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.

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.

Casiopeinas® third generation, with indomethacin: synthesis, characterization, DFT studies, antiproliferative activity, and nanoencapsulation.

Seven new Casiopeinas® were synthesized and properly characterized. These novel compounds have a general formula [Cu(N-N)(Indo)]NO3, where Indo is deprotonated indomethacin and N-N is either bipyridine or phenanthroline with some methyl-substituted derivatives, belonging to the third generation of Casiopeinas®. Spectroscopic characterization suggests a square-based pyramid geometry and voltammetry experiments indicate that the redox potential is strongly dependent on the N-N ligand. All the presented compounds show high cytotoxic efficiency, and most of them exhibit higher efficacy compared to the well-known cisplatin drug and acetylacetonate analogs of the first generation. Computational calculations show that antiproliferative behavior can be directly related to the volume of the molecules. Besides, a chitosan (CS)-polyacrylamide (PNIPAAm) nanogel was synthesized and characterized to examine the encapsulation and release properties of the [Cu(4,7-dimethyl-1,10-phenanthroline)(Indo)]NO3 compound. The results show good encapsulation performance in acidic conditions and a higher kinetic drug release in acidic media than at neutral pH. This result can be described by the Peppas-Sahlin model and indicates a release mechanism predominantly by Fick diffusion.

Heteroleptic NiII complexes: Synthesis, structural characterization, computational studies and amoebicidal activity evaluation.

In this work, we present the synthesis, characterization, electrochemical studies, DFT calculations, and in vitro amoebicidal effect of seven new heteroleptic NiII coordination compounds. The crystal structures of [H2(pdto)](NO3)2 and [Ni(pdto)(NO3)]PF6 are presented, pdto = 2,2'-[1,2-ethanediylbis-(sulfanediyl-2,1-ethanediyl)]dipyridine. The rest of the compounds have general formulae: [Ni(pdto)(NN)](PF6) where N-N = 2,2'-bipyridine (bpy), 4,4'-dimethyl-2,2'-bipyridine (44dmbpy), 5,5'-dimethyl-2,2'-bipyridine (55dmbpy), 1,10-phenanthroline (phen), 4,7-dimethyl-1,10-phenanthroline (47dmphen) and 5,6-dimethyl-1,10-phenanthroline (56dmphen). The size of NN ligand and its substituents modulate the compound electronic features and influence their antiproliferative efficiency against Entamoeba histolytica. 56dmphen derivative, shows the biggest molar volume and presents a powerful amoebicidal activity (IC50 = 1.2 µM), being seven times more effective than the first-line drug for human amoebiasis metronidazole. Also, increases the reactive oxygen species concentration within the trophozoites. This could be the trigger of the E. histolytica growth inhibition. The antiparasitic effect is described using NiII electron density, molar volume, estimated by DFT, as well as the experimental redox potential and diffusion coefficients. In general, amoebicidal efficiency is directly proportional to the increment of the molar volume and decreases when the redox potential becomes more positive.

Identification of descriptors for structure-activity relationship in ruthenium (II) mixed compounds with antiparasitic activity.

Herein is presented the synthesis, characterization, electrochemical studies, DFT calculations and in vitro evaluation of amoebicidal activity in trophozoites of Entamoeba histolytica of twenty ruthenium (II) mixed compounds with general formulae: [Ru(pdto)(E-E)]Clx (E-E bidentate, either neutral or negatively charged ligands). For compounds under study, O-O, N-O and N-N auxiliary donor ligands demonstrate to have a crucial impact on the electronic properties and that it is possible to modulate the antiparasitic activity. Among analyzed complexes, only four present a better performance compared to typically used metronidazole drug (IC50 < 6.80 µmol/L) to treat amebiasis disease. For studied compounds, structure-activity relationships are strongly determined by either the redox potential (E1/2) of RuII/RuIII and calculated molar volume (V) of the complexes.