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by Keyword: Derivatives

Fonte M, Fontinha D, Moita D, Caño-Prades O, Avalos-Padilla Y, Fernàndez-Busquets X, Prudêncio M, Gomes P, Teixeira C, (2023). New 4-(N-cinnamoylbutyl)aminoacridines as potential multi-stage antiplasmodial leads European Journal Of Medicinal Chemistry 258, 115575

A novel family of 4-aminoacridine derivatives was obtained by linking this heteroaromatic core to different trans-cinnamic acids. The 4-(N-cinnamoylbutyl)aminoacridines obtained exhibited in vitro activity in the low- or sub-micromolar range against (i) hepatic stages of Plasmodium berghei, (ii) erythrocytic forms of Plasmodium falciparum, and (iii) early and mature gametocytes of Plasmodium falciparum. The most active compound, having a meta-fluorocinnamoyl group linked to the acridine core, was 20- and 120-fold more potent, respectively, against the hepatic and gametocyte stages of Plasmodium infection than the reference drug, primaquine. Moreover, no cytotoxicity towards mammalian and red blood cells at the concentrations tested was observed for any of the compounds under investigation. These novel conjugates represent promising leads for the development of new multi-target antiplasmodials.Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

JTD Keywords: agents, analogs, antimalarial, artemisinin, blood-stage, cinnamic acid, gametocyte, hybrid, liver-stage, malaria, multi-target, plasmodium-falciparum, primaquine, quinacrine, resistance, Acridine, Antimalarial, Blood-stage, Cinnamic acid, Cinnamic acid-derivatives, Gametocyte, Hybrid, Liver-stage, Multi-target


Fontana-Escartín, A, El Hauadi, K, Lanzalaco, S, Pérez-Madrigal, MM, Armelin, E, Turon, P, Alemán, C, (2023). Smart Design of Sensor-Coated Surgical Sutures for Bacterial Infection Monitoring Macromolecular Bioscience 23, 2300024

Virtually, all implantable medical devices are susceptible to infection. As the main healthcare issue concerning implantable devices is the elevated risk of infection, different strategies based on the coating or functionalization of biomedical devices with antiseptic agents or antibiotics are proposed. In this work, an alternative approach is presented, which consists of the functionalization of implantable medical devices with sensors capable of detecting infection at very early stages through continuous monitoring of the bacteria metabolism. This approach, which is implemented in surgical sutures as a representative case of implantable devices susceptible to bacteria colonization, is expected to minimize the risk of worsening the patient's clinical condition. More specifically, non-absorbable polypropylene/polyethylene (PP/PE) surgical sutures are functionalized with conducting polymers using a combination of low-pressure oxygen plasma, chemical oxidative polymerization, and anodic polymerization, to detect metabolites coming from bacteria respiration. Functionalized suture yarns are used for real-time monitoring of bacteria growth, demonstrating the potential of this strategy to fight against infections.© 2023 Wiley-VCH GmbH.

JTD Keywords: adhesion, biofilm, conducting polymers, contamination, derivatives, detections, functionalized sutures, nadh, poly(3,4-ethylenedioxythiophene), Bacteria growth, Conducting polymers, Detections, Functionalized sutures, Monofilament, Nadh


Tonelli M, Catto M, Sabaté R, Francesconi V, Laurini E, Pricl S, Pisani L, Miniero DV, Liuzzi GM, Gatta E, Relini A, Gavín R, Del Rio JA, Sparatore F, Carotti A, (2023). Thioxanthenone-based derivatives as multitarget therapeutic leads for Alzheimer's disease European Journal Of Medicinal Chemistry 250, 115169

A set of twenty-five thioxanthene-9-one and xanthene-9-one derivatives, that were previously shown to inhibit cholinesterases (ChEs) and amyloid β (Aβ40) aggregation, were evaluated for the inhibition of tau protein aggregation. All compounds exhibited a good activity, and eight of them (5-8, 10, 14, 15 and 20) shared comparable low micromolar inhibitory potency versus Aβ40 aggregation and human acetylcholinesterase (AChE), while inhibiting human butyrylcholinesterase (BChE) even at submicromolar concentration. Compound 20 showed outstanding biological data, inhibiting tau protein and Aβ40 aggregation with IC50 = 1.8 and 1.3 μM, respectively. Moreover, at 0.1-10 μM it also exhibited neuroprotective activity against tau toxicity induced by okadoic acid in human neuroblastoma SH-SY5Y cells, that was comparable to that of estradiol and PD38. In preliminary toxicity studies, these interesting results for compound 20 are somewhat conflicting with a narrow safety window. However, compound 10, although endowed with a little lower potency for tau and Aβ aggregation inhibition additionally demonstrated good inhibition of ChEs and rather low cytotoxicity. Compound 4 is also worth of note for its high potency as hBChE inhibitor (IC50 = 7 nM) and for the three order of magnitude selectivity versus hAChE. Molecular modelling studies were performed to explain the different behavior of compounds 4 and 20 towards hBChE. The observed balance of the inhibitory potencies versus the relevant targets indicates the thioxanthene-9-one derivatives as potential MTDLs for AD therapy, provided that the safety window will be improved by further structural variations, currently under investigation.Copyright © 2023 Elsevier Masson SAS. All rights reserved.

JTD Keywords: a? and tau aggregation inhibition, ache and bche inhibition, aggregation, alzheimer?s disease, butyrylcholinesterase, design, drugs, dual inhibitors, fibrillization, multitarget-directed ligands (mtdls), peptide, polyphenols, potent, rivatives, Ache and bche inhibition, Alzheimer's disease, Amyloid-beta, Aβ and tau aggregation inhibition, Multitarget-directed ligands (mtdls), Thioxanthene-9-one and xanthen-9-one de, Thioxanthene-9-one and xanthen-9-one derivatives


Cao, HZ, Zhong, SQ, Shen, Y, Lv, MQ, Zhu, YH, Tian, YP, Luo, K, Huang, W, Battaglia, G, Gong, QY, Tian, XH, (2022). MtDNA specific fluorescent probe uncovering mitochondrial nucleoids dynamics during programmed cell death under super-resolution nanoscopy Chemical Engineering Journal 449, 137763

Mitochondrial nucleoids or mitochondrial DNA (mtDNA) encodes for a variety of enzymes and proteins that are essential for oxidative phosphorylation, mitochondrial fussion/fission and apoptotic processes. However, visulization of mtDNA dynamics in response to external stumili has not yet been achieved. Herein, we developed a fluorescent probe, named BDP, that is capable of specifically bind to mtDNA in vitro and in living cells, without interfering mitochondrial functions. Its large Stokes-Shift and red-emission tail render its suitability for stimulated emission depletion (STED) visulization of mtDNA dynamics in living cells. We sucessfully demonstrated for the first time how apoptotic induced anti-cancer drug could impact on mitochondrial nucleoids, and the morphology evolution of mtDNA from segmentation to dispersion was recorded, in a single mitochondria at nanoscale.

JTD Keywords: Dna, Mitochondrial dna (mtdna), Pyridine salt derivatives, Stimulated emission depletion (sted), Tumor


Bouzon-Arnaiz, I, Avalos-Padilla, Y, Biosca, A, Cano-Prades, O, Roman-Alamo, L, Valle, J, Andreu, D, Moita, D, Prudencio, M, Arce, EM, Munoz-Torrero, D, Fernandez-Busquets, X, (2022). The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures Bmc Biology 20, 197

Background By 2016, signs of emergence of Plasmodium falciparum resistance to artemisinin and partner drugs were detected in the Greater Mekong Subregion. Recently, the independent evolution of artemisinin resistance has also been reported in Africa and South America. This alarming scenario calls for the urgent development of new antimalarials with novel modes of action. We investigated the interference with protein aggregation, which is potentially toxic for the cell and occurs abundantly in all Plasmodium stages, as a hitherto unexplored drug target in the pathogen. Results Attempts to exacerbate the P. falciparum proteome's propensity to aggregation by delivering endogenous aggregative peptides to in vitro cultures of this parasite did not significantly affect their growth. In contrast, protein aggregation inhibitors clearly reduced the pathogen's viability. One such compound, the bis(styrylpyridinium) salt YAT2150, exhibited potent antiplasmodial activity with an in vitro IC50 of 90 nM for chloroquine- and artemisinin-resistant lines, arresting asexual blood parasites at the trophozoite stage, as well as interfering with the development of both sexual and hepatic forms of Plasmodium. At its IC50, this compound is a powerful inhibitor of the aggregation of the model amyloid beta peptide fragment 1-40, and it reduces the amount of aggregated proteins in P. falciparum cultures, suggesting that the underlying antimalarial mechanism consists in a generalized impairment of proteostasis in the pathogen. YAT2150 has an easy, rapid, and inexpensive synthesis, and because it fluoresces when it accumulates in its main localization in the Plasmodium cytosol, it is a theranostic agent. Conclusions Inhibiting protein aggregation in Plasmodium significantly reduces the parasite's viability in vitro. Since YAT2150 belongs to a novel structural class of antiplasmodials with a mode of action that potentially targets multiple gene products, rapid evolution of resistance to this drug is unlikely to occur, making it a promising compound for the post-artemisinin era.

JTD Keywords: amyloid pan-inhibitors, antimalarial drugs, malaria, plasmodium falciparum, protein aggregation, Amyloid formation, Amyloid pan-inhibitors, Antimalarial drugs, Colocalization, Cytosolic delivery, Derivatives, Disease, Drug, In-vitro, Malaria, Mechanism, Plasmodium falciparum, Polyglutamine, Protein aggregation, Yat2150


Zeinali, R, del Valle, LJ, Franco, L, Yousef, I, Rintjema, J, Aleman, C, Bravo, F, Kleij, AW, Puiggali, J, (2022). Biobased Terpene Derivatives: Stiff and Biocompatible Compounds to Tune Biodegradability and Properties of Poly(butylene succinate) Polymers 14, 161

Different copolymers incorporating terpene oxide units (e.g., limonene oxide) have been evaluated considering thermal properties, degradability, and biocompatibility. Thus, polycarbonates and polyesters derived from aromatic, monocyclic and bicyclic anhydrides have been considered. Furthermore, ring substitution with myrcene terpene has been evaluated. All polymers were amorphous when evaluated directly from synthesis. However, spherulites could be observed after the slow evaporation of diluted chloroform solutions of polylimonene carbonate, with all isopropene units possessing an R configuration. This feature was surprising considering the reported information that suggested only the racemic polymer was able to crystallize. All polymers were thermally stable and showed a dependence of the maximum degradation rate temperature (from 242 °C to 342 °C) with the type of terpene oxide. The graduation of glass transition temperatures (from 44 °C to 172 °C) was also observed, being higher than those corresponding to the unsubstituted polymers. The chain stiffness of the studied polymers hindered both hydrolytic and enzymatic degradation while a higher rate was detected when an oxidative medium was assayed (e.g., weight losses around 12% after 21 days of exposure). All samples were biocompatible according to the adhesion and proliferation tests performed with fibroblast cells. Hydrophobic and mechanically consistent films (i.e., contact angles between 90° and 110°) were obtained after the evaporation of chloroform from the solutions, having different ratios of the studied biobased polyterpenes and poly(butylene succinate) (PBS). The blend films were comparable in tensile modulus and tensile strength with the pure PBS (e.g., values of 330 MPa and 7 MPa were determined for samples incorporating 30 wt.% of poly(PA-LO), the copolyester derived from limonene oxide and phthalic anhydride. Blends were degradable, biocompatible and appropriate to produce oriented-pore and random-pore scaffolds via a thermally-induced phase separation (TIPS) method and using 1,4-dioxane as solvent. The best results were attained with the blend composed of 70 wt.% PBS and 30 wt.% poly(PA-LO). In summary, the studied biobased terpene derivatives showed promising properties to be used in a blended form for biomedical applications such as scaffolds for tissue engineering.

JTD Keywords: alternating copolymerization, biobased materials, biodegradability, composites, crystallization, cyclohexene oxide, induced phase-separation, limonene oxide, mechanical-properties, polyesters, scaffolds, spherulites, terpene derivatives, thermal properties, thermally-induced phase separation, Acetone, Bio-based, Bio-based materials, Biobased materials, Biocompatibility, Biodegradability, Butenes, Cell culture, Chlorine compounds, Degradation, Evaporation, Glass transition, Limonene oxide, Monoterpenes, Phase separation, Poly (butylenes succinate), Polybutylene succinate, Property, Ring-opening copolymerization, Scaffolds, Spheru-lites, Tensile strength, Terpene derivatives, Thermal properties, Thermally induced phase separation, Thermally-induced phase separation, Thermally?induced phase separation, Thermodynamic properties, Thermogravimetric analysis


Abramov, A, Maiti, B, Keridou, I, Puiggalí, J, Reiser, O, Díaz, DD, (2021). A pH-Triggered Polymer Degradation or Drug Delivery System by Light-Mediated Cis/Trans Isomerization of o-Hydroxy Cinnamates Macromolecular Rapid Communications 42, 2100213

A new methodology for the pH-triggered degradation of polymers or for the release of drugs under visible light irradiation based on the cyclization of ortho-hydroxy-cinnamates (oHC) to coumarins is described. The key oHC structural motif can be readily incorporated into the rational design of novel photocleavable polymers via click chemistry. This main-chain moiety undergoes a fast photocleavage when irradiated with 455 nm light provided that a suitable base is added. A series of polyethylene glycol-alt-ortho-hydroxy cinnamate (polyethylene glycol (PEG)(n)-alt-oHC)-based polymers are synthesized and the time-dependent visible-light initiated cleavage of the photoactive monomer and polymer is investigated in solution by a variety of spectroscopic and chromatographic techniques. The photo-degradation behavior of the water-soluble poly(PEG(2000)-alt-oHC) is investigated within a broad pH range (pH = 2.1-11.8), demonstrating fast degradation at pH 11.8, while the stability of the polymer is greatly enhanced at pH 2.1. Moreover, the neat polymer shows long-term stability under daylight conditions, thus allowing its storage without special precautions. In addition, two water-soluble PEG-based drug-carrier molecules (mPEG(2000)-oHC-benzhydrol/phenol) are synthesized and used for drug delivery studies, monitoring the process by UV-vis spectroscopy in an ON/OFF intermittent manner.

JTD Keywords: coumarins, drug delivery, e/z-double bond isomerization, o-hydroxy cinnamates, polymer degradation, Aliphatic compounds, Antioxidant activity, Antitumor, Chromatographic techniques, Chromatography, Cis/trans isomerization, Controlled drug delivery, Coumarin derivatives, Coumarins, Drug delivery, Drug delivery system, E/z-double bond isomerization, Films, Hydrogels, Image enhancement, Light, Long term stability, O-hydroxy cinnamates, Particles, Photoactive monomers, Photodegradation, Polyethylene glycols, Polyethylenes, Polymer degradation, Responsive polymers, Salts, Structural motifs, Synthesis (chemical), Targeted drug delivery, Visible light photocatalysis, Visible-light irradiation


Darwish, Nadim., Aragonès, A. C., Darwish, T., Ciampi, S., Díez-Pérez, I., (2014). Multi-responsive photo- and chemo-electrical single-molecule switches Nano Letters 14, (12), 7064-7070

Incorporating molecular switches as the active components in nanoscale electrical devices represents a current challenge in molecular electronics. It demands key requirements that need to be simultaneously addressed including fast responses to external stimuli and stable attachment of the molecules to the electrodes while mimicking the operation of conventional electronic components. Here, we report a single-molecule switching device that responds electrically to optical and chemical stimuli. A light pointer or a chemical signal can rapidly and reversibly induce the isomerization of bifunctional spiropyran derivatives in the bulk reservoir and, consequently, switch the electrical conductivity of the single-molecule device between a low and a high level. The spiropyran derivatives employed are chemically functionalized such that they can respond in fast but practical time scales. The unique multistimuli response and the synthetic versatility to control the switching schemes of this single-molecule device suggest spiropyran derivatives as key candidates for molecular circuitry.

JTD Keywords: Molecular Electronics, Multi-Responsive Molecular Switches, Photo- and Chemo-Switches Spiropyran, Single-Molecule Conductance, STM Break-Junction, Electronic equipment, Isomerization, Molecular electronics, Photochromism, Electrical conductivity, Electronic component, Molecular switches, Single-molecule conductances, Single-molecule devices, Spiropyran derivatives, Spiropyrans, STM Break-Junction, Molecules