Synthesis of Fluorescent Pyrrolo[1,2-a]pyrimidines from Fischer Carbene Complexes as Building Blocks.

A novel synthetic methodology is reported for the synthesis of fluorescent pyrrolo[1,2-a]pyrimidines. Fischer carbene complexes served as the synthetic platform for (3+3) cyclization to form the heterocyclic moiety. The reaction process furnished two products, their ratio being modulated by the metal, base, and solvent. The selectivity exhibited was studied by analyzing the potential energy surface with density functional theory tools. The photophysical properties of absorption and emission were also evaluated. The dyes absorbed at wavelengths of 240-440 nm, depending on the substituents. The maximum emission wavelength was in the range of 470-513 nm, with quantum yields of 0.36-1.0 and a high Stokes shift range of 75-226 nm.

Modeling Adsorption of CO2 in Rutile Metallic Oxide Surfaces: Implications in CO2 Catalysis.

CO2 is the most abundant greenhouse gas, and for this reason, it is the main target for finding solutions to climatic change. A strategy of environmental remediation is the transformation of CO2 to an aggregated value product to generate a carbon-neutral cycle. CO2 reduction is a great challenge because of the large C=O dissociation energy, ~179 kcal/mol. Heterogeneous photocatalysis is a strategy to address this issue, where the adsorption process is the fundamental step. The focus of this work is the role of adsorption in CO2 reduction by means of modeling the CO2 adsorption in rutile metallic oxides (TiO2, GeO2, SnO2, IrO2 and PbO2) using Density Functional Theory (DFT) and periodic DFT methods. The comparison of adsorption on different metal oxides forming the same type of crystal structure allowed us to observe the influence of the metal in the adsorption process. In the same way, we performed a comparison of the adsorption capability between two different surface planes, (001) and (110). Two CO2 configurations were observed, linear and folded: the folded conformations were observed in TiO2, GeO2 and SnO2, while the linear conformations were present in IrO2 and PbO2. The largest adsorption efficiency was displayed by the (001) surface planes. The CO2 linear and folded configurations were related to the interaction of the oxygen on the metallic surface with the adsorbate carbon, and the linear conformations were associated with the physisorption and folded configurations with chemisorption. TiO2 was the material with the best performance for CO2 interactions during the adsorption.

Grammatical evolution-based design of SARS-CoV-2 main protease inhibitors.

A series of SARS-CoV-2 main protease (SARS-CoV-2-Mpro) inhibitors were modeled using evolutive grammar algorithms. We have generated an automated program that finds the best candidate to inhibit the main protease, Mpro, of SARS-CoV-2. The candidates were constructed based on a pharmacophore model of the above-mentioned target; relevant moieties of such molecules were modified using data-basis sets with similar chemical behavior to the reference moieties. Additionally, we used the SMILES language to translate 3D chemical structures to 1D words; then, an evolutive grammar algorithm was used to explore the chemical space and obtain new candidates, which were evaluated via the binding energy of molecular coupling assays as an evaluation function. Finally, sixteen molecules were obtained in 3 runs of our program, three of which show promising binding properties as SARS-CoV-2-Mpro inhibitors. One of them, TTO, maintained its relevant binding properties during 100 ns molecular dynamics experiments. For this reason, TTO is the best candidate to inhibit SARS-CoV-2-Mpro. The software we developed for this contribution is available at the following URL: https://github.com/masotelof/GEMolecularDesign.

Effect of the substituents of new coumarin-imidazo[1,2-a]heterocyclic-3-acrylate derivatives on nonlinear optical properties: a combined experimental-theoretical approach.

A series of new coumarin-imidazo[1,2-a]heterocyclic-3-acrylate derivatives 7a-h were synthesized by the Heck reaction between the corresponding 3-(imidazo[1,2-a]pyrimidines)-(2-yl)-2H-chromen-2-ones 4a-e and methyl acrylate in 45-87% yields. The effect of the distinct substituents on third-order nonlinear optical properties was examined, experimentally measuring their nonlinear refractive indexes by the Z-scan technique. Density functional theory and time-dependent density functional theory were utilized with the B3LYP, CAM-B3LYP, PBE (PBEPBE), and M062X functionals on Gaussian09 software to calculate the vertical excitation, relaxation of the brightest excited states, conformation, HOMO-LUMO gaps, oscillator strength, polarizability, and hyperpolarizabilities of all derivatives. Although all acrylates showed a nonlinear response at a certain level of power, the compounds bearing a diethylamino electron-donating group exhibited higher nonlinear refractive index values (∼10-9 cm2 W-1), which is in agreement with the trend in the computational calculations of the first and second hyperpolarization. According to the structural analysis, the electron-withdrawing group (acrylate) is mainly responsible for the loss of coplanarity because of increasing the dihedral angle between the coumarin and imidazo[1,2-a]heterocyclic moieties (to 39.1°). On the other hand, the unsubstituted compound 4a presented the greatest nonlinearity due to its almost coplanar structure (n2 ∼ 10-8 cm2 W-1), highlighting the importance of this feature.

Modeling Adsorption and Optical Properties for the Design of CO2 Photocatalytic Metal-Organic Frameworks.

Four Metal-Organic Frameworks (MOFs) were modeled (IRMOF-C-BF2, IRMOF-C-(2)-BF2, IRMOF-C'-BF2, and IRMOF-C-CH2BF2) based on IRMOF-1. A series of linkers, based on Frustrated Lewis Pairs and coumarin moieties, were attached to IRMOF-1 to obtain MOFs with photocatalytic properties. Four different linkers were used: (a) a BF2 attached to a coumarin moiety at position 3, (b) two BF2 attached to a coumarin moiety in positions 3 and 7, (c) a BF2 attached in the coumarin moiety at position 7, and (d) a CH2BF2 attached at position 3. An analysis of the adsorption properties of H2, CO2, H2O and possible CO2 photocatalytic capabilities was performed by means of computational modeling using Density Functional Theory (DFT), Time-Dependent Density Functional (TD-DFT) methods, and periodic quantum chemical wave function approach. The results show that the proposed linkers are good enough to improve the CO2 adsorption, to hold better bulk properties, and obtain satisfactory optical properties in comparison with IRMOF-1 by itself.

Design of Fluorescent Coumarin-Hydroxamic Acid Derivatives as Inhibitors of HDACs: Synthesis, Anti-Proliferative Evaluation and Docking Studies.

Coumarin-hydroxamic acid derivatives 7a-k were herein designed with a dual purpose: as antiproliferative agents and fluorescent probes. The compounds were synthesized in moderate yields (30-87%) through a simple methodology, biological evaluation was carried out on prostate (PC3) and breast cancer (BT-474 and MDA-MB-231) cell lines to determine the effects on cell proliferation and gene expression. For compounds 7c, 7e, 7f, 7i and 7j the inhibition of cancer cell proliferation was similar to that found with the reference compound at a comparable concentration (10 µM), in addition, their molecular docking studies performed on histone deacetylases 1, 6 and 8 showed strong binding to the respective active sites. In most cases, antiproliferative activity was accompanied by greater levels of cyclin-dependent kinase inhibitor p21, downregulation of the p53 tumor suppressor gene, and regulation of cyclin D1 gene expression. We conclude that compounds 7c, 7e, 7f, 7i and 7j may be considered as potential anticancer agents, considering their antiproliferative properties, their effect on the regulation of the genes, as well as their capacity to dock to the active sites. The fluorescent properties of compound 7j and 7k suggest that they can provide further insight into the mechanism of action.

Effects of lead and lead-melatonin exposure on protein and gene expression of metal transporters, proteins and the copper/zinc ratio in rats.

Human lead (Pb) exposure induces many adverse health effects, including some related to lead accumulation in organs. Although lead bio-distribution in the body has been described, the molecular mechanism underlying distribution and excretion is not well understood. The transport of essential and toxic metals is principally mediated by proteins. How lead affects the expression of metal transporter proteins in the principal metal excretory organs, i.e., the liver and kidney, is unknown. Considering that co-administration of melatonin and lead reduces the toxic effects of lead and lead levels in the blood in vivo, we examined how lead and co-administration of lead and melatonin affect the gene and protein expression of metal transporter proteins (ZIP8, ZIP14, CTR1 and DMT1) in these organs. Rats were exposed intraperitoneally to lead or lead-melatonin. Our results show that Pb exposure induces changes in the protein and gene expression of ZIP8, ZIP14 and CTR1. Alterations in the copper/zinc ratio found in the blood, liver and kidney were likely related to these changes. With DMT1 expression (gene and protein), a positive correlation was found with lead levels in the kidney. Co-administration of melatonin and lead reduced lead-induced DMT1 expression through an unknown mechanism. This effect of melatonin relates to reduced lead levels in the blood and kidney. The metal transport protein function and our results suggest that DMT1 likely contributes to lead accumulation in organs. These data further elucidate the effects of lead on Cu and Zn and the molecular mechanism underlying lead bio-distribution in animals.

Evaluation of doxorubicin and ß-lapachone analogs as anticancer agents, a biological and computational study.

We have conducted an experimental and computational evaluation of new doxorubicin (4a-c) and ß-lapachone (5a-c) analogs. These novel anticancer analogs were previously synthesized, but had not been tested or characterized until now. We have evaluated their antiproliferative and DNA cleavage inhibition properties using breast (MCF-7 and MDA-MB-231) and prostate (PC3) cancer cell lines. Additionally, cell cycle analysis was performed using flow cytometry. Computational studies, including molecular docking, pharmacokinetic properties, and an analysis of DFT and QTAIM chemical descriptors, were performed to gain insights into the electronic structure and elucidate the molecular binding of the new ß-lapachone and doxorubicin analogs with a DNA sequence and Topoisomerase II (Topo II)α. Our results show that 4a analog displays the highest antiproliferative activity in cancer cell lines by inducing cell death. We observed that stacking interactions and hydrogen bonding are essential to stabilize the molecule-DNA-Topo IIα complex. Moreover, 4a and 5a analogs inhibited Topo's DNA cleavage activity. Pharmacodynamic results indicated that studied molecules have favorable adsorption and permeability properties. The calculated chemical descriptors indicate that electron accumulation in quinone rings is relevant to the reactivity and biological activity. Based on our results, 4a is a strong candidate for becoming an anticancer drug.

Structure and Conformation of Novel BODIPY Ugi Adducts.

Two novel BODIPY-Ugi (boron dipyrromethene) adducts exhibit peculiar room temperature (T=20 °C) H-1 NMR spectra in that several protons located at the aromatic aniline-type ring are lost in the baseline. This observation revealed the existence of a dynamic conformational process where rotation around the C-N bond is hindered. Variable-temperature H-1 and C-13 NMR spectroscopic analysis confirmed this conclusion; that is, low-temperature spectra show distinct signals for all four aromatic protons below coalescence, whereas average signals are recorded above coalescence (T=+120 °C). Particularly interesting was the rather large difference in chemical shifts for the ortho protons below coalescence, Δδ=1.45 ppm, which was explained based on DFT computational analysis. Indeed, the calculated lowest-energy gas-phase conformation of the BODIPY Ugi adducts locates one half of the aniline-type ring in the shielding anisotropic cone of the bridge phenyl ring in the BODIPY segment. This is in contrast to the solid-state conformation established by X-ray diffraction analysis that shows a nearly parallel arrangement of the aromatic rings, probably induced by crystal packing forces.

Predictive Global Models of Cruzain Inhibitors with Large Chemical Coverage.

Chagas disease affects 8-11 million people worldwide, most of them living in Latin America. Moreover, migratory phenomena have spread the infection beyond endemic areas. Efforts for the development of new pharmacological therapies are paramount as the pharmacological profile of the two marketed drugs currently available, nifurtimox and benznidazole, needs to be improved. Cruzain, a parasitic cysteine protease, is one of the most attractive biological targets due to its roles in parasite survival and immune evasion. In this work, we compiled and curated a database of diverse cruzain inhibitors previously reported in the literature. From this data set, quantitative structure-activity relationship (QSAR) models for the prediction of their pIC50 values were generated using k-nearest neighbors and random forest algorithms. Local and global models were calculated and compared. The statistical parameters for internal and external validation indicate a significant predictability, with q loo 2 values around 0.66 and 0.61 and external R 2 coefficients of 0.725 and 0.766. The applicability domain is quantitatively defined, according to QSAR good practices, using the leverage and similarity methods. The models described in this work are readily available in a Python script for the discovery of novel cruzain inhibitors.

Exploring novel capping framework: high substituent pyridine-hydroxamic acid derivatives as potential antiproliferative agents.

PURPOSE: Histone deacetylases (HDACs) play a vital role in the epigenetic regulation of gene expression due to their overexpression in several cancer forms. Therefore, these enzymes are considered as a potential anticancer drug target. Different synthetic and natural structures have been studied as HDACs inhibitors; based on available structural design information, the capping group is important for the biological activity due to the different interactions in the active site entrance. The present study aimed to analyze high substituted pyridine as a capping group, which included carrying out the synthesis, antiproliferative activity analysis, and docking studies of these novel compounds. METHODS: To achieve the synthesis of these derivatives, four reaction steps were performed, generating desired products 15a-k. Their effects on cell proliferation and gene expression of p21, cyclin D1, and p53 were determined using the sulphorhodamine B (SRB) method and quantitative real-time polymerase chain reaction. The HDAC1, HDAC6, and HDAC8 isoforms were used for performing docking experiments with our 15a-k products. RESULT: The products 15a-k were obtained in overall yields of 40-71%. Compounds 15j and 15k showed the highest antiproliferative activity in the breast (BT-474 and MDA-MB-231) and prostate (PC3) cancer cell lines at a concentration of 10 µM. These compounds increased p21 mRNA levels and decreased cyclin D1 and p53 gene expression. The docking study showed an increment in the strength, and in the number of interactions performed by the capping moiety of the tested molecules compared with SAHA; interactions displayed are mainly van der Waals, π-stacking, and hydrogen bond. CONCLUSION: The synthesized compounds 2-thiophene (15j) and 2-furan (15k) pyridine displayed cell growth inhibition, regulation of genes related to cell cycle progression in highly metastatic cancer cell lines. The molecular coupling analysis performed with HDAC1, HDAC6 and HDAC8 showed an increment in the number of interactions performed by the capping moiety and consequently in the strength of the capping group interaction.

Computational study of metal complexes formed with EDTA, melatonin, and its main metabolites: implications in lead intoxication and clues to a plausible alternative treatment.

Melatonin has been proposed as an alternative treatment to the usage of EDTA for lead intoxication. In this computational paper, since previous work has not systematically studied the complexes that may be formed in the existing and proposed treatments, we study 45 possible complexes that we suggest may be formed between Pb and some essential metals with melatonin, melatonin metabolites, and EDTA, analyzing the stability and viability of these through the Gibbs free energy of complexation (ΔΔG), molecular orbitals, and energy decomposition analysis at the DFT level of theory PBE/TZ2P. Our findings show that most complexes present exergonic energies of reaction, and thus spontaneous complex formation. In addition, we show that the AMK and 3OHM melatonin metabolites possess electronic and thermodynamic properties adequate to act as lead trapping molecules due to the lower Pauli repulsion energies involved in the complexes they form and their large negative values of ΔΔG. Therefore, it is shown that both melatonin and some of its metabolites may be employed in a viable treatment for lead intoxication through formation of stable Pb-complexes. Graphical abstract Metal complexes formed with EDTA, melatonin, and its main metabolites.

Binding of Pb-Melatonin and Pb-(Melatonin-metabolites) complexes with DMT1 and ZIP8: implications for lead detoxification.

We have applied the docking methodology to characterize the binding modes of the divalent metal transporter 1 (DMT1) and the zinc transporter 8 (ZIP8) protein channels with: melatonin, some melatonin metabolites, and a few lead complexes of melatonin and its metabolites, in three different coordination modes (mono-coordinated, bi-coordinated and tri-coordinated). Our results show that bi-coordinated and tri-coordinated lead complexes prefer to bind inside the central region of ZIP8. Moreover, the interaction strength is larger compared with that of the free melatonin and melatonin metabolites. On the other hand, the binding modes with DMT1 of such complexes display lower binding energies, compared with the free melatonin and melatonin metabolites. Our results suggest that ZIP8 plays a major role in the translocation of Pb, bi or tri coordinated, when melatonin metabolites are present. Finally, we have characterized the binding modes responsible for the ZIP8 large affinities, found in bi-coordinated and tri-coordinated lead complexes. Our results show that such interactions are greater, because of an increase of the number of hydrogen bonds, the number and intensity of electrostatic interactions, and the interaction overlay degree in each binding mode. Our results give insight into the importance of the ZIP8 channel on lead transport and a possible elimination mechanism in lead detoxification processes. Graphical abstract .