Designing Antitrypanosomal and Antileishmanial BODIPY Derivatives: A Computational and In Vitro Assessment.

Leishmaniasis and Human African trypanosomiasis pose significant public health threats in resource-limited regions, accentuated by the drawbacks of the current antiprotozoal treatments and the lack of approved vaccines. Considering the demand for novel therapeutic drugs, a series of BODIPY derivatives with several functionalizations at the meso, 2 and/or 6 positions of the core were synthesized and characterized. The in vitro activity against Trypanosoma brucei and Leishmania major parasites was carried out alongside a human healthy cell line (MRC-5) to establish selectivity indices (SIs). Notably, the meso-substituted BODIPY, with 1-dimethylaminonaphthalene (1b) and anthracene moiety (1c), were the most active against L. major, displaying IC50 = 4.84 and 5.41 µM, with a 16 and 18-fold selectivity over MRC-5 cells, respectively. In contrast, the mono-formylated analogues 2b and 2c exhibited the highest toxicity (IC50 = 2.84 and 6.17 µM, respectively) and selectivity (SI = 24 and 11, respectively) against T. brucei. Further insights on the activity of these compounds were gathered from molecular docking studies. The results suggest that these BODIPYs act as competitive inhibitors targeting the NADPH/NADP+ linkage site of the pteridine reductase (PR) enzyme. Additionally, these findings unveil a range of quasi-degenerate binding complexes formed between the PRs and the investigated BODIPY derivatives. These results suggest a potential correlation between the anti-parasitic activity and the presence of multiple configurations that block the same site of the enzyme.

Polyaromatic Bis(indolyl)methane Derivatives with Antiproliferative and Antiparasitic Activity.

Bis(indolyl)methanes (BIMs) are a class of compounds that have been recognized as an important core in the design of drugs with important pharmacological properties, such as promising anticancer and antiparasitic activities. Here, we explored the biological activity of the BIM core functionalized with different (hetero)aromatic moieties. We synthesized substituted BIM derivatives with triphenylamine, N,N-dimethyl-1-naphthylamine and 8-hydroxylquinolyl groups, studied their photophysical properties and evaluated their in vitro antiproliferative and antiparasitic activities. The triphenylamine BIM derivative 2a displayed an IC50 of 3.21, 3.30 and 3.93 µM against Trypanosoma brucei, Leishmania major and HT-29 cancer cell line, respectively. The selectivity index demonstrated that compound 2a was up to eight-fold more active against the parasites and HT-29 than against the healthy cell line MRC-5. Fluorescence microscopy studies with MRC-5 cells and T. brucei parasites incubated with derivative 2a indicate that the compound seems to accumulate in the cell's mitochondria and in the parasite's nucleus. In conclusion, the BIM scaffold functionalized with the triphenylamine moiety proved to be the most promising antiparasitic and anticancer agent of this series.

New Amino Acid-Based Thiosemicarbazones and Hydrazones: Synthesis and Evaluation as Fluorimetric Chemosensors in Aqueous Mixtures.

Bearing in mind the interest in the development and application of amino acids/peptides as bioinspired systems for sensing, a series of new phenylalanine derivatives bearing thiosemicarbazone and hydrazone units at the side chain were synthesised and evaluated as fluorimetric chemosensors for ions. Thiosemicarbazone and hydrazone moieties were chosen because they are considered both proton-donor and proton-acceptor, which is an interesting feature in the design of chemosensors. The obtained compounds were tested for the recognition of organic and inorganic anions (such as AcO-, F-, Cl-, Br-, I-, ClO4-, CN-, NO3-, BzO-, OH-, H2PO4- and HSO4-) and of alkaline, alkaline-earth, and transition metal cations, (such as Na+, K+, Cs+, Ag+, Cu+, Cu2+, Ca2+, Cd2+, Co2+, Pb2+, Pd2+, Ni2+, Hg2+, Zn2+, Fe2+, Fe3+ and Cr3+) in acetonitrile and its aqueous mixtures in varying ratios via spectrofluorimetric titrations. The results indicate that there is a strong interaction via the donor N, O and S atoms at the side chain of the various phenylalanines, with higher sensitivity for Cu2+, Fe3+ and F- in a 1:2 ligand-ion stoichiometry. The photophysical and metal ion-sensing properties of these phenylalanines suggest that they might be suitable for incorporation into peptide chemosensory frameworks.

Amino-Alcohol Organic-Inorganic Hybrid Sol-Gel Materials Based on an Epoxy Bicyclic Silane: Synthesis and Characterization.

Organic-inorganic hybrids (OIHs) are a type of material that can be obtained using the sol-gel process and has the advantages of organic and inorganic moieties in a single material. Polyetheramines have been widely used in the preparation of this type of material, particularly in combination with epoxy-based alkoxysilanes. Nevertheless, epoxyciclohexylethyltrimethoxysilane (ECHETMS) is a promising alkoxysilane with an epoxy terminal group that is quite unexplored. In this work, four novel OIH materials were synthesized using the sol-gel method. The OIHs were based on Jeffamines® of different molecular weights (D-230, D-400, ED-600, and ED-900), together with ECHETMS. The materials were characterized using multinuclear solid state NMR, FTIR, BET, UV/Vis spectroscopy, EIS, and TGA. The influence of the Jeffamine molecular weight and the suitability of these materials to act as a supporting matrix for heteroaromatic probes were assessed and discussed. The materials show interesting properties in order to be applied in a wide range of sensing applications.

Dabcyl as a Naked Eye Colorimetric Chemosensor for Palladium Detection in Aqueous Medium.

Industrial activity has raised significant concerns regarding the widespread pollution caused by metal ions, contaminating ecosystems and causing adverse effects on human health. Therefore, the development of sensors for selective and sensitive detection of these analytes is extremely important. In this regard, an azo dye, Dabcyl 2, was synthesised and investigated for sensing metal ions with environmental and industrial relevance. The cation binding character of 2 was evaluated by colour changes as seen by the naked eye, UV-Vis and 1H NMR titrations in aqueous mixtures of SDS (0.02 M, pH 6) solution with acetonitrile (99:1, v/v). Out of the several cations tested, chemosensor 2 had a selective response for Pd2+, Sn2+ and Fe3+, showing a remarkable colour change visible to the naked eye and large bathochromic shifts in the UV-Vis spectrum of 2. This compound was very sensitive for Pd2+, Sn2+ and Fe3+, with a detection limit as low as 5.4 × 10-8 M, 1.3 × 10-7 M and 5.2 × 10-8 M, respectively. Moreover, comparative studies revealed that chemosensor 2 had high selectivity towards Pd2+ even in the presence of other metal ions in SDS aqueous mixtures.

Colorimetric Chemosensor for Cu2+ and Fe3+ Based on a meso-Triphenylamine-BODIPY Derivative.

Optical chemosensors are a practical tool for the detection and quantification of important analytes in biological and environmental fields, such as Cu2+ and Fe3+. To the best of our knowledge, a BODIPY derivative capable of detecting Cu2+ and Fe3+ simultaneously through a colorimetric response has not yet been described in the literature. In this work, a meso-triphenylamine-BODIPY derivative is reported for the highly selective detection of Cu2+ and Fe3+. In the preliminary chemosensing study, this compound showed a significant color change from yellow to blue-green in the presence of Cu2+ and Fe3+. With only one equivalent of cation, a change in the absorption band of the compound and the appearance of a new band around 700 nm were observed. Furthermore, only 10 equivalents of Cu2+/Fe3+ were needed to reach the absorption plateau in the UV-visible titrations. Compound 1 showed excellent sensitivity toward Cu2+ and Fe3+ detection, with LODs of 0.63 µM and 1.06 µM, respectively. The binding constant calculation indicated a strong complexation between compound 1 and Cu2+/Fe3+ ions. The 1H and 19F NMR titrations showed that an increasing concentration of cations induced a broadening and shifting of the aromatic region peaks, as well as the disappearance of the original fluorine peaks of the BODIPY core, which suggests that the ligand-metal (1:2) interaction may occur through the triphenylamino group and the BODIPY core.

Sodium alginate/polycaprolactone co-axial wet-spun microfibers modified with N-carboxymethyl chitosan and the peptide AAPV for Staphylococcus aureus and human neutrophil elastase inhibition in potential chronic wound scenarios.

In chronic wound (CW) scenarios, Staphylococcus aureus-induced infections are very prevalent. This leads to abnormal inflammatory processes, in which proteolytic enzymes, such as human neutrophil elastase (HNE), become highly expressed. Alanine-Alanine-Proline-Valine (AAPV) is an antimicrobial tetrapeptide capable of suppressing the HNE activity, restoring its expression to standard rates. Here, we proposed the incorporation of the peptide AAPV within an innovative co-axial drug delivery system, in which the peptide liberation was controlled by N-carboxymethyl chitosan (NCMC) solubilization, a pH-sensitive antimicrobial polymer effective against Staphylococcus aureus. The microfibers' core was composed of polycaprolactone (PCL), a mechanically resilient polymer, and AAPV, while the shell was made of the highly hydrated and absorbent sodium alginate (SA) and NCMC, responsive to neutral-basic pH (characteristic of CW). NCMC was loaded at twice its minimum bactericidal concentration (6.144 mg/mL) against S. aureus, while AAPV was loaded at its maximum inhibitory concentration against HNE (50 µg/mL), and the production of fibers with a core-shell structure, in which all components could be detected (directly or indirectly), was confirmed. Core-shell fibers were characterized as flexible and mechanically resilient, and structurally stable after 28-days of immersion in physiological-like environments. Time-kill kinetics evaluations revealed the effective action of NCMC against S. aureus, while elastase inhibitory activity examinations proved the ability of AAPV to reduce HNE levels. Cell biology testing confirmed the safety of the engineered fiber system for human tissue contact, with fibroblast-like cells and human keratinocytes maintaining their morphology while in contact with the produced fibers. Data confirmed the engineered drug delivery platform as potentially effective for applications in CW care.

Novel Crown Ether Amino Acids as Fluorescent Reporters for Metal Ions.

Unnatural amino acids with enhanced properties, such as increased complexing ability and luminescence, are considered to be highly attractive building blocks for bioinspired frameworks, such as probes for biomolecule dynamics, sensitive fluorescent chemosensors, and peptides for molecular imaging, among others. Therefore, a novel series of highly emissive heterocyclic alanines bearing a benzo[d]oxazolyl unit functionalized with different heterocyclic π-spacers and (aza)crown ether moieties was synthesized. The new compounds were completely characterized using the usual spectroscopic techniques and evaluated as fluorimetric chemosensors in acetonitrile and aqueous mixtures in the presence of various alkaline, alkaline-earth, and transition metal ions. The different crown ether binding moieties as well as the electronic nature of the π-bridge allowed for fine tuning of the sensory properties of these unnatural amino acids towards Pd2+ and Fe3+, as seen by spectrofluorimetric titrations.

Essential Oils Encapsulated in Zeolite Structures as Delivery Systems (EODS): An Overview.

Essential oils (EO) obtained from plants have proven industrial applications in the manufacturing of perfumes and cosmetics, in the production and flavoring of foods and beverages, as therapeutic agents in aromatherapy, and as the active principles or excipients of medicines and pharmaceutics due to their olfactory, physical-chemical, and biological characteristics. On behalf of the new paradigm of a more natural and sustainable lifestyle, EO are rather appealing due to their physical, chemical, and physiological actions in human beings. However, EO are unstable and susceptible to degradation or loss. To tackle this aspect, the encapsulation of EO in microporous structures as zeolites is an attractive solution, since these host materials are cheap and non-toxic to biological environments. This overview provides basic information regarding essential oils, including their recognized benefits and functional properties. Current progress regarding EO encapsulation in zeolite structures is also discussed, highlighting some representative examples of essential oil delivery systems (EODS) based on zeolites for healthcare applications or aromatherapy.

Bioimaging of Lysosomes with a BODIPY pH-Dependent Fluorescent Probe.

Fluorescence-based probes represent a powerful tool for noninvasive imaging of living systems in real time and with a high temporal and spatial resolution. Amongst several known fluorophores, 3-difluoroborodipyrromethene (BODIPY) derivatives have become a cornerstone for innovative fluorescent labelling applications, mainly due to their advantageous features including their facile synthesis, structural versatility and exceptional photophysical properties. In this context, we report a BODIPY-based fluorescent probe for imaging of lysosomes in living cells. The BODIPY derivative displayed a remarkable fluorescence enhancement at low pH values with a pKa* of 3.1. In vitro studies by confocal microscopy in HeLa cells demonstrated that the compound was able to permeate cell membrane and selectively label lysosome whilst remaining innocuous to the cell culture at the maximum concentration tested. Herein, the BODIPY derivative holds the promise of investigating lysosomal dynamics and function in living cells through fluorescence imaging.

Tunable Spun Fiber Constructs in Biomedicine: Influence of Processing Parameters in the Fibers' Architecture.

Electrospinning and wet-spinning have been recognized as two of the most efficient and promising techniques for producing polymeric fibrous constructs for a wide range of applications, including optics, electronics, food industry and biomedical applications. They have gained considerable attention in the past few decades because of their unique features and tunable architectures that can mimic desirable biological features, responding more effectively to local demands. In this review, various fiber architectures and configurations, varying from monolayer and core-shell fibers to tri-axial, porous, multilayer, side-by-side and helical fibers, are discussed, highlighting the influence of processing parameters in the final constructs. Additionally, the envisaged biomedical purposes for the examined fiber architectures, mainly focused on drug delivery and tissue engineering applications, are explored at great length.

Hybrid Sol-Gel Matrices Doped with Colorimetric/Fluorimetric Imidazole Derivatives.

Organic-inorganic hybrids (OIH) are materials that can be easily synthesized by the sol-gel method and combine the advantages of organic and inorganic moieties within a single polymeric matrix. Imidazole derivatives are versatile organic compounds that can change their optical properties with the variation of pH due to the protonation or deprotonation of the nitrogen atoms. This work reports the preparation of different OIHs doped with different contents of two imidazole compounds (3a,b). The obtained materials were characterized structurally by FTIR, and the dielectric properties were studied by electrochemical impedance spectroscopy. The optical properties were studied by UV-Vis absorption and fluorescence spectroscopies. The FTIR analysis showed that the presence of the imidazole does not change the structural properties of the matrices. The normalized resistance values obtained for the doped matrices ranged between 8.57 and 9.32 Ω cm2, all being higher than the undoped matrix. The σ ranged between 9.49 and 10.28 S cm-1, being all higher than the pure OIH samples. Compound 3a showed a maximum absorption peak at 390 nm, which is present in the OIH spectra, proving the presence of the compound. In the case of compound 3b, a maximum absorption wavelength at 412 nm was found, and the compound peak was not clear, which may indicate that an interaction between the compound and the matrix occurred. A synergetic effect between the intrinsic emission of the matrix and the fluorescence of 3a is found on the OIH-doped matrices.

Organic-inorganic hybrid sol-gel materials doped with a fluorescent triarylimidazole derivative.

The development of sensors for pH monitoring is of extreme importance in the monitoring of concrete and reinforced concrete structures. Imidazole derivatives are promising probes for pH sensing due to the amphoteric nature of their heterocyclic ring, which can be protonated/deprotonated upon pH changes. In this work, a triarylimidazole was synthesised and used as a dopant in an organic-inorganic hybrid (OIH) sol-gel matrix to obtain a pH-sensitive membrane for further application in optical fibre sensors (OFS). The triarylimidazole probe shows fluorimetric response in pH between 9 and 13, which is the desired range for monitoring carbonation of concrete. This degradation process lowers the highly alkaline pH of concrete (12.5-13) to values below 9, which creates favourable conditions for corrosion of concrete reinforcement. The OIH membranes used were based on Jeffamine THF170 and 3-glycidoxypropytrimethoxysilane precursors, which had already been shown to be suitable and resistant in contact with cement-based materials. The OIHs were doped with three different contents of the triarylimidazole and the structural, dielectric, thermal and optical properties of the pure and doped OIH materials were evaluated. The structural analysis showed that the presence of the triarylimidazole did not change the structural properties of the OIH material. Electrochemical impedance spectroscopy showed that in the doped samples the conductivity increased with the imidazole concentration. The ε r obtained for the doped samples ranged approximately from 11 to 19 and for the pure matrices was 8. Thermal analysis showed that these materials are stable up to 350 °C and that the presence of the probe did not change that feature. The optical properties showed that the prepared OIH materials have promising properties to be used as pH sensitive fluorimetric probes.

Optical Fiber Sensors for Biocide Monitoring: Examples, Transduction Materials, and Prospects.

Antifouling biocides are toxic to the marine environment impacting negatively on the aquatic ecosystems. These biocides, namely, tributyltin (TBT) and Cu(I) compounds, are used to avoid biofouling; however, their toxicity turns TBT and Cu(I) monitoring an important health issue. Current monitoring methods are expensive and time-consuming. This review provides an overview of the actual state of the art of antifouling paints' biocides, including their impact and toxicity, as well as the reported methods for TBT and Cu(I) detection over the past decade. The principles of optical fiber sensors (OFS) applications, with focus on environmental applications, and the use of organic chemosensors in this type of sensors are debated. The multiplexing ability of OFS and their application on aquatic environments are also discussed.

Synthesis, Optical and Electrical Characterization of Amino-alcohol Based Sol-gel Hybrid Materials.

This manuscript describes the synthesis and characterization of five new organic-inorganic hybrid (OIH) sol-gel materials that were obtained from a functionalized siloxane 3-glycidoxypropyltrimethoxysilane (GPTMS) by the reaction with the new Jeffamine®, namely three different diamines, i.e., EDR-148, RFD-270, and THF-170, a secondary diamine, i.e., SD-2001, and a triamine, i.e., T-403. The OIH sol-gel materials were characterized by UV-visible absorption spectrophotometry, steady-state photoluminescence spectroscopy, and electrochemical impedance spectroscopy. The reported OIH sol-gel materials showed that, with the exception of the samples prepared with Jeffamine® SD-2001, the transmittance values ranged between 61% and 79%. Regarding the capacitance data, the values reported changed between 0.008 and 0.013 nF cm-2. Due to their optical and electrical properties these new OIH materials show promising properties for applications as support films in an optical sensor area such as fiber sensor devices. Studies to assess the chemical stability of the OIH materials in contact with cement pastes after 7, 14, and 28 days were also performed. The samples prepared with THF-170 and GPTMS, when compared to the samples prepared with RFD-270 and T-403, exhibited improved behavior in the cement paste (alkaline environment), showing promising properties for application as support film in optical fiber sensors in the civil engineering field.

PDMS Based Hybrid Sol-Gel Materials for Sensing Applications in Alkaline Environments: Synthesis and Characterization.

Nowadays, concrete degradation is a major problem in the civil engineering field. Concrete carbonation, one of the main sources of structures' degradation, causes concrete's pH to decrease; hence, enabling the necessary conditions for corrosion reinforcement. An accurate, non-destructive sensor able to monitor the pH decrease resistant to concrete conditions is envisaged by many researchers. Optical fibre sensors (OFS) are generally used for concrete applications due to their high sensitivity and resistance to external interferences. Organic-inorganic hybrid (OIH) films, for potential functionalization of OFS to be applied in concrete structures, were developed. Polydimethylsiloxane (PDMS) based sol-gel materials were synthesized by the formation of an amino alcohol precursor followed by hydrolysis and condensation. Different ratios between PDMS and (3-aminopropyl)triethoxysilane (3-APTES) were studied. The synthesized OIH films were characterized by Fourier-transformed infrared spectroscopy (FTIR), UV-Vis spectroscopy, electrochemical impedance spectroscopy (EIS) and thermogravimetric analysis (TGA). The OIH films were doped with phenolphthalein (Phph), a pH indicator, and were characterized by UV-Vis and EIS. FTIR characterization showed that the reaction between both precursors, the hydrolysis and the condensation reactions occurred successfully. UV-Vis characterization confirmed the presence of Phph embedded in the OIH matrices. Dielectric and thermal properties of the materials showed promising properties for application in contact with a high alkaline environment.

Anisotropic PCL nanofibers embedded with nonlinear nanocrystals as strong generators of polarized second harmonic light and piezoelectric currents.

Using the electrospinning technique nanofibers consisting of organic nonlinear optical 3-nitroaniline (3NA, C6H6N2O2) nanocrystals embedded in poly-ε-caprolactone (PCL) polymer, 3NA@PCL nanofibers, were produced. Polarimetry optical second harmonic generation and X-ray diffraction studies show that 3NA push-pull molecules crystallize inside the polymer fibers with a strong preferential orientation giving rise to an alignment of the molecular dipole moments along the nanofibers longitudinal axis. This alignment strongly enhances the second order nonlinear optical response of the fibers. Intense second harmonic generation emission was observed from a single nanofiber, corresponding to an effective second order susceptibility of 80 pm V-1, four times greater than the largest second order susceptibility tensor element (21 pm V-1) associated with a macroscopic 3NA crystal. Moreover, when subjected to a modest periodically applied force of 3 N, a piezoelectric current of 70 nA generated by a 4 cm2 electrospun nanofiber mat amounted to 122 nW cm-2 of instantaneous density power, sufficient to power a LCD display. The results show that the electrospinning technique is a powerful technique to fabricate organic functional materials with oriented nanocrystals made of highly polarizable molecules, embedded in a polymer matrix.

Self-assembly of dipeptide Boc-diphenylalanine nanotubes inside electrospun polymeric fibers with strong piezoelectric response.

Dipeptide biomaterials are strong piezoelectric materials that can convert applied mechanical forces into electricity. We have developed large-scale hybrid electrospun arrays containing N-tert-butoxycarbonyl (Boc) diphenylalanine in the form of nanotubes embedded in biocompatible polymers. These nanofibers exhibit strong piezoelectric properties when a periodic mechanical force is applied. The nanostructured hybrid materials were produced by the electrospinning technique. Optical absorption measurements show four bands in the spectral region 240-280 nm indicating quantum confinement due to nanotube formation of Boc-diphenylalanine in dichloromethane solutions. A strong blue photoluminescence emission was observed from nanotubes crystallized inside the fiber arrays during the electrospinning process. These two dimensional hybrid biomaterial structures are able to generate voltage, current and density power of up to 30 V, 300 nA and 2.3 µW cm-2, respectively, when a periodical force of 1.5 N is applied. The dipeptide-polymer electrospun arrays can power several liquid-crystal display panels and may be used for biomedical applications and as bio-energy sources.

Novel alanines bearing a heteroaromatic side chain: synthesis and studies on fluorescent chemosensing of metal cations with biological relevance.

A family of novel thienylbenzoxazol-5-yl-L-alanines, consisting of an alanine core bearing a benzoxazole at the side chain with a thiophene ring at position 2, substituted with different (hetero)aryl substituents, was synthesised to study the tuning of the photophysical and chemosensory properties of the resulting compounds. These novel heterocyclic alanines 3a-f and a series of structurally related bis-thienylbenzoxazolyl-alanines 3g-j were evaluated for the first time in the recognition of selected metal cations with environmental, medicinal and analytical interest such as Co2+, Cu2+, Zn2+ and Ni2+, in acetonitrile solution, with the heterocycles at the side chain acting simultaneously as the coordinating and reporting units, via fluorescence changes. This behaviour can be explained by the involvement of the electron donor heteroatoms in the recognition event, through complexation of the metal cations. The spectrofluorimetric titrations showed that thienylbenzoxazolyl-alanines 3a-j and 4a,b were non-selective fluorimetric chemosensors for the above-mentioned cations, with the best results being obtained for the interaction of Cu2+ with bis-alanine 3j and deprotected alanines 4a,b. The encouraging photophysical and metal ion sensing properties of these thienylbenzoxazolyl-alanines suggest that they can be used to obtain bioinspired fluorescent reporters for metal ion such as peptides/proteins with chemosensory/probing ability.

Phototriggered release of tetrapeptide AAPV from coumarinyl and pyrenyl cages.

Ala-Ala-Pro-Val (AAPV) is a bioactive tetrapeptide that inhibits human neutrophil elastase, an enzyme involved in skin chronic inflammatory diseases like psoriasis. Caged derivatives of this peptide were prepared by proper N- and C-terminal derivatisation through a carbamate or ester linkage, respectively, with two photoactive moieties, namely 7-methoxycoumarin-2-ylmethyl and pyren-2-ylmethyl groups. These groups were chosen to assess the influence of the photosensitive group and the type of linkage in the controlled photo release of the active molecule. The caged peptides were irradiated at selected wavelengths of irradiation (254, 300, and 350 nm), and the photolytic process was monitored by HPLC-UV. The results established the applicability of the tested photoactive groups for the release of AAPV, especially for the derivative bearing the carbamate-linked pyrenylmethyl group, which displayed the shortest irradiation times for the release at the various wavelengths of irradiation (ca. 4 min at 254 nm, 8 min at 300 nm and 46 min at 350 nm).