The study of natural products as potential drug leads has gained tremendous research interest. Quercetin is one of those natural products. It belongs to the family of flavonoids and, more specifically, flavonols. This review summarizes the beneficial pharmaceutical effects of quercetin, such as its anti-cancer, anti-inflammatory, and antimicrobial properties, which are some of the quercetin effects described in this review. Nevertheless, quercetin shows poor bioavailability and low solubility. For this reason, its encapsulation in macromolecules increases its bioavailability and therefore pharmaceutical efficiency. In this review, a brief description of the different forms of encapsulation of quercetin are described, and new ones are proposed. The beneficial effects of applying new pharmaceutical forms of nanotechnology are outlined.

It is well-known that monoamine oxidase (MAO) plays a pivotal role in neurodegeneration and the inhibition of this enzyme can manifest antidepressant properties as well as have a positive impact in Alzheimer’s and Parkinson’s diseases. MAO has two isoforms: MAO-A and MAO-B. The main hMAO-B inhibitors used for the treatment of Alzheimer’s and Parkinson’s diseases, encompass a terminal triple bond in their structure, which provides their potency. Recently, a new class of inhibitors has emerged, bearing the carbon–carbon triple bond not necessarily at the end of the chain. In this review, the structure and physiological function of the MAO enzymes is discussed, the general synthetic procedures of propargylamines, as well as their mechanism of inhibition. Moreover, it is highlighted the current development and discovery of potential hMAO-B inhibitors from propargylamine scaffolds, showcasing their structure–activity relationships (SARs) with the enzyme. Conformational relationships’ analysis is performed as well. Induced fit docking is performed, also, to the most potent compounds revealed in order to assess their binding energy and interactions with the enzyme. Finally, molecules which do not contain a propargylamine moiety in their structure were studied and compared against a known hMAO-B inhibitor, deprenyl. From the superimposition results of these molecules with deprenyl, as well as the interactions of the molecules with the amino acids of the active site of hMAO-B, it appears that these compounds have several similarities with deprenyl, opening new paths for the creation of novel molecules against Alzheimer’s disease (AD).

The structure assignment and conformational analysis of thiosemicarbazone KKI15 and thiocarbohydrazone KKI18 were performed through homonuclear and heteronuclear 2D Nuclear Magnetic Resonance (NMR) spectroscopy (2D-COSY, 2D-NOESY, 2D-HSQC, and 2D-HMBC) and quantum mechanics (QM) calculations using Functional Density Theory (DFT). After the structure identification of the compounds, various conformations of the two compounds were calculated using DFT. The two molecules showed the most energy-favorable values when their two double bonds adopted the E configuration. These configurations were compatible with the spatial correlations observed in the 2D-NOESY spectrum. In addition, due to the various isomers that occurred, the energy of the transition states from one isomer to another was calculated. Finally, molecular binding experiments were performed to detect potential targets for KKI15 and KKI18 derived from SwissAdme. In silico molecular binding experiments showed favorable binding energy values for all four enzymes studied. The strongest binding energy was observed in the enzyme butyrylcholinesterase. ADMET calculations using the preADMET and pKCSm software showed that the two molecules appear as possible drug leads.

Quercetin (QUE) is a well-known natural product that can exert beneficial properties on human health. However, due to its low solubility its bioavailability is limited. In the present study, we examine whether its formulation with two cyclodextrins (CDs) may enhance its pharmacological profile. Comparative interaction studies of quercetin with 2-hydroxyl-propyl-β-cyclodextrin (2HP-β-CD) and 2,6-methylated cyclodextrin (2,6Me-β-CD) were performed using NMR spectroscopy, DFT calculations, and in silico molecular dynamics (MD) simulations. Using T1 relaxation experiments and 2D DOSY it was illustrated that both cyclodextrin vehicles can host quercetin. Quantum mechanical calculations showed the formation of hydrogen bonds between QUE with 2HP-β-CD and 2,6Μe-β-CD. Six hydrogen bonds are formed ranging between 2 to 2.8 Å with 2HP-β-CD and four hydrogen bonds within 2.8 Å with 2,6Μe-β-CD. Calculations of absolute binding free energies show that quercetin binds favorably to both 2,6Me-β-CD and 2HP-β-CD. MM/GBSA results show equally favorable binding of quercetin in the two CDs. Fluorescence spectroscopy shows moderate binding of quercetin in 2HP-β-CD (520 M⁻¹) and 2,6Me-β-CD (770 M⁻¹). Thus, we propose that both formulations (2HP-β-CD:quercetin, 2,6Me-β-CD:quercetin) could be further explored and exploited as small molecule carriers in biological studies.

The potential of the 4,6-diphenyl-3,4-dihydropyrimidine-2(1H)-thione (abbreviated as KKII5) and (E)-N '-benzylidenehydrazinecarbothiohydrazide (abbreviated as DKI5) compounds as possible drug leads is investigated. KKII5 and DKI5 are synthesized in high yield of up to 97%. Their structure, binding in the active site of the LOX-1 enzyme, and their toxicity are studied via joint experimental and computational methodologies. Specifically, the structure assignment and conformational analysis were achieved by applying homonuclear and heteronuclear 2D nuclear magnetic resonance (NMR) spectroscopy (2D-COSY, 2D-NOESY, 2D-HSQC, and 2D-HMBC) and density functional theory (DFT). The obtained DFT lowest energy conformers were in agreement with the NOE correlations observed in the 2D-NOESY spectra. Additionally, docking and molecular dynamics simulations were performed to discover their ability to bind and remain stabile in the active site of the LOX-1 enzyme. These in silico experiments and DFT calculations indicated favorable binding for the enzyme under study. The strongest binding energy, -9.60 kcal/mol, was observed for dihydropyrimidinethione KKII5 in the active site of LOX-1. ADMET calculations showed that the two molecules lack major toxicities and could serve as possible drug leads. The redox potential of the active center of LOX-1 with the binding molecules was calculated via DFT methodology. The results showed a significantly smaller energy attachment of 2.8 eV with KKII5 binding in comparison to DKI5. Thus, KKII5 enhanced the ability of the active center to receive electrons compared to DKI5. This is related to the stronger binding interaction of KKII5 relative to that of DK15 to LOX-1. The two very potent LOX-1 inhibitors exerted IC50 19 mu M (KKII5) and 22.5 mu M (DKI5). Furthermore, they both strongly inhibit lipid peroxidation, namely, 98% for KKII5 and 94% for DKI5.

Hypertension is one of the most common diseases nowadays and is still the major cause of premature death despite of the continuous discovery of novel therapeutics. The discovery of the Renin Angiotensin System (RAS) unveiled a path to develop efficient drugs to fruitfully combat hypertension. Several compounds that prevent the Angiotensin II hormone from binding and activating the AT1R, named sartans, have been developed. Herein, we report a comprehensive review of the synthetic paths followed for the development of different sartans since the discovery of the first sartan, Losartan.