Evaluating Quinolines: Molecular Dynamics Approach to Assess Their Potential as Acetylcholinesterase Inhibitors for Alzheimer's Disease.

Quinoline represents a promising scaffold for developing potential drugs because of the wide range of biological and pharmacological activities it exhibits. In the present study, quinoline derivatives obtained from CADMA-Chem docking protocol were investigated in the mean of molecular dynamics simulations as potential inhibitors of acetylcholinesterase enzyme. The examined species can be partitioned between neutral, dq815 (2,3 dihydroxyl-quinoline-4-carbaldehyde), dq829 (2,3 dihydroxyl-quinoline-8-carboxylic acid methane ester), dq1356 (3,4 dihydroxyl-quinoline-6-carbaldehyde), dq1368 (3,4 dihydroxyl-quinoline-8-carboxylic acid methane ester) and dq2357 (5,6 dihydroxyl-quinoline-8-carboxylic acid methane ester), and deprotonated, dq815_dep, dq829_dep, dq1356_dep and dq2357_dep. Twelve molecular dynamics simulations were performed including those of natural acetylcholine, of the well-known donepezil inhibitor and of the founder quinoline chosen as reference. Key intermolecular interactions were detected and discussed to describe the different dynamic behavior of all the considered species. Binding energies calculation from MMPBSA well accounts for the dynamic behavior observed in the simulation time proposing dq1368 as promising candidate for the inhibition of acetylcholinesterase. Retrosynthetic route for the production of the investigated compounds is also proposed.

On the dual role of (+)-catechin as primary antioxidant and inhibitor of viral proteases.

Natural antioxidants have become the subject of many investigations due to the role that they play in the reduction of oxidative stress. Their main scavenging mechanisms concern the direct inactivation of free radicals and the coordination of metal ions involved in Fenton-like reactions. Recently, increasing attention has been paid to non-covalent inhibition of enzymes involved in different diseases by the antioxidants. Here, a computational investigation on the primary antioxidant power of (+)-catechin against the •OOH radical has been performed in both lipid-like and aqueous environments, taking into account the relevant species present in the simulated acid-base equilibria at the physiological pH. Hydrogen Atom Transfer (HAT), Single Electron Transfer (SET), and Radical Adduct Formation (RAF) mechanisms were studied, and relative rate constants were estimated. The potential inhibitory activity of the (+)-catechin towards the most important proteases from SARS-CoV-2, 3C-like (Mpro) and papain-like (PLpro) proteases was also investigated by MD simulations to provide deeper atomistic insights on the binding sites. Based on the antioxidant and antiviral properties also unravelled by comparison with other molecules having similar chemical scaffold, our results propose that (+)-CTc satisfies can explicate a dual action as antioxidant and antiviral in particular versus Mpro from SARS-CoV-2.

Quinoline Derivatives: Promising Antioxidants with Neuroprotective Potential.

Quinoline has been proposed as a privileged molecular framework in medicinal chemistry. Although by itself it has very few applications, its derivatives have diverse biological activities. In this work, 8536 quinoline derivatives, strategically designed using the CADMA-Chem protocol, are presented. This large chemical space was sampled, analyzed and reduced using selection and elimination scores that combine their properties of bioavailability, toxicity and manufacturability. After applying several filters, 25 derivatives were selected to investigate their acid-base, antioxidant and neuroprotective properties. The antioxidant activity was predicted based on the ionization potential and bond dissociation energies, parameters directly related to the transfer of hydrogen atoms and of a single electron, respectively. These two mechanisms are typically involved in the radical scavenging processes. The antioxidant efficiency was compared with reference compounds, and the most promising antioxidants were found to be more efficient than Trolox but less efficient than ascorbate. In addition, based on molecular docking simulations, some derivatives are expected to act as inhibitors of catechol-O methyltransferase (COMT), acetylcholinesterase (AChE) and monoamine oxidase type B (MAO-B) enzymes. Some structural insights about the compounds were found to enhance or decrease the neuroprotection activity. Based on the results, four quinoline derivatives are proposed as candidates to act as multifunctional antioxidants against Alzheimer's (AD) and Parkinson's (PD) diseases.

Calmodulin-Targeting Molecules from Ageratina grandifolia.

Four new natural chemical entities, including 2-hydroxy-α-truxillic acid (2), (3R,4S)-2,2-dimethyl-3-hydroxy-4-(1-angeloyloxy)-6-acetyl-7-methoxychromane (3), N-tricosanoyltyramine (4), and grandifolamide (5), were isolated along with 11 known compounds (1, 6-15) from the aerial parts of Ageratina grandifolia. The chemical structures were elucidated using chemical derivatization and HR-MS, NMR, and DFT-calculated chemical shifts, combined with DP4+ statistical analysis. It was found that 2 decomposed into its biogenetic precursor, o-coumaric acid, upon standing at room temperature for a few weeks. 3,5-Diprenyl-4-hydroxyacetophenone (8), O-methylencecalinol (10), encecalin (11), and encecalinol (12) bound to calmodulin (CaM) with higher affinity than chlorpromazine, a well-known CaM inhibitor. Molecular dynamics studies revealed that the complexes of these compounds with CaM remained stable during the simulation. Altogether these results revealed the therapeutic and research tool potential of compounds 8, 10, 11, and 12.

Rational Design of Multifunctional Ferulic Acid Derivatives Aimed for Alzheimer's and Parkinson's Diseases.

Ferulic acid has numerous beneficial effects on human health, which are frequently attributed to its antioxidant behavior. In this report, many of them are reviewed, and 185 new ferulic acid derivatives are computationally designed using the CADMA-Chem protocol. Consequently, their chemical space was sampled and evaluated. To that purpose, selection and elimination scores were used, which are built from a set of descriptors accounting for ADME properties, toxicity, and synthetic accessibility. After the first screening, 12 derivatives were selected and further investigated. Their potential role as antioxidants was predicted from reactivity indexes directly related to the formal hydrogen atom transfer and the single electron transfer mechanisms. The best performing molecules were identified by comparisons with the parent molecule and two references: Trolox and α-tocopherol. Their potential as polygenic neuroprotectors was investigated through the interactions with enzymes directly related to the etiologies of Parkinson's and Alzheimer's diseases. These enzymes are acetylcholinesterase, catechol-O-methyltransferase, and monoamine oxidase B. Based on the obtained results, the most promising candidates (FA-26, FA-118, and FA-138) are proposed as multifunctional antioxidants with potential neuroprotective effects. The findings derived from this investigation are encouraging and might promote further investigations on these molecules.

CADMA-Chem: A Computational Protocol Based on Chemical Properties Aimed to Design Multifunctional Antioxidants.

A computational protocol aimed to design new antioxidants with versatile behavior is presented. It is called Computer-Assisted Design of Multifunctional Antioxidants and is based on chemical properties (CADMA-Chem). The desired multi-functionality consists of in different methods of antioxidant protection combined with neuroprotection, although the protocol can also be used to pursue other health benefits. The dM38 melatonin derivative is used as a study case to illustrate the protocol in detail. This was found to be a highly promising candidate for the treatment of neurodegeneration, in particular Parkinson's and Alzheimer's diseases. This also has the desired properties of an oral-drug, which is significantly better than Trolox for scavenging free radicals, and has chelates redox metals, prevents the ●OH production, via Fenton-like reactions, repairs oxidative damage in biomolecules (lipids, proteins, and DNA), and acts as a polygenic neuroprotector by inhibiting catechol-O-methyl transferase (COMT), acetylcholinesterase (AChE) and monoamine oxidase B (MAOB). To the best of our best knowledge, CADMA-Chem is currently the only protocol that simultaneously involves the analyses of drug-like behavior, toxicity, manufacturability, versatile antioxidant protection, and receptor-ligand binding affinities. It is expected to provide a starting point that helps to accelerate the discovery of oral drugs with the potential to prevent, or slow down, multifactorial human health disorders.

Chalcone Derivatives with a High Potential as Multifunctional Antioxidant Neuroprotectors.

A systematic, rational search for chalcone derivatives with multifunctional behavior has been carried out, with the support of a computer-assisted protocol (CADMA-Chem). A total of 568 derivatives were constructed by incorporating functional groups into the chalcone structure. Selection scores were calculated from ADME properties, toxicity, and manufacturability descriptors. They were used to select a subset of molecules (23) with the best drug-like behavior. Reactivity indices were calculated for this subset. They were chosen to account for electron and hydrogen atom donating capabilities, which are key processes for antioxidant activity. The indexes showed that four chalcone derivatives (dCHA-279, dCHA-568, dCHA-553, and dCHA-283) are better electron and H donors than the parent molecule and some reference antioxidants (Trolox, ascorbic acid, and α-tocopherol). In addition, based on molecular docking, they are predicted to act as catechol-O-methyltransferase (COMT), acetylcholinesterase (AChE), and monoamine oxidase B (MAO-B) inhibitors. Therefore, these four molecules are proposed as promising candidates to act as multifunctional antioxidants with neuroprotective effects.

Antioxidants into Nopal (Opuntia ficus-indica), Important Inhibitors of Free Radicals' Formation.

Nopal (Opuntia ficus indica) belonging to the Cactacea family has many nutritional benefits attributed to a wide variety of phenolic and flavonoid compounds. Coumaric acid (COA), ferulic acid (FLA), protocatechuic acid (PRA), and gallic acid (GAA) are the phenolic acids (PhAs) present in nopal. In this study, the role of these PhAs in copper-induced oxidative stress was investigated using the density functional theory (DFT). The PhAs form 5 thermodynamically favorable complexes with Cu(II), their conditional Gibbs free energies of reaction (ΔG', at pH = 7.4, in kcal/mol) are from -23 kcal/mol to -18 kcal/mol. All of them are bi-dentate complexes. The complexes of PRA and GAA are capable of inhibiting the Cu(II) reduction by both O2•- and Asc-, their reactions with the chelated metal are endergonic having rate constants about ~10-5-102 M-1 s-1, PhAs can prevent the formation of hydroxyl free radicals by chelating the copper ions. Once the hydroxyl radicals are formed by Fenton reactions, the complexes of PhAs with Cu(II) can immediately react with them, thus inhibiting the damage that they can cause to molecules of biological interest. The reactions between PhAs-Cu(II) complexes and hydroxyl free radical were estimated to be diffusion-limited (~108 M-1s-1). Thus, these chelates can reduce the harmful effects caused by the most reactive free radical existent immediately after it is formed by Fenton reactions.

Potentiating the Benefits of Melatonin through Chemical Functionalization: Possible Impact on Multifactorial Neurodegenerative Disorders.

Although melatonin is an astonishing molecule, it is possible that chemistry will help in the discovery of new compounds derived from it that may exceed our expectations regarding antioxidant protection and perhaps even neuroprotection. This review briefly summarizes the significant amount of data gathered to date regarding the multiple health benefits of melatonin and related compounds. This review also highlights some of the most recent directions in the discovery of multifunctional pharmaceuticals intended to act as one-molecule multiple-target drugs with potential use in multifactorial diseases, including neurodegenerative disorders. Herein, we discuss the beneficial activities of melatonin derivatives reported to date, in addition to computational strategies to rationally design new derivatives by functionalization of the melatonin molecular framework. It is hoped that this review will promote more investigations on the subject from both experimental and theoretical perspectives.

Capsaicin, a Powerful •OH-Inactivating Ligand.

Oxidative conditions are frequently enhanced by the presence of redox metal ions. In this study, the role of capsaicin (8-methyl-N-vanillyl-6-nonenamide, CAP) in copper-induced oxidative stress was investigated using density functional theory simulations. It was found that CAP has the capability to chelate Cu(II), leading to complexes that are harder to reduce than free Cu(II). CAP fully turns off the Cu(II) reduction by Asc-, and slows down the reduction in this cation by O2•-. Therefore, CAP is proposed as an •OH-inactivating ligand by impeding the reduction in metal ions (OIL-1), hindering the production of •OH via Fenton-like reactions, at physiological pH. CAP is also predicted to be an excellent antioxidant as a scavenger of •OH, yielded through Fenton-like reactions (OIL-2). The reactions between CAP-Cu(II) chelates and •OH were estimated to be diffusion-limited. Thus, these chelates are capable of deactivating this dangerous radical immediately after being formed by Fenton-like reactions.

Computationally Designed Sesamol Derivatives Proposed as Potent Antioxidants.

Oxidative stress has been recognized to play an important role in several diseases, such as Parkinson's and Alzheimer's disease, which justifies the beneficial effects of antioxidants in ameliorating the deleterious effects of these health disorders. Sesamol, in particular, has been investigated for the treatment of several conditions because of its antioxidant properties. This article reports a rational computational design of new sesamol derivatives. They were constructed by adding four functional groups (-OH, -NH2, -COOH, and -SH) in three different positions of the sesamol molecular framework. A total of 50 derivatives between mono-, di-, and trisubstituted compounds were obtained. All the derivatives were evaluated and compared with a reference set of commercial neuroprotective drugs. The estimated properties are absorption, distribution, metabolism, excretion, toxicity, and synthetic accessibility. Selection and elimination scores were used to choose a first set of promising candidates. Acid-based properties and reactivity indexes were then estimated using the density functional theory. Four sesamol derivatives were finally selected, which are hypothesized to be potent antioxidants, even better than sesamol and Trolox for that purpose.

The Antioxidant Capability of Higenamine: Insights from Theory.

Density functional theory was employed to highlight the antioxidant working mechanism of higenamine in aqueous and lipid-like environments. Different reaction mechanisms were considered for the reaction of higenamine with the •OOH radical. The pH values and the molar fraction at physiological pH were determined in aqueous solution. The results show that the preferred reaction mechanism was the hydrogen atom transfer from the catecholic ring. The computed kinetic constants revealed that, in order to obtain reliable results, it is important to consider all the species present in water solution derived from acid-base equilibria. From the present investigation, it emerges that at physiological pH (7.4), the scavenging activity of higenamine against the •OOH radical is higher than that of Trolox, chosen as a reference antioxidant. Furthermore, higenamine results to be more efficient for that purpose than melatonin and caffeine, whose protective action against oxidative stress is frequently associated with their reactive oxygen species (ROS) scavenging activity.

Detailed Investigation of the Outstanding Peroxyl Radical Scavenging Activity of Two Novel Amino-Pyridinol-Based Compounds.

The ability of two novel amino-pyridinol based compounds (NPyr6 and NPyr7) as peroxyl radical scavengers was investigated in silico. The gathered data indicate that they are exceptionally efficient in that role. However, solvent polarity influences their relative efficiency for that purpose. NPyr6 was identified as the best peroxyl radical scavenger in lipid solution, while NPyr7 takes that place in aqueous solution. Both compounds present two acid-base equilibria, which influence their reactivity in aqueous solution. The associated pKa values were estimated. Several reaction mechanisms were explored. Hydrogen transfer from the phenolic group was identified as the chemical route with the highest contribution to the antioxidant behavior of the investigated compounds in both, nonpolar medium and aqueous solution (at 2 ≤ pH ≤ 10). At higher pH other reaction pathways become the most relevant ones. In addition, their bioavailability, cell permeability, safety, and manufacturability were evaluated. According to these, particularly toxicity, NPyr7 seems to be a better candidate for use as an oral drug to fight oxidative stress than NPyr6.

Melatonin and its metabolites as chemical agents capable of directly repairing oxidized DNA.

Oxidative stress mediates chemical damage to DNA yielding a wide variety of products. In this work, the potential capability of melatonin and several of its metabolites to repair directly (chemically) oxidative lesions in DNA was explored. It was found that all the investigated molecules are capable of repairing guanine-centered radical cations by electron transfer at very high rates, that is, diffusion-limited. They are also capable of repairing C-centered radicals in the sugar moiety of 2'-deoxyguanosine (2dG) by hydrogen atom transfer. Although this was identified as a rather slow process, with rate constants ranging from 1.75 to 5.32 × 102  M-1 s-1 , it is expected to be fast enough to prevent propagation of the DNA damage. Melatonin metabolites 6-hydroxymelatonin (6OHM) and 4-hydroxymelatonin (4OHM) are also predicted to repair OH adducts in the imidazole ring. In particular, the rate constants corresponding to the repair of 8-OH-G adducts were found to be in the order of 104  M-1 s-1 and are assisted by a water molecule. The results presented here strongly suggest that the role of melatonin in preventing DNA damage might be mediated by its capability, combined with that of its metabolites, to directly repair oxidized sites in DNA through different chemical routes.

The other side of the superoxide radical anion: its ability to chemically repair DNA oxidized sites.

The superoxide radical anion can repair oxidative damage. In particular, it was demonstrated that O2˙- can repair oxidized DNA by electron transfer, restoring the original structure of this important molecule. Acid-base equilibria have been considered, and the influence of the pH on the main reaction mechanism has been explored.

The reactions of plant hormones with reactive oxygen species: chemical insights at a molecular level.

The reactions of two plant hormones, namely jasmonic acid (JA) and methyl jasmonate (MJ), with different reactive oxygen species (ROS) were investigated using the density functional theory. Different reaction sites and mechanisms were explored, as well as solvents of different polarity, and pH in aqueous solution. The thermochemical viability and kinetics of the investigated reaction pathways were found to be strongly influenced by the reacting ROS. All the investigated pathways were found to be exergonic, both in aqueous and lipid solution and for both JA and MJ, when the reactions involve •OH and •OCH3. On the contrary, for the reactions with peroxy radicals (•OOH and •OOCH2CHCH2) only a few hydrogen transfer pathways were found to be thermochemically viable. The reactions involving •OH were found to be diffusion-controlled, with both JA and MJ, regardless of the polarity of the solvent. This led to the hypothesis that the direct •OH scavenging activity of JA and MJ might play a role in the beneficial effects of the jasmonate family regarding the antioxidant defense of plants against metal-induced oxidative stress. The deprotonated fraction of JA is, to some extent, more reactive than the neutral fraction toward ROS. This, together with the acid-base equilibria inherent to some ROS, make the pH an influential environmental factor on the overall reactivity of JA toward ROS.

Melatonin Mitigates Mitochondrial Meltdown: Interactions with SIRT3.

Melatonin exhibits extraordinary diversity in terms of its functions and distribution. When discovered, it was thought to be uniquely of pineal gland origin. Subsequently, melatonin synthesis was identified in a variety of organs and recently it was shown to be produced in the mitochondria. Since mitochondria exist in every cell, with a few exceptions, it means that every vertebrate, invertebrate, and plant cell produces melatonin. The mitochondrial synthesis of melatonin is not photoperiod-dependent, but it may be inducible under conditions of stress. Mitochondria-produced melatonin is not released into the systemic circulation, but rather is used primarily in its cell of origin. Melatonin's functions in the mitochondria are highly diverse, not unlike those of sirtuin 3 (SIRT3). SIRT3 is an NAD+-dependent deacetylase which regulates, among many functions, the redox state of the mitochondria. Recent data proves that melatonin and SIRT3 post-translationally collaborate in regulating free radical generation and removal from mitochondria. Since melatonin and SIRT3 have cohabitated in the mitochondria for many eons, we predict that these molecules interact in many other ways to control mitochondrial physiology. It is predicted that these mutual functions will be intensely investigated in the next decade and importantly, we assume that the findings will have significant applications for preventing/delaying some age-related diseases and aging itself.

Scavenging Ability of Homogentisic Acid and Ergosterol toward Free Radicals Derived from Ethanol Consumption.

Acute, or chronic, ethanol consumption leads to the formation of free radicals in the liver, which is related to hepatic damage. Among these radicals 1-hydroxyethyl, •CH(OH)CH3, is the most abundant one. Thus, efficient •CH(OH)CH3 scavengers are likely candidates to offer liver protection after ethanol consumption. In the present work ergosterol and homogentisic acid (HGA), which are found in edible mushrooms, were investigated as potential candidates to that purpose. The investigation was carried out following the QM-ORSA protocol, and using the density functional theory (DFT). The overall rate constants calculated for the •CH(OH)CH3 radical scavenging activity of ergosterol in lipid and ethanol media are 1.34 × 107 and 1.86 × 107 M-1 s-1, respectively. For homogentisic acid the overall rate constant in lipid, ethanol and aqueous media are 4.33 × 108, 2.74 × 106, and 3.62 × 107 M-1 s-1, respectively. Accordingly, both compounds are predicted to efficiently scavenge the •CH(OH)CH3 radical. Thus, the results from this investigation support the antioxidant capability of edible mushrooms, their potential beneficial effects against ethanol hepatotoxicity, and the nutraceuticals properties of ergosterol and homogentisic acid.

Melatonin and its metabolites vs oxidative stress: From individual actions to collective protection.

Oxidative stress (OS) represents a threat to the chemical integrity of biomolecules including lipids, proteins, and DNA. The associated molecular damage frequently results in serious health issues, which justifies our concern about this phenomenon. In addition to enzymatic defense mechanisms, there are compounds (usually referred to as antioxidants) that offer chemical protection against oxidative events. Among them, melatonin and its metabolites constitute a particularly efficient chemical family. They offer protection against OS as individual chemical entities through a wide variety of mechanisms including electron transfer, hydrogen transfer, radical adduct formation, and metal chelation, and by repairing biological targets. In fact, many of them including melatonin can be classified as multipurpose antioxidants. However, what seems to be unique to the melatonin's family is their collective effects. Because the members of this family are metabolically related, most of them are expected to be present in living organisms wherever melatonin is produced. Therefore, the protection exerted by melatonin against OS may be viewed as a result of the combined antioxidant effects of the parent molecule and its metabolites. Melatonin's family is rather exceptional in this regard, offering versatile and collective antioxidant protection against OS. It certainly seems that melatonin is one of the best nature's defenses against oxidative damage.

Comprehensive Investigation of the Antioxidant and Pro-oxidant Effects of Phenolic Compounds: A Double-Edged Sword in the Context of Oxidative Stress?

Oxidative stress (OS) is a health-threatening process that is involved, at least partially, in the development of several diseases. Although antioxidants can be used as a chemical defense against OS, they might also exhibit pro-oxidant effects, depending on environmental conditions. In this work, such a dual behavior was investigated for phenolic compounds (PhCs) within the framework of the density functional theory and based on kinetic data. Multiple reaction mechanisms were considered in both cases. The presence of redox metals, the pH, and the possibility that PhCs might be transformed into benzoquinones were identified as key aspects in the antioxidant versus pro-oxidant effects of these compounds. The main virtues of PhCs as antioxidants are their radical trapping activity, their regeneration under physiological conditions, and their behavior as OH-inactivating ligands. The main risks of PhCs as pro-oxidants are predicted to be the role of phenolate ions in the reduction of metal ions, which can promote Fenton-like reactions, and the formation of benzoquinones that might cause protein arylation at cysteine sites. Although the benefits seem to overcome the hazards, to properly design chemical strategies against OS using PhCs, it is highly recommended to carefully explore their duality in this context.