillin trihydrate and tetracycline, respectively. An in vivo toxicity assessment and an in vivo therapeutic evaluation of the most active compounds was completed, using Galleria mellonella and infected Galleria mellonella respectively. Here, the pyrazolo[1,5-a]pyrimidin-7-ones evaluated were shown to be non-toxic and, in the therapeutic evaluation study, where Galleria mellonella were infected with MRSA and subsequently treated with was 2-(4- trifluoromethylphenyl)-5-(3,5-bis(trifluoromethyl))phenylpyrazolo[1,5-a]pyrimidin- 7(4H)-one, the survival rate improved by 25% for the treated Galleria mellonella over the non-treated. Chapter two is dedicated to the development of a synthetic methodology that allows access to electron deficient trienes. Important applications of trienes can be broadly divided into (i) medicinal applications and (ii) synthetic applications. An initial attempt to access (1E,3E,5E)-1,3-bis-phenylsulfonyl-6-phenyl-hexa-1,3,5-triene from trans-cinnamaldehyde and (E)-1,3-bis-phenylsulfonylprop-1-ene, using traditional Knoevenagel-condensation reaction conditions, was unsuccessful. We then undertook a study to determine Knoevenagel-type condensation reaction conditions that would allow access to the desired triene. The model reaction chosen was that between transcinnamaldehyde and (E)-1,3-bis-phenylsulfonylprop-1-ene. The study explored reaction variables such as solvent, base, equivalents of base, and temperature, with conversion to triene estimated using quantitative NMR. This allowed us to establish the preferred reaction conditions for our Knoevenagel-type condensation synthetic strategy which used DCM as solvent, 20 ℃, and 15 equivalents of Al2O3 as base. The desired triene was generated in 93% isolated yield and the methodology was successfully applied to the synthesis of 20 trienes. All of these novel compounds underwent full structural characterization using NMR spectroscopy, liquid chromatography-mass spectrometry (LC-MS), high resolution-mass spectrometry (HR-MS), and infrared (IR) spectroscopy. In terms of substrate scope, our synthetic strategy allowed for variation of the starting cinnamaldehyde, and some variation of the starting propene (nitrile and sulfonyl electron withdrawing groups). However, our studies to date suggest that employing esters as an electron withdrawing group on the propene may not be well tolerated. Within our attempts to employ the esters, an alternative biaryl product was generated when dimethyl glutaconate was employed as the starting ester propene. Other ester variations resulted in the generation of complex mixtures. In chapter three we report a thermal electrocyclization of our electron poor trienes in the synthesis of a family of phenylsulfonyl biaryls. An optimization study led to the identification of preferred reaction conditions and an isolated yield of 88% for our model reaction was obtained using (1E,3E,5E)-1,3-bis-phenylsulfonyl-6-phenyl-hexa-1,3,5- triene as the substrate. This allowed us to access nine phenylsulfonyl biaryl products. All novel compounds underwent full structural characterization using NMR spectroscopy, LC-MS, HR-MS, and IR spectroscopy. A photophysical study was also performed, as the structure of the biaryls suggested that they may possess some interesting fluorescent properties via a possible twisted intramolecular charge transfer (TICT) process. The dimethylamino derivative showed the greatest sensitivity to solvent choice. In terms of the molar extinction coefficient (ε), values of between 17332 and 37964 M-1 cm-1 were recorded in chloroform. The highest value was obtained for the choro derivative, and the lowest value for the dimethylamino substituted derivative. The derivative with the highest quantum yield of 0.92 was also the dimethylamino derivative, but this was only observed in the aprotic solvent chloroform. In methanol, the quantum yield dropped dramatically for the dimethylamino derivative due to a suspected hydrogen bonding effect. The preliminary photophysical properties suggest that these biaryls are potentially useful and versatile fluorescent small molecules.

    Item Type: Thesis (PhD)
    Keywords: organic and medicinal chemistry; Synthesis; antimicrobial evaluation; photophysical studies; novel conjugated systems; Antimicrobial evaluation; pyrazolopyrimidinone heterocycles;
    Academic Unit: Faculty of Science and Engineering > Chemistry
    Item ID: 16847
    Depositing User: IR eTheses
    Date Deposited: 12 Jan 2023 11:44
      Use Licence: This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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