Carlos A. de Simone

Theoretical and Experimental Studies of the Photoluminescent Properties of the Coordination Polymer [Eu(DPA)(HDPA)(H2O)2]·4H2O

We report on the hydrothermal synthesis of the [Eu(DPA)(HDPA)(H(2)O)(2)].4H(2)O lanthanide-organic framework (where H2DPA stands for pyridine-2,6-dicarboxylic acid), its full structural characterization including single-crystal X-ray diffraction and vibrational spectroscopy studies, plus detailed investigations on the experimental and predicted (using the Sparkle/PM3 model) photophysical luminescent properties. We demonstrate that the Sparkle/PM3 model arises as a valid and efficient alternative to the simulation and prediction of the photoluminescent properties of lanthanide-organic frameworks when compared with methods traditionally used. Crystallographic investigations showed that the material is composed of neutral one-dimensional coordination polymers infinity(1)[Eu(DPA)(HDPA)(H(2)O)(2)] which are interconnected via a series of hydrogen bonding interactions involving the water molecules (both coordinated and located in the interstitial spaces of the structure). In particular, connections between bilayer arrangements of infinity(1)[Eu(DPA)(HDPA)(H(2)O)(2)] are assured by a centrosymmetric hexameric water cluster. The presence of this large number of O-H oscillators intensifies the vibronic coupling with water molecules and, as a consequence, increases the number of nonradiative decay pathways controlling the relaxation process, ultimately considerably reducing the quantum efficiency (eta = 12.7%). The intensity parameters (Omega(2), Omega(4), and Omega(6)) were first calculated by using both the X-ray and the Sparkle/PM3 structures and were then used to calculate the rates of energy transfer (W(ET)) and back-transfer (W(BT)). Intensity parameters were used to predict the radiative decay rate. The calculated quantum yield obtained from the X-ray and Sparkle/PM3 structures (both of about 12.5%) are in good agreement with the experimental value (12.0 +/- 5%). These results clearly attest for the efficacy of the theoretical models employed in all calculations and create open new interesting possibilities for the design in silico of novel and highly efficient lanthanide-organic frameworks.

3-Arylamino and 3-Alkoxy-nor-β-lapachone Derivatives: Synthesis and Cytotoxicity against Cancer Cell Lines

Several 3-arylamino and 3-alkoxy-nor-beta-lapachone derivatives were synthesized in moderate to high yields and found to be highly potent against cancer cells SF295 (central nervous system), HCT8 (colon), MDA-MB435 (melanoma), and HL60 (leukemia), with IC(50) below 2 microM. The arylamino para-nitro and the 2,4-dimethoxy substituted naphthoquinones showed the best cytoxicity profile, while the ortho-nitro and the 2,4-dimethoxy substituted ones were more selective than doxorubicin and similar to the precursor lapachones, thus emerging as promising new lead compounds in anticancer drug development.

Studies towards the identification of putative bioactive conformation of potent vasodilator arylidene N-acylhydrazone derivatives

In this report we disclose the synthesis, vasodilatory activity, and identification of bioactive conformation of new N-acylhydrazone and N-methyl-N-acylhydrazone derivatives, structurally designed by bioisosteric replacements of previously described cardioactive compounds LASSBio-294 and its N-methyl derivative LASSBio-785. Some of these novel derivatives presented improved vasorelaxant properties, being new cardiovascular drug candidates.

Potential of a metal-organic framework as a new material for solid-phase extraction of pesticides from lettuce (Lactuca sativa), with analysis by gas chromatography-mass spectrometry.

The metal-organic framework (∞)[(La(0.9)Eu(0.1))(2)(DPA)(3)(H(2)O)(3)] was tested for extraction of pyrimicarb, procymidone, malathion, methyl parathion and α- and β-endosulfan from lettuce, with analysis using GC/MS in SIM mode. Experiments were carried out in triplicate at two fortification levels (0.1 and 0.5 mg/kg), and resulted in recoveries in the range of 78-107%, with RSD values between 1.6 and 8.0% for (∞)[(La(0.9)Eu(0.1))(2)(DPA)(3)(H(2)O)(3)] sorbent. Detection and quantification limits ranged from 0.02 to 0.05 mg/kg and from 0.05 to 0.10 mg/kg, respectively, for the different pesticides studied. The method developed was linear over the range tested (0.05-10.0 μg/mL), with correlation coefficients ranging from 0.9990 to 0.9997. Comparison between (∞)[(La(0.9)Eu(0.1))(2)(DPA)(3)(H(2)O)(3)] and conventional sorbent (silica gel) showed better performance of the (∞)[(La(0.9)Eu(0.1))(2)(DPA)(3)(H(2)O)(3)] polymeric sorbent for all pesticides tested.

Theoretical and Experimental Spectroscopic Approach of Fluorinated Ln3+−β-Diketonate Complexes

In this paper we report the synthesis of two new complexes, [Eu(fod)(3)(phen)] and [Tb(fod)(3)(phen)] (fod = 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octadionate and phen = 1,10-phenanthroline), and their complete characterization, including single-crystal X-ray diffraction, UV-vis spectroscopy, IR spectroscopy, and TGA. The complexes were studied in detail via both theoretical and experimental approaches to the photophysical properties. The [Eu(fod)(3)(phen)] complex crystallizes in the monoclinic space group P2(1)/c. The crystal structure of [Eu(fod)(3)(phen)] exhibits an offset pi-pi stacking interaction between the phenanthroline ligands of adjacent lanthanide complexes. The Eu(3+) cation is coordinated to three fod anionic ligands and to one phen. The symmetry around Eu(3+) is best described as a highly distorted square antiprism. The molar absorption coefficients of [Eu(fod)(3)(phen)] and [Tb(fod)(3)(phen)] revealed an improved ability to absorb light in comparison with the stand-alone phen and fod molecules. [Tb(fod)(3)(phen)] emits weak UV excitation, with this feature being explained by the triplet-(5)D(4) resonance, which contributes significantly to the nonradiative deactivation of Tb(3+), causing a short lifetime and low quantum yield. The intensity parameters (Omega(2), Omega(4), and Omega(6)) of [Eu(fod)(3)(phen)] were calculated for the X-ray and Sparkle/AM1 structures and compared with values obtained for [Eu(fod)(3)(H(2)O)(2)] and [Eu(fod)(3)(phen-N-O)] (phen-N-O = 1,10-phenanthroline N-oxide) samples. Intensity parameters were used to predict the radiative decay rate. The theoretical quantum efficiencies from the X-ray and Sparkle/AM1 structures are in good agreement with the experimental values, clearly attesting to the efficacy of the theoretical models.

On the search for potential anti-Trypanosoma cruzi drugs: Synthesis and biological evaluation of 2-hydroxy-3-methylamino and 1,2,3-triazolic naphthoquinoidal compounds obtained by click chemistry reactions

Five 2-hydroxy-3-substituted-aminomethyl naphthoquinones, nine 1,2,3-triazolic para-naphthoquinones, five nor-β-lapachone-based 1,2,3-triazoles, and several other naphthoquinonoid compounds were synthesized and evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease, continuing our screening program for new trypanocidal compounds. Among all the substances, 16-18, 23, 25-29 and 30-33 were herein described for the first time and fifteen substances were identified as more potent than the standard drug benznidazole, with IC(50)/24h values in the range of 10.9-101.5 μM. Compounds 14 and 19 with Selectivity Index of 18.9 and 6.1 are important structures for further studies.

Structural investigation of anti-Trypanosoma cruzi 2-iminothiazolidin-4-ones allows the identification of agents with efficacy in infected mice.

We modified the thiazolidinic ring at positions N3, C4, and C5, yielding compounds 6-24. Compounds with a phenyl at position N3, 15-19, 22-24, exhibited better inhibitory properties for cruzain and against the parasite than 2-iminothiazolidin-4-one 5. We were able to identify one high-efficacy trypanocidal compound, 2-minothiazolidin-4-one 18, which inhibited the activity of cruzain and the proliferation of epimastigotes and was cidal for trypomastigotes but was not toxic for splenocytes. Having located some of the structural determinants of the trypanocidal properties, we subsequently wished to determine if the exchange of the thiazolidine for a thiazole ring leaves the functional properties unaffected. We therefore tested thiazoles 26-45 and observed that they did not inhibit cruzain, but they exhibited trypanocidal effects. Parasite development was severely impaired when treated with 18, thus reinforcing the notion that this class of heterocycles can lead to useful cidal agents for Chagas disease.

1,3-Azoles from ortho-naphthoquinones: synthesis of aryl substituted imidazoles and oxazoles and their potent activity against Mycobacterium tuberculosis.

Twenty-three naphthoimidazoles and six naphthoxazoles were synthesised and evaluated against susceptible and rifampicin- and isoniazid-resistant strains of Mycobacterium tuberculosis. Among all the compounds evaluated, fourteen presented MIC values in the range of 0.78 to 6.25 μg/mL against susceptible and resistant strains of M. tuberculosis. Five structures were solved by X-ray crystallographic analysis. These substances are promising antimycobacterial prototypes.

Synthesis, Structure-Activity Relationships (SAR) and in Silico Studies of Coumarin Derivatives with Antifungal Activity

The increased incidence of opportunistic fungal infections, associated with greater resistance to the antifungal drugs currently in use has highlighted the need for new solutions. In this study twenty four coumarin derivatives were screened in vitro for antifungal activity against strains of Aspergillus. Some of the compounds exhibited significant antifungal activity with MICs values ranging between 16 and 32 μg/mL. The structure-activity relationships (SAR) study demonstrated that O-substitutions are essential for antifungal activity. It also showed that the presence of a short aliphatic chain and/or electron withdrawing groups (NO2 and/or acetate) favor activity. These findings were confirmed using density functional theory (DFT), when calculating the LUMO density. In Principal Component Analysis (PCA), two significant principal components (PCs) explained more than 60% of the total variance. The best Partial Least Squares Regression (PLS) model showed an r2 of 0.86 and q2cv of 0.64 corroborating the SAR observations as well as demonstrating a greater probe N1 interaction for active compounds. Descriptors generated by TIP correlogram demonstrated the importance of the molecular shape for antifungal activity.

Structural Design, Synthesis and Structure–Activity Relationships of Thiazolidinones with Enhanced Anti‐Trypanosoma cruzi Activity

Pharmacological treatment of Chagas disease is based on benznidazole, which displays poor efficacy when administered during the chronic phase of infection. Therefore, the development of new therapeutic options is needed. This study reports on the structural design and synthesis of a new class of anti‐Trypanosoma cruzi thiazolidinones (4 a–p). (2‐[2‐Phenoxy‐1‐(4‐bromophenyl)ethylidene)hydrazono]‐5‐ethylthiazolidin‐4‐one (4 h) and (2‐[2‐phenoxy‐1‐(4‐phenylphenyl)ethylidene)hydrazono]‐5‐ethylthiazolidin‐4‐one (4 l) were the most potent compounds, resulting in reduced epimastigote proliferation and were toxic for trypomastigotes at concentrations below 10 μM, while they did not display host cell toxicity up to 200 μM. Thiazolidinone 4 h was able to reduce the in vitro parasite burden and the blood parasitemia in mice with similar potency to benznidazole. More importantly, T. cruzi infection reduction was achieved without exhibiting mouse toxicity. Regarding the molecular mechanism of action, these thiazolidinones did not inhibit cruzain activity, which is the major trypanosomal protease. However, investigating the cellular mechanism of action, thiazolidinones altered Golgi complex and endoplasmic reticulum (ER) morphology, produced atypical cytosolic vacuoles, as well as induced necrotic parasite death. This structural design employed for the new anti‐T. cruzi thiazolidinones (4 a–p) led to the identification of compounds with enhanced potency and selectivity compared to first‐generation thiazolidinones. These compounds did not inhibit cruzain activity, but exhibited strong antiparasitic activity by acting as parasiticidal agents and inducing a necrotic parasite cell death.