Gold(I) and Silver(I) Complexes Containing Hybrid Sulfonamide/Thiourea Ligands as Potential Leishmanicidal Agents.

Leishmaniasis is a group of parasitic diseases with the potential to infect more than 1 billion people; however, its treatment is still old and inadequate. In order to contribute to changing this view, this work consisted of the development of complexes derived from MI metal ions with thioureas, aiming to obtain potential leishmanicidal agents. The thiourea ligands (HLR) were obtained by reactions of p-toluenesulfohydrazide with R-isothiocyanates and were used in complexation reactions with AgI and AuI, leading to the formation of complexes of composition [M(HLR)2]X (M = Ag or Au; X = NO3- or Cl-). All compounds were characterized by FTIR, 1H NMR, UV-vis, emission spectroscopy and elemental analysis. Some representatives were additionally studied by ESI-MS and single-crystal XRD. Their properties were further analyzed by DFT calculations. Their cytotoxicity on Vero cells and the extracellular leishmanicidal activity on Leishmania infantum and Leishmania braziliensis cells were evaluated. Additionally, the interaction of the complexes with the Old Yellow enzyme of the L. braziliensis (LbOYE) was examined. The biological tests showed that some compounds present remarkable leishmanicidal activity, even higher than that of the standard drug Glucantime, with different selectivity for the two species of Leishmania. Finally, the interaction studies with LbOYE revealed that this enzyme could be one of their biological targets.

Substitution-inert polynuclear platinum complexes and Glycosaminoglycans: A molecular dynamics study of its non-covalent interactions.

An impressive class of formally substitution-inert polynuclear platinum complexes known as Substitution-inert Polynuclear Platinum (II) Complexes (SI-PPCs) present an attractive approach for medicinal inorganic chemistry through high-affinity non-covalent interactions with biomolecules, such as DNA and Glycosaminoglycans (GAGs). This interaction occurs through the formation of non-covalent cyclic structures called clamps and forks with the phosphate and sulfate groups present in these biomolecules. This work shows several analyses of the non-covalent interactions formed between heparin (PDB code: 1HPN) and SI-PPCs obtained through molecular dynamics (MD) simulations. Root Mean Square Deviation (RMSD) results showed that the "non-covalent" di-nuclear platinum compound, DiplatinNC ([{trans-Pt(NH3)2(NH2(CH2)6NH3+)}2-µ-NH2(CH2)6NH2]6+) and AH44 ([{Pt(NH3)3}2{(µ-(H2N(CH2)6NH2)2-(trans-Pt(NH3)2}]6+, 0,0,0/t,t,t,) complexes, which are both 6+ charged complexes, were the most rigid. On the other hand, the Root Mean Square Fluctuation (RMSF) showed that there is a reduction in the atomic fluctuation of atoms in the central region of the heparin molecule; the solvent accessible surface area (SASA) analysis also indicates a reduction in the accessible area by the heparin when interacting with SI-PPCs. The evaluation of H-Bond data confirms the formation of the non-covalent interactions, which may suggest a decrease in the action of 1HPN by preventing the action of enzymes on this substrate. In addition, thermodynamic results indicate that this interaction is spontaneous, considering the negative variations in the Gibbs free energy presented by the studied systems.

Antivirals virtual screening to SARS-CoV-2 non-structural proteins.

In March 2020, the World Health Organization (WHO) declared coronavirus disease-19 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a pandemic. Since then, the search for a vaccine or drug for COVID-19 treatment has started worldwide. In this regard, a fast approach is the repurposing of drugs, primarily antiviral drugs. Herein, we performed a virtual screening using 22 antiviral drugs retrieved from the DrugBank repository, azithromycin (antibiotic), ivermectin (antinematode), and seven non-structural proteins (Nsps) of SARS-CoV-2, which are considered important targets for drugs, via molecular docking and molecular dynamics simulations. Drug-receptor binding energy was employed as the main descriptor. Based on the results, paritaprevir was predicted as a promising multi-target drug that favorably bound to all tested Nsps, mainly adipose differentiation-related protein (ADRP) (-36.2 kcal mol-1) and coronavirus main proteinase (Mpro) (-32.2 kcal mol-1). Moreover, the results suggest that simeprevir is a strong inhibitor of Mpro (-37.2 kcal mol-1), which is an interesting finding because Mpro plays an important role in viral replication. In addition to drug-receptor affinity, hot spot residues were characterized to facilitate the design of new drug derivatives with improved biological responses.

Molecular dynamics simulation of non-covalent interactions between polynuclear platinum(II) complexes and DNA.

Several studies with substitution-inert polynuclear platinum(II) complexes (SI-PPC) have been carried out in recent years due to the form of DNA binding presented by these compounds. This form of bonding is achieved by molecular recognition through the formation of non-covalent structures, commonly called phosphate clamps and forks, which generate small extensions of the major and minor grooves. In this work, we use molecular dynamics simulations (MD) to study the formation of these cyclical structures between six different SI-PPCs and a double DNA dodecamer, here called 24_bp_DNA. The results showed the influence of the complex expressed on the number of phosphate clamps and forks formed. Based on the conformational characterization of the DNA fragment, we show that the studied SI-PPCs interact preferentially in the minor groove, causing groove spanning, except for two of them, Monoplatin and AH44. The phosphates of C-G pairs are the main sites for such non-covalent interactions. The Gibbs interaction energy of solvated species points out to AH78P, AH78H, and TriplatinNC as the most probable ones when coupled with DNA. As far as we know, this work is the very first one related to SI-PPCs which brings MD simulations and a complete analysis of the non-covalent interactions with a double DNA dodecamer.

Photophysical and electrochemical properties of two trans-A2B-corroles: differences between phenyl or pyrenyl groups at the meso-10 position.

The present study reports on the optical and photophysical properties of trans-A2B-corroles possessing pyrenyl units attached at the meso-10-position and compares them with those of model trans-A2B-corroles having phenyl substituents at that position. In contrast to the model meso-substituted corrole, the new pyrenyl-corrole shows slightly red-shifted absorption bands and blue-shifted emission, slightly higher fluorescence quantum yield, and more importantly, it shows better photo-stability under white-light illumination. Theoretical calculations were used to determine the electronic transitions and geometries of the singlet and triplet excited states (TD-DFT and NTO). Moreover, we demonstrate that the pyrenyl-corrole in analogy to previously studied model corroles is able to generate reactive oxygen species (ROS) under visible light using photo-degradation of 1,3-diphenylisobenzofuran (DBPF), a singlet oxygen quencher, and EPR spectroscopy allied with the spin-trapping method is used for identifying singlet oxygen species. The results show that the pyrenyl unit attached at the meso-10-position of the corrole increases the photo-stability and efficiency in ROS generation compared to the phenyl substituent.

Syntheses and electronic, electrochemical, and theoretical studies of a series of µ-oxo-triruthenium carboxylates bearing orthometalated phenazines.

This work reports a series of five-acetate triruthenium clusters [Ru3O(OAc)5(L)(py)2]PF6, where L = dppn (benzo[i]dipyrido[3,2-a:2',3'-c]phenazine, 1); dppz (dipyrido[3,2-a:2',3'-c]phenazine, 2); CH3-dppz (7-methyldipyrido [3,2-a:2',3'-c] phenazine, 3); Cl-dppz (7-chlorodipyrido [3,2-a:2',3'-c] phenazine, 4); and phen (1,10-phenanthroline, 5). The EPR spectra collected at 10 K displayed one isotropic signal without a hyperfine structure and with g values of ∼2.0, which showed that the five-acetate triruthenium clusters are paramagnetic, and that their electronic delocalization resembled the electronic delocalization of the parent hexa-acetate complexes. 1H NMR analysis showed that the orthometalated phenazines lowered the symmetry of the compounds significantly. Inductive effects from the carbanion and ring current effects outweighed the effect of paramagnetic anisotropy and dominated the spectra. This resulted in a lack of typical correlations with ligand parameters such as pKa that are observed for the parent hexa-acetate compounds. DFT calculations allowed for a discussion of those parameters in terms of the optimized geometry of compound 2. Natural bond orbital (NBO) results, in turn, aided the rationalization of the orthometalation reaction. The intra-cluster transitions (IC) at ∼690 nm consistently shifted to higher energies, and the redox pair [Ru3O]0/+1 also shifted to more positive E1/2 values. Again, the shifts were small and produced poor correlations with phenazine basicity. Overall, the substitution of one acetate bridge caused poor π-interactions between the delocalized [Ru3O] unit and the phenazine electron cloud. fsTA experiments, performed for the first time for such systems, showed that an 2IC excited state decayed very fast on the picosecond timescale.

TriplatinNC and Biomolecules: Building Models Based on Non-covalent Interactions.

The class of polynuclear platinum(II) compounds have demonstrated a great interest because their high activity against cancer cells. Among these new compounds, the TriplatinNC also called AH78, demonstrated surprising antitumor activity, in some cases equivalent to cisplatin. It is well-known that complex charge +8 favors interaction with DNA and other biomolecules non-covalently, through the hydrogen bonds with phosphate and sulfate groups present in these structures. The hydrogen atoms of the amine interact with the oxygen atoms of the phosphate and sulfate groups present in the DNA strand and heparan sulfate, respectively. These interactions can cause significant twists in double helix and inhibit the activity of these biomolecules. The present investigation is an attempt to provide a benchmark theoretical study about TriplatinNC. We have described the non-covalent interactions through small reliable mimetic models. The non-covalent interactions were also evaluated on larger models containing DNA fractions with six nitrogenous base pairs (CGCGAA) and fractions of the disaccharide that makes the HS evaluated by the hybrid QM/MM ONIOM methodology.

Insights on the transport of tamoxifen by gold nanoparticles for MCF-7 breast cancer cells based on SERS spectroscopy.

Gold nanoparticles (AuNP) were synthesized and modified with anti-folate receptor antibody (AB), folic acid (FA), crystal violet (CV), poly (ethyleneglycol) methyl ether thiol and the antineoplastic drug tamoxifen (TAM). Such a preparation was incubated in vitro with MCF-7 human breast cancer cells, showing a decrease in the TAM dosage for the reduction of cell viability. The adsorption of TAM on gold surface was investigated by surface-enhanced Raman scattering (SERS) spectroscopy and the assignment based on Density Functional Theory calculations showed that the ether moiety was involved in the interactions with the metal. Such a chemical affinity was correlated with the carrying of TAM in the biological media. CV was included in the preparation as a molecular probe for SERS spectroscopy, whose signal was monitored to analyse the efficiency of the modified AuNP in the target of neoplastic cells. The results showed AB, FA and TAM components had complementary roles in the cell recognition and, therefore, in the efficiency of the drug carrier nanosystem.

Synthesis, characterization, and NMR studies of 1,2,3-triazolium ionic liquids: a good perspective regarding cytotoxicity.

Ionic liquids (ILs) have been extensively studied and are considered green solvents capable of replacing traditional organic solvents. In this study, seven 1,2,3-triazolium derivative ILs have been synthesized. In order to study the effect of the cation nature on the ILs cytotoxicity, their structures were first identified by 1H, 13C NMR 1D, and 2D spectroscopy. DFT calculations have also been performed in a way to help to provide an insightful structural analysis from 13C NMR spectroscopy. The comparison made with the NMR experimental shifts was quite important to show that the 1,2,3-triazolium derivatives have the expected structure shown here. The in vitro cytotoxicity of ILs toward macrophages showed that among the compounds tested, five did not exhibit expressive cytotoxicity on mammalian cells. Besides the well-established relationship between the carbonic chain size of the cation and the cytotoxicity, the log P of the compounds predicts that the toxicity increases with the size of the carbon chain, demonstrating that the most cytotoxic compound is also the most lipophilic one. The low cytotoxicity effect of ILs on mammalian cells points to their potential application in large-scale by industry. Graphical abstract Seven triazolium ILs were synthesized and their in vitro cytotoxicity on murine macrophages showed a relationship with the carbonic chain size.

Theoretical Proposal for the Whole Phosphate Diester Hydrolysis Mechanism Promoted by a Catalytic Promiscuous Dinuclear Copper(II) Complex.

The catalytic mechanism that involves the cleavage of the phosphate diester model BDNPP (bis(2,4-dinitrophenyl) phosphate) catalyzed through a dinuclear copper complex is investigated in the current study. The metal complex was originally designed to catalyze catechol oxidation, and it showed an interesting catalytic promiscuity case in biomimetic systems. The current study investigates two different reaction mechanisms through quantum mechanics calculations in the gas phase, and it also includes the solvent effect through PCM (polarizable continuum model) single-point calculations using water as solvent. Two mechanisms are presented in order to fully describe the phosphate diester hydrolysis. Mechanism 1 is of the S(N)2 type, which involves the direct attack of the µ-OH bridge between the two copper(II) ions toward the phosphorus center, whereas mechanism 2 is the process in which hydrolysis takes place through proton transfer between the oxygen atom in the bridging hydroxo ligand and the other oxygen atom in the phosphate model. Actually, the present theoretical study shows two possible reaction paths in mechanism 1. Its first reaction path (p1) involves a proton transfer that occurs immediately after the hydrolytic cleavage, so that the proton transfer is the rate-determining step, which is followed by the entry of two water molecules. Its second reaction path (p2) consists of the entry of two water molecules right after the hydrolytic cleavage, but with no proton transfer; thus, hydrolytic cleavage is the rate-limiting step. The most likely catalytic path occurs in mechanism 1, following the second reaction path (p2), since it involves the lowest free energy activation barrier (ΔG(⧧) = 23.7 kcal mol(-1), in aqueous solution). A kinetic analysis showed that the experimental k(obs) value of 1.7 × 10(-5) s(-1) agrees with the calculated value k1 = 2.6 × 10(-5) s(-1); the concerted mechanism is kinetically favorable. The KIE (kinetic isotope effect) analysis applied to the second reaction path (p2) in mechanism 1 was also taken into account to assess the changes that take place in TS1-i (transition state of mechanism 1) and to perfectly characterize the mechanism described herein.

The conformation effect of the diamine bridge on the stability of dinuclear platinum(II) complexes and their hydrolysis.

In this paper, the hydrolysis process of a bisplatinum complex containing the flexible chain 1,6-hexanediamine between the two metal centers was investigated through the use of density functional theory (DFT) with the analysis of the role of the spacing group arrangement on the values of free energy activation barrier. All structures were fully optimized in aqueous solution using implicit model for solvent at DFT level. The energy profiles for the hydrolysis reaction were determined by using the supermolecule approach. Five transition states were proposed differing by the conformation of the bridge group, and the activation free energy calculated as a weighted average within the selected forms. The Gibbs population for reactant was used as a statistical weight leading to the predicted value of 23.1kcalmol(-1), in good accordance with experiment, 23.8kcalmol(-1). Our results suggests that for 1,6-hexanediamine bridge ligand, the extend forms with average torsional angle over the carbon chain larger than 130° have the greatest contribution to the hydrolysis kinetics. The results presented here point out that the hydrolysis mechanism might follow different paths for each conformation and each of these contributes to the observed energy barrier.

Raman spectroscopy as a tool in differentiating conjugated polyenes from synthetic and natural sources.

This work presents the Raman spectroscopic characterization of synthetic analogs of natural conjugated polyenals found in octocorals, focusing the unequivocal identification of the chemical species present in these systems. The synthetic material was produced by the autocondensation reaction of crotonaldehyde, generating a demethylated conjugated polyene containing 11 carbon-carbon double bonds, with just a methyl group on the end of the carbon chain. The resonance Raman spectra of such pigment has shown the existence of enhanced modes assigned to ν1(CC) and ν2(CC) modes of the main chain. For the resonance Raman spectra of natural pigments from octocorals collected in the Brazilian coast, besides the previously cited bands, it could be also observed the presence of the ν4(CCH3), related to the vibrational mode who describes the vibration of the methyl group of the central carbon chain of carotenoids. Other interesting point is the observation of overtones and combination bands, which for carotenoids involves the presence of the ν4 mode, whereas for the synthetic polyene this band, besides be seen at a slightly different wavenumber position, does not appear as an enhanced mode and also as a combination, such as for the natural carotenoids. Theoretical molecular orbital analysis of polyenal-11 and lycopene has shown the structural differences which are also responsible for the resonance Raman data, based on the appearance of the (CH3) vibrational mode in the resonant transition only for lycopene. At last, the Raman band at ca. 1010 cm(-1), assigned to the (CH3) vibrational mode, can be used for attributing the presence of each one of the conjugated polyenes: the resonance Raman spectrum containing the band at ca. 1010 cm(-1) refers to the carotenoid (in this case lycopene), and the absence of such band in resonance conditions refers to the polyenal (in this case the polyenal-11).

Structure and properties of the 5a,6-anhydrotetracycline-platinum(II) dichloride complex: a theoretical ab initio study.

Ab initio structural parameters, relative energies and spectroscopic properties are reported for the 5a,6-anhydrotetracycline-platinum(II) dichloride complex. Distinct coordination modes were analyzed in gas phase and aqueous medium indicating the tricarbonylmethane moiety (O3-Oam-O1) as the most probable Pt(II) complexation sites, supporting experimental proposals. The theoretical (1)H NMR analysis in conjunction with the observed data suggests that the Pt(II) might be bound to the O3-Oam preferentially, even though this site was found slightly unfavorable, based on energetic grounds, relative to O1-Oam. The aquation reaction, which is an important activation step in the action mechanism of cisplatin like molecules, was also investigated showing rate constants (0.5-1 x 10(-5) M(-1) s(-1)) of the same order of magnitude as those for the parent cisplatin compound. This is an important result stressing the importance of tetracyclines-Pt(II) complexes as lead compounds for the development of new platinum based antitumor drugs.

Linear free energy relationship for 4-substituted (o-phenylenediamine)platinum(II) dichloride derivatives using quantum mechanical descriptors.

In the present work quantum mechanical methods were used to calculate the rate constants for the first step of the aquation of a set of 4-substituted (o-phenylenediamine)platinum(II) dichloride derivatives containing electron-donating and withdrawing substituents at the 4-position of the aromatic ring. A linear free energy relationship was obtained for log(k(X)/k(H)), k being the rate constant for the first step of hydrolysis, and the electronic Hammett constants sigma(m) and sigma(p). The results showed that electron-donating groups promote the hydrolysis reaction. The quantitative models described here may be useful for the rational design of new, less mutagenic drugs based on platinum complexes.