Author ORCID Identifier
Date of Award
5-31-2026
Document Type
Open Access Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry/Organic Chemistry
First Advisor
Prof. Béla Török
Second Advisor
Prof. Marianna Török
Third Advisor
Prof. Jason Green
Abstract
Physiological redox homeostasis is a fine balance between prooxidants and antioxidants that are integrated elements of several reduction-oxidation mechanisms at molecular, organellar, cellular and tissue levels. When this equilibrium is disrupted and prooxidants become dominant, the body relies on endogenous and exogenous antioxidants to counterbalance the dysregulation and ultimately prevent the progression of oxidative stress. Reactive species (reactive oxygen species, reactive nitrogen species, or reactive sulfur species) are significant contributors to prooxidant activity. Over the years, substantial knowledge has been accumulated regarding their origin and roles in disease development, leading to the discovery and development of antioxidants that effectively target the production and detoxification of these oxidants. The present thesis addresses the structural drivers of antioxidant activity in thiophenols, diarylhydrazones and their v quaternary ammonium salts. In addition, green and benign synthetic protocols were developed and are presented for the studied antioxidants, as well as for benzimidazoles and benzothiazoles.
Phenols and polyphenols are well-known and widely investigated antioxidants, however their thiol counterparts, thiophenols, remain somehow understudied, despite the essential role of the thiol-based glutathione in cellular antioxidant defense. To address this gap, in Chapter 2 the antioxidant capacity of structurally versatile thiophenols is evaluated, incorporating both electron-donating and electron-withdrawing substituents as well as structurally more complex heteroaryl groups, and compared them with their phenol analogues. 17 phenol-thiophenol pairs were examined to identify structural factors governing antioxidant activity. Several physicochemical descriptors were calculated for all 34 compounds by DFT approaches and correlated with experimental data to determine the most predictive parameters. The antioxidant activity of the selected derivatives was assessed using standard DPPH and ABTS radical-scavenging assays.
In Chapter 3, another class of antioxidants, diarylhydrazones are evaluated experimentally as well as theoretically. As in the previous thiophenol-phenol study, global and local reactivity indices were calculated using DFT functionals to simulate antioxidant behavior. All calculations were performed using well-established B3LYP and M06-2X functionals along with 6-311++G(d,p) basis set and validated against a high-level method, DLPNO-CCSD(T). Ten of the total 34 compounds were further analyzed using Fukui functions to identify regions within the compounds most susceptible to nucleophilic or electrophilic attack. Additionally, an essential antioxidant feature, the electron delocalization was characterized based on the electron density of delocalized bonds descriptor, EDDB(r), values. Learning from these findings, in Chapter 4 we selected and investigated six high-performing diarylhydrazones and derivatized them to methylated and benzylated quaternary ammonium salts. The focus of their computational analysis was on how vi quaternization affects antioxidant activity, as well as on the effect of solvation, both in water and lipid-mimicking (pentyl-ethanoate) media. The computational results were compared to these compounds’ experimental activities in DPPH and ABTS assays.
In Chapters 5 and 6, the developed and employed synthetic methodologies are presented. The only exceptions are thiophenols and phenols presented in Chapter 2, which were all commercially available compounds. For the synthesis of diarylhydrazones, a microwave-assisted condensation protocol was developed, which involves an ethanol-water solvent system and offers shorter reaction times as well as simple product isolation. A wide scope of substrates was tested under these conditions. The resulting diarylhydrazones were subsequently transformed via a Menshutkin SN2 reaction using benzyl bromide to generate benzylated quaternary ammonium salts. Because of a dominant side product formation in similar methylation reactions, an alternative strategy was developed, which involved the direct coupling of hydrazine precursors with 4-formyl-N,N,N-trimethylbenzenaminium or N-benzyl-4-formyl-N,N-dimethylbenzenaminium salts. Both yielded the desired salts with good yield and selectivity.
Finally, a mild, metal- and acid-free protocol is presented for the preparation of 2-alkyl and aryl benzimidazoles and benzothiazoles using substituted aldehydes and ortho-phenylenediamine or 2-aminobenzenethiol as precursors. The advantages of this method include nearly quantitative yields of the desired product, along with the overall high atom economy, and the absence of toxic waste formation. Additionally, because the process is without the use of any catalyst, it also eliminates the need for catalyst separation or recycling. Finally, the use of ethanol as a green solvent, as well as the predominant room-temperature and short reaction conditions, contribute to the overall energy efficiency of the protocol.
Recommended Citation
Vlocsko, Rita Bernadett, "Computer-aided Development of Novel Antioxidants" (2026). Graduate Doctoral Dissertations. 1162.
https://scholarworks.umb.edu/doctoral_dissertations/1162
Included in
Computational Chemistry Commons, Medicinal-Pharmaceutical Chemistry Commons, Organic Chemistry Commons
Comments
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