William Horton

Theoretical and experimental analysis of the antioxidant features of diarylhydrazones

Structural and energetic features of a series of 15 diarylhydrazone derivatives were studied via density functional theory (DFT) in order to identify the key features that most likely contribute to their antioxidant effect. Theoretical calculations were carried out at the B3LYP/6-31G(d,p) level. The calculated physicochemical parameters included the ionization potential, N-H dissociation enthalpy, proton affinity, HOMO/LUMO energies, and the band gaps of the most stable conformation of the compounds. To assess the contribution of these factors to the in vitro activity, the compounds were synthesized and their antioxidant activity was also determined in three commonly used assays. The hydrazones were evaluated for their radical scavenging against the 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS), and peroxyl (ORAC assay) radicals. The experimental radical scavenging data of the compounds have been then plotted against the physicochemical characteristics and based on the obtained fits conclusions have been drawn regarding the relative importance of the respective factors.

Synthesis and application of β-carbolines as novel multi-functional anti-Alzheimer’s disease agents

The design, synthesis and assessment of β-carboline core-based compounds as potential multifunctional agents against several processes that are believed to play a significant role in Alzheimers disease (AD) pathology, are described. The activity of the compounds was determined in Aβ self-assembly (fibril and oligomer formation) and cholinesterase (AChE, BuChE) activity inhibition, and their antioxidant properties were also assessed. To obtain insight into the mode of action of the compounds, HR-MS studies were carried out on the inhibitor-Aβ complex formation and molecular docking was performed on inhibitor-BuChE interactions. While several compounds exhibited strong activities in individual assays, compound 14 emerged as a promising multi-target lead for the further structure-activity relationship studies.

Theoretical and experimental analysis of the antioxidant features of substituted phenol and aniline model compounds

Although natural polyphenols have attracted extended attention as antioxidants, there is only limited information available on their structure-activity relationship (SAR). In addition, while often having significant antioxidant activity, amino group-containing compounds have only been sporadically studied. Often, the complex structure makes studying the individual contribution of aromatic OH or NH2 groups on the activity of these antioxidants difficult. In this work, several substituted simple phenols and anilines were selected as model compounds. Both the experimental radical scavenging activity and major structural descriptors have been determined to gain more insights into the potential SAR. Physicochemical properties pertaining to energetic and structural parameters were determined and experimental data gathered from three antioxidant assays to identify fundamental features with reasonable effect on antioxidant activity. Density functional theory (DFT) calculations were carried out at the B3LYP/6-31G(d,p) level to determine the N–H and O–H bond distances, dipole moments, logP values, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) orbital energies, HOMO-LUMO gaps, radical spin densities, proton affinities, and ionization potentials. The compounds were screened for activity against the 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS), 2,2-diphenyl-1picrylhydrazyl (DPPH), and peroxyl (ORAC assay) radicals. Based on the results, ABTS antioxidant activity was selected for further investigations to observe correlations with the calculated properties. The HOMO energies, bond-dissociation energy values, HOMO-LUMO gap energies, dipole moment, proton affinity, and the Hammett constants appear to show meaningful correlation with the experimental data.

Effects of Environmental Factors on DNA: Damage and Mutations

Chemicals in the environment pose myriad challenges to organisms, principally via toxicity or mutagenesis. Mutations are the result of changes in the DNA base sequence or the chemical addition of adducts onto the bases, which prevent correct DNA replication and/or transcription of the DNA into RNA. Additionally, spontaneous mutation of DNA bases can also occur by tautomerization, base deletions or additions, deamination, etc. Every human cell experiences about 10,000 “insults” every day, most of which are repaired by one of the multiple DNA repair systems of the cell. DNA replication itself results in a few base changes every cycle. Io protect itself from accumulating mutations, cells typically divide (mitosis) between 40 and 70 times (the so-called Hayflick number) before they undergo programmed cell death (apoptosis). Hence, it is the accumulation of mutations in the DNA due to chemicals in the environment that seems to be a causative agent of maladies, including cancer. (It is currently hypothesized that multiple DNA base changes, DNA rearrangements, etc., are necessary for the induction of cancer, which is uncontrolled and unregulated cell growth and division). Environmental chemicals that are linked to DNA damage include (but are not limited to) alkylating agents, Agent Orange, intercalating agents, dichlorodiphenyltrichloroethane, triclosan, and plasticizers (including polyvinyl chloride, phthalates, and bisphenol A and its derivatives). Some of the environmental chemicals may not cause DNA damage directly; they can cause epigenetic changes. This means that the DNA base sequence is not altered but the base is chemically modified so that the genetic information is expressed in a manner abnormal to correct cellular function. Moreover, it has become evident that posttranslational modifications of proteins associated with DNA (e.g., histones) can also lead to mutation via incorrect regulation of gene expression. Results of contemporary studies on animals (including human) have also indicated that epigenetic changes can occur in response to environmental distress (e.g., famine, toxic chemicals) and cause an ailment(s) in the individual due to altered gene expression, and that these epigenetic changes, altered gene expression, and ailment(s) are passed on to at least two and maybe three generations of offspring. The gene sequence, however, remains unchanged! This is referred to as transgenerational inheritance.

4,5-Dimethoxy-2-nitrobenzohydrazides and 1-(1-Benzylpiperidin-4-yl)ethan-1-ones as Potential Antioxidant/Cholinergic Endowed Small Molecule Leads

The objective of this research is to generate leads for developing our ultimate poly-active molecules with utility in central nervous system (CNS) diseases. Indeed, poly-active molecules capable of mitigating brain free radical damage while enhancing acetylcholine signaling (via cholinesterase inhibition) are still being sought for combating Alzheimer’s disease (AD). We differentiate “poly-active” agents from “multi-target” ones by defining them as single molecular entities designed to target only specific contributory synergistic pharmacologies in a disease. For instance, in AD, free radicals either initiate or act in synergy with other pharmacologies, leading to disease worsening. For this preliminary report, a total of 14 (i.e., 4,5-dimethoxy-2-nitrobenzohydrazide plus 1-(1-benzylpiperidin-4-yl)ethan-1-one) derivatives were synthesized and screened, in silico and in vitro, for their ability to scavenge free radicals and inhibit acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) enzymes. Overall, six derivatives (4a, 4d, 4e, 4f, 4g, 9b) exhibited potent (>30%) antioxidant properties in the oxygen radical absorbance capacity (ORAC) assay. The antioxidant values were either comparable or more potent than the comparator molecules (ascorbic acid, resveratrol, and trolox). Only three compounds (4d, 9a, 9c) yielded modest AChE/BuChE inhibitions (>10%). Please note that a SciFinder substance data base search confirmed that most of the compounds reported herein are new, except 9a and 9c which are also commercially available.

Natural and Nature-Inspired Synthetic Small Molecule Antioxidants in the Context of Green Chemistry

Abstract Environmental triggers may aggravate oxidative stress due to an excess accumulation of free radicals in the human body, leading to cellular damage and potentially resulting in pathological conditions. Low-molecular-weight antioxidants, important tools of the biochemical defense system, are discussed in this chapter. The identification of the most common food-derived small molecule antioxidants along with their isolation (with emphasis on green methodologies) and structural characterization are summarized, followed by a listing of the limitations of their use in preventing and/or treating diseases. Finally, recent examples of chemical modifications and formulations to improve the druglike properties and therapeutic potential of the natural antioxidants are introduced.