http://hdl.handle.net/10366/149436 Fri, 01 May 2026 05:57:51 GMT 2026-05-01T05:57:51Z http://hdl.handle.net/10366/170989 [ES] Durante los últimos años las infecciones fúngicas invasivas (IFI) han adquirido una importancia creciente en el ámbito hospitalario. En muchas ocasiones se presentan como infecciones oportunistas y comportan una elevada morbimortalidad, especialmente en algunos grupos de pacientes inmunodeprimidos como aquellos con enfermedades oncohematológicas, autoinmunes e inflamatorias, o los receptores de trasplantes de progenitores hematopoyéticos y de órgano sólido. Aunque los avances en la terapéutica han permitido disminuir de forma muy significativa la mortalidad y mejorar la calidad de vida, han supuesto un incremento del número de pacientes susceptibles al desarrollo de una IFI (1). La mejora de los métodos diagnósticos, microbiológicos y no microbiológicos (tomografía computarizada de alta resolución, galactomanano, betaglucano, etc.) ha contribuido al aumento del número de casos diagnosticados, así como a un diagnóstico más precoz. Esto, junto con la introducción de nuevos antifúngicos ha permitido que el pronóstico de las IFI haya mejorado en los últimos años (2). No obstante, estas infecciones continúan siendo un reto para los clínicos. Esta tesis tiene como objetivo la implantación en la práctica clínica de un programa de monitorización farmacocinética de antifúngicos del grupo de los triazoles en pacientes que reciben estos fármacos como profilaxis o tratamiento de IFI permite optimizar el tratamiento, aumentando la eficacia y reduciendo la toxicidad. Las decisiones terapéuticas basadas no sólo en la respuesta clínica y microbiológica, sino también en los resultados de la TDM de triazoles, contribuyen a mejorar los resultados clínicos a corto y largo plazo. Thu, 01 Jan 2026 00:00:00 GMT http://hdl.handle.net/10366/170989 2026-01-01T00:00:00Z http://hdl.handle.net/10366/170753 [EN] The pharmaceutical industry is considered one of the industries with the largest carbon footprint. Concern about the impact of the chemical industry on the environment gave rise to a movement now known as Green Chemistry or Sustainable Chemistry. Its goal is to move from traditional methods, which focus on chemical yields, to cleaner methods and alternatives. Many of the chemical processes used to produce pharmaceuticals still rely on traditional synthetic methods. The application of more sustainable methods is of particular interest for the synthesis of structures with bioactivity, such as quinolines. Quinoline is a structural unit present in natural and pharmaceutical products. Since its discovery in the 19th century, numerous medicinal properties have been described for compounds with a quinoline skeleton. First against malaria and then against many other diseases, such as other parasitic and bacterial infections, HIV and cancer. Consequently, many synthetic methods have been developed to obtain the quinoline ring as well as its subsequent application in other strategies to improve its biological activity, such as hybridization. Hybridization, used in medicinal chemistry, allows combining several bioactive chemical structures by means of connectors or spacers in a single molecule and is used with the aim of improving their pharmacological properties. In previous projects, the research group applied this strategy in the synthesis of hybrid compounds of naphthohydroquinones and podophyllotoxin. The subsequent biological evaluation of these compounds showed good results against cancer. In this thesis the synthesis of quinolines, such as 4-carboxyquinolines, with possible bioactivity against diseases like cancer, was proposed using methods that are in accordance with the principles of green chemistry. Thus, this project focused on the following aspects of green chemistry: use of less toxic solvents and reagents, atomic efficiency, multicomponent synthesis and use of catalysts. The obtained quinoline compounds were used to prepare new hybrid-type compounds with a naphthohydroquinone. The naphthohydroquinone moiety was synthesized based on the method previously optimized by the group from myrcene and p-benzoquinone. The two moieties were then linked through several linkers with ester bonds using a,w-dibromo-reagents or with amide bonds using diamines. Aiming to obtain new hybrid compounds, it was also explored the synthesis of bisquinolines, both symmetrical and asymmetrical. In addition, in this work, a new research line was opened in the group with the long-term objective of a possible application of dextran-quinoline conjugates in controlled and targeted drug delivery systems. Different binding methods between the obtained quinolines and dextran were evaluated, and it was obtained one of these quinoline-dextran conjugates. The obtained hybrid compounds and their precursors were further evaluated considering their biological activity. Antioxidant properties were evaluated using the DPPH method, where one hybrid compound showed better results than its precursors. Cytotoxic activity was carried out using MTT method against HT-29, H460 and MCF-7 cell lines. It was observed that hybridization improves the compounds activity, since all compounds showed cytotoxicity in the order of μM for at least one cell line. ADME prediction of the most promising compounds allowed to conclude that, in general, compounds from the same family present the same pharmaceutical characteristics. In summary, in this thesis it has been possible to obtain 4-carboxyquinolines by a new method. The obtained quinolines were used to synthesize quinoline-naphthohydroquinone hybrid compounds and bisquinolines, as well as, for exploring the possibility of dextranquinolines conjugates. In the subsequent biological evaluation, hybrid compounds have presented not only better antioxidant capacity but also an improvement in activity against the tested cell lines, showing hybridization as a good strategy to improve pharmacological properties. Wed, 01 Jan 2025 00:00:00 GMT http://hdl.handle.net/10366/170753 2025-01-01T00:00:00Z http://hdl.handle.net/10366/169965 [ES] Dentro de la superfamilia de las quinesinas, un grupo de proteínas motoras que se desplazan a través de los microtúbulos, se encuentran las quinesinas mitóticas, presentes en todas las células eucariotas. Entre ellas, destaca la quinesina 5 humana, también conocida como Eg5. Esta proteína motora es fundamental para el ensamblaje y mantenimiento del huso mitótico bipolar durante la prometafase. Cuando se inhibe, la mitosis celular se detiene, lo que provoca la muerte celular. Dado que no se conocen otras funciones de Eg5, esta proteína constituye una diana prometedora para el desarrollo de nuevos fármacos antimitóticos, los cuales evitarían la neurotoxicidad asociada a los que actualmente se utilizan en clínica. En este trabajo se ha llevado a cabo la síntesis y caracterización de 1H-1,2,3-triazoles trisustituidos en las posiciones 1, 4 y 5. Estos triazoles han sido diseñados para interactuar con el sitio L5 de Eg5. Además, se han obtenido sus intermedios de síntesis: azidas bencílicas y las chalconas y heterochalconas; dímeros de heterochalconas con estructura de ciclobutano; enaminas secundarias formadas en la síntesis de triazoles; y compuestos de adición conjugada a las heterochalconas. También se ha investigado la reactividad y el mecanismo de reacción de diversas heterochalconas frente a la cicloadición [2+2] fotoinducida. La potencial actividad antimitótica de los compuestos obtenidos se ha evaluado mediante la determinación de la citotoxicidad de 31 triazoles, 3 enaminas, 3 ciclobutanos, 17 heterochalconas y 1 compuesto de adición conjugada a heterochalcona frente a las líneas tumorales de mieloma MM.1S y RPMI8226. Los compuestos que mostraron una mayor citotoxicidad fueron las heterochalconas, especialmente aquellas con anillos de piridina y, en particular, cuando el fragmento benzoilo contiene átomos de flúor. Asimismo, dado que las quinesinas también se encuentran en parásitos, se ha evaluado la actividad tripanocida de 30 triazoles, 3 enaminas, 3 ciclobutanos, 17 heterochalconas y 1 compuesto de adición conjugada a heterochalcona sobre epimastigotes y amastigotes de Trypanosoma cruzi, así como su citotoxicidad sobre células Vero, hospedadoras de amastigotes. En este caso, los triazoles demostraron una mayor potencia tripanocida y selectividad, destacando especialmente los triazoles que contienen un fragmento indolilo. Finalmente, Un análisis preliminar de la selectividad de los compuestos mostró resultados prometedores, ya que aquellos con mayor citotoxicidad fueron selectivos hacia las células tumorales en comparación con las no tumorales.; [EN] Within the kinesin superfamily, a group of motor proteins that move along microtubules, there is a subgroup known as mitotic kinesins, which are found in all eukaryotic cells. Among them, human kinesin-5, also referred to as Eg5, plays a particularly important role. This motor protein is essential for the assembly and maintenance of the bipolar mitotic spindle during prometaphase. Inhibiting Eg5 disrupts cell division, ultimately leading to cell death. Since no other cellular functions have been attributed to Eg5, it represents a promising target for the development of new antimitotic drugs that could avoid the neurotoxicity often associated with current antimitotic treatments. In this study, a series of 1H-1,2,3-triazoles substituted at positions 1, 4, and 5 were synthesized and characterized. These compounds were specifically designed to interact with the L5 binding site of Eg5. Alongside the triazoles, their synthetic intermediates, benzyl azides, chalcones, and heterochalcones, were also prepared. Cyclobutane-structured heterochalcone dimers, secondary enamines formed during triazole synthesis, and conjugate addition products to heterochalcones were also obtained. Furthermore, the reactivity and reaction mechanisms of [2+2] photoinduced cycloaddition of several heterochalcones were also studied. To assess the potential antimitotic activity of these compounds, cytotoxicity tests were conducted on multiple series: 31 triazoles, 3 enamines, 3 cyclobutanes, 17 heterochalcones, and 1 conjugate addition product to heterochalcone. These were tested against the MM.1S and RPMI8226 multiple myeloma cell lines. Heterochalcones showed the highest cytotoxicity, particularly those containing pyridine rings and, more notably, those with fluorine atoms on the benzoyl moiety. Given that kinesins are also present in parasites, the trypanocidal activity of 30 triazoles, 3 enamines, 3 cyclobutanes, 17 heterochalcones, and 1 conjugate addition compound to heterochalcone was evaluated against both epimastigote and amastigote forms of Trypanosoma cruzi, along with their cytotoxicity on Vero cells (the host cells of amastigotes). In this context, the triazoles displayed stronger trypanocidal activity and better selectivity, with indole-containing triazoles standing out. Lastly, a preliminary analysis of compound selectivity yielded promising results, with the most cytotoxic compounds showing a higher selectivity toward tumor cells compared to non-tumor cells. Wed, 01 Jan 2025 00:00:00 GMT http://hdl.handle.net/10366/169965 2025-01-01T00:00:00Z http://hdl.handle.net/10366/169325 Fermented foods have been used for several years all over the world, due to their unique nutritional characteristics and because fermentation promotes conservation and food security. Moreover, fermented foods and beverages have a strong impact on human gut microbiota. Papaya is the fruit of the Carica papaya plant, traditionally used as a medicinal fruit, but there are also references to the use of the fermented form of this fruit. The main purpose of this review is to provide an improved understanding of fermented papaya nutritional and health applications. A literature search was conducted in the PubMed and Google Scholar databases. Both in vitro and in vivo studies were included. According to the retrieved studies, fermented papaya has proven to be an excellent antioxidant and an excellent nutraceutical adjuvant in combined therapies against several diseases, such as Alzheimer’s disease, allergic reactions, anticancer activity, and anemias. Therefore, it is concluded that fermented papaya has many benefits for human health and can be used as prevention or aid in the treatment of various diseases. Wed, 16 Feb 2022 00:00:00 GMT http://hdl.handle.net/10366/169325 2022-02-16T00:00:00Z http://hdl.handle.net/10366/169083 Background The genus Cytinus, recognised as one of the most enigmatic in the plant kingdom, has garnered attention for its bioactive potential, particularly its skin anti-ageing properties. Despite this recognition, much remains to be accomplished regarding deciphering and isolating its most active compounds. Hypothesis This study aimed to identify the compounds responsible for C. hypocistis skin anti-ageing potential. Methods Using multivariate analysis, a biochemometric approach was applied to identify the discriminant metabolites by integrating extracts' chemical profile (Liquid Chromatography–High-Resolution Mass Spectrometry, LCsingle bondHRMS) and bioactive properties. The identified bioactive metabolite was structurally elucidated by 1D and 2D Nuclear Magnetic Resonance (NMR). Results Among the studied bioactivities, the anti-elastase results exhibited a significant variation among the samples from different years. After the biochemometric analysis, the compound 2,3:4,6-bis(hexahydroxydiphenoyl)glucose, with a molecular mass of 784.075 Da, was structurally elucidated as the discriminant feature responsible for the outstanding human neutrophil elastase inhibition. Remarkably, the subfraction containing this compound exhibited a tenfold improvement in neutrophil elastase inhibition efficacy compared to the crude extract; its effectiveness fell within the same range as SPCK, a potent irreversible neutrophil elastase inhibitor. Moreover, this subfraction displayed no cytotoxicity or phototoxicity and excellent efficacy for the tested anti-ageing properties. Conclusions Hydrolysable tannins were confirmed as the metabolites behind C. hypocistis skin anti-ageing properties, effectively mitigating critical molecular mechanisms that influence the phenotypically distinct ageing clinical manifestations. Pedunculagin was particularly effective in inhibiting neutrophil elastase, considered one of the most destructive enzymes in skin ageing. Mon, 01 Jul 2024 00:00:00 GMT http://hdl.handle.net/10366/169083 2024-07-01T00:00:00Z http://hdl.handle.net/10366/169081 Tannins are a class of phenolic compounds commonly found in plants and studied for their bioactive and inhibitory enzyme properties. Cytinus hypocistis (L.) L. is a wild edible parasitic plant whose biological properties have been correlated with its high tannin content. Thus, studying the extraction of tannins from C. hypocistis will give comprehensive clues to enhance the recovery of these high added-value bioactive compounds. The present work applied Response Surface Methodology (RSM) to optimise tannins extraction using Heat-Assisted (HAE) and Ultrasound-Assisted (UAE) methods. Two three-factor Rotatable Central Composite Designs were used to assess the linear, quadratic, and interaction effects of the independent variables on the target responses. The obtained results from both extraction systems revealed high ethanol percentages as the critical factor in increasing tannin content. The optimum global processing conditions predicted by the polynomial models were 95.1 min, 46.4 °C, and 74.3% ethanol for HAE; and 18.7 min, 327.4 W, and 69.3% ethanol for UAE. Following these conditions, 200 mg and 178 mg of total tannins per g of extract were recovered using HAE and UAE, correspondingly. Although HAE presented a higher final response, the UAE stood out as a time-saving technique. Wed, 01 Dec 2021 00:00:00 GMT http://hdl.handle.net/10366/169081 2021-12-01T00:00:00Z http://hdl.handle.net/10366/169079 Cytinus hypocistis whole plant and its three different parts (petals, stalks, and nectar) were chemically characterised and their biological properties evaluated. A total of 17 phenolic compounds were identified, being galloyl-bis-HHDP-glucose the most abundant. All the tested extracts showed high antioxidant capacity, with the petals exhibiting the most promising results both in the OxHLIA (IC50 = 0.279 ng/mL) and TBARS (IC50 = 0.342 ng/mL) assays. For the antidiabetic and anti-tyrosinase enzyme inhibitory assays, the stalk extract presented the lowest IC50 values, 0.039 mg/mL and 0.09 mg/mL, respectively. Regarding antibacterial activity, all tested extracts displayed broad-spectrum microbial inhibition against both Gram-positive and Gram-negative bacteria. Similarly, all extracts displayed effective anti-proliferation activity against four tested tumour cell lines (NCI–H460, HeLa, HepG2, and MCF-7), with no toxicity observed for a non-tumour cell line. Considering the anti-inflammatory activity, the petals showed the highest nitric oxide inhibition (IC50 = 127 μg/mL). These results point C. hypocistis as a promising source of health-promoting biomolecules. Sat, 01 Feb 2020 00:00:00 GMT http://hdl.handle.net/10366/169079 2020-02-01T00:00:00Z http://hdl.handle.net/10366/168864 Cytinus hypocistis (L.) L. is a comestible holoparasite with great potential for cosmeceutical application. Although its high tannin content has been associated with its bioactive and inhibitory enzyme properties, this is the first report establishing a relationship between parasite and host (Halimium lasianthum (Lam.) Greuter) phenolic profile and bioactive properties. Thus, five extracts (aerial and root extracts of non-parasited and parasited H. lasianthum and C. hypocistis) were evaluated. The tentative identification of both species comprises 39 phenolic compounds. Hydrolysable tannins and flavonoids were the main identified groups in C. hypocistis and H. lasianthum extracts, respectively. Regarding bioactivities, C. hypocistis exhibited excellent antioxidant results both in Oxidative Haemolysis (OxHLIA) and inhibition of Thiobarbituric Acid Reactive Substances Formation (TBARS). The tested extracts presented antimicrobial inhibition, anti-inflammatory activity, and effective cytotoxicity against tumour cells. C. hypocistis exhibited the lowest cytotoxicity on a non-tumour cell line. Principal Component Analysis (PCA) was a suitable approach to analyse differences among samples, explaining up to 67% of data variability and suggesting no similarities between parasite and host phenolic composition and bioactivities. Therefore, this comparative study emphasises the significance of both species as a source of biologically active compounds. Tue, 01 Feb 2022 00:00:00 GMT http://hdl.handle.net/10366/168864 2022-02-01T00:00:00Z http://hdl.handle.net/10366/168760 Ethnopharmacological relevance: Medicinal plants are rich in bioactive compounds with diverse properties that can preserve human health. Eryngium bourgatii is used in traditional medicine to purify the blood. Species of this genus have been used for their antibacterial, antitumor, antifungal or antiparasitic properties among others. Aim of the study: In this work, the antiparasitic properties against Leishmania donovani, Trypanosoma cruzi, and Plasmodium falciparum were evaluated. Materials and methods: Methyl tert-butyl ether (MTBE), dichloromethane (DCM), and ethyl acetate (EtOAc) extracts of the roots and the non-flowering aerial parts were obtained by maceration at room temperature. Some of them were partitioned with solvents of increasing polarity, specifically n-hexane (n-Hex), dichloromethane (DCM), and ethyl acetate (EA) to isolate different fractions. Growth inhibition assays were performed against the three protozoa (L. donovani, T. cruzi, and P. falciparum). The active fractions were subsequently separated by chromatography to determine the secondary metabolites responsible for the activity. In addition, GC-MS studies were performed to further analyse the composition of the extracts and fractions. Results: Regarding the roots, the MTBE extract was the most potent leishmanicidal (77.7 % inhibition at 10 μg/ mL). The activity increased in its n-Hex fraction (95.3 % inhibition), and in the DCM fraction, both leishmanicidal (93.6 %) and anti-Chagas activity (92.2 %) improved. Furanone 12, a new natural compound, was the main component of the extract and the most potent leishmanicide (96.7 %), sixteen times less than the reference drug, Amphotericin B. 11-Acetoxyfalcarindiol (19) was the most potent anti-Chagas (89.1 % inhibition). Regarding the aerial parts, the DCM extract was the most potent leishmanicide (83.3 %), which improved in its DCM fraction (95.7 %), mainly attributed to compound 12. The DCM fraction of the MTBE extract produced the best antichagasic result (93.3 % inhibition), attributed to falcarindiol (17). Practically, the same compounds were identified in the roots as in the aerial parts, but in different proportions. Nine pure compounds were isolated; 34 were identified in roots and 37 in the aerial parts by GC-MS, with alkyne compounds leading, followed by sesquiterpenes and fatty acids. Sat, 19 Apr 2025 00:00:00 GMT http://hdl.handle.net/10366/168760 2025-04-19T00:00:00Z http://hdl.handle.net/10366/168759 Monoaminooxidases (MAOs) are important targets for drugs used in the treatment of neurological and psychiatric disorders and particularly on Parkinson’s Disease (PD). Compounds containing a trans-stilbenoid skeleton have demonstrated good selective and reversible MAO-B inhibition. Here, twenty-two (Z)-3-benzylidenephthalides (benzalphthalides, BPHs) displaying a trans-stilbenoid skeleton have been synthesised and evaluated as inhibitors of the MAO-A and MAO-B isoforms. Some BPHs have selectively inhibited MAO-B, with IC50 values ranging from sub-nM to μM. The most potent compound with IC50 = 0.6 nM was the 3′,4′-dichloro-BPH 16, which showed highly selective and reversible MAO-B inhibitory activity. Furthermore, the most selective BPHs displayed a significant protection against the apoptosis, and mitochondrial toxic effects induced by 6-hydroxydopamine (6OHDA) on SH-SY5Y cells, used as a cellular model of PD. The results of virtual binding studies on the most potent compounds docked in MAO-B and MAO-A were in agreement with the potencies and selectivity indexes found experimentally. Additionally, related to toxicity risks, drug-likeness and ADME properties, the predictions found for the most relevant BPHs in this research were within those ranges established for drug candidates. Sun, 03 Mar 2024 00:00:00 GMT http://hdl.handle.net/10366/168759 2024-03-03T00:00:00Z http://hdl.handle.net/10366/168756 Tuberculosis remains a major public health problem and one of the top ten causes of death worldwide. The alarming increase in multidrug-resistant and extensively resistant variants (MDR, pre-XDR, and XDR) makes the disease more difficult to treat and control. New drugs that act against MDR/XDR strains are needed for programs to contain this major epidemic. The present study aimed to evaluate new compounds related to dihydro-sphingosine and ethambutol against sensitive and pre-XDR Mycobacterium strains, as well as to characterize the pharmacological activity through in vitro and in silico approaches in mmpL3 protein. Of the 48 compounds analyzed, 11 demonstrated good to moderate activity on sensitive and MDR Mycobacterium tuberculosis (Mtb), with a Minimum Inhibitory Concentration (MIC) ranging from 1.5 to 8 μM. They presented 2 to 14 times greater potency of activity when compared to ethambutol in pre-XDR strain, and demonstrated a selectivity index varying between 2.21 and 82.17. The substance 12b when combined with rifampicin, showed a synergistic effect (FICI = 0.5) on sensitive and MDR Mtb. It has also been shown to have a concentration-dependent intracellular bactericidal effect, and a time-dependent bactericidal effect in M. smegmatis and pre-XDR M. tuberculosis. The binding mode of the compounds in its cavity was identified through molecular docking and using a predicted structural model of mmpL3. Finally, we observed by transmission electron microscopy the induction of damage to the cell wall integrity of M. tuberculosis treated with the substance 12b. With these findings, we demonstrate the potential of a 2-aminoalkanol derivative to be a prototype substance and candidate for further optimization of molecular structure and anti-tubercular activity in preclinical studies. Thu, 05 Oct 2023 00:00:00 GMT http://hdl.handle.net/10366/168756 2023-10-05T00:00:00Z http://hdl.handle.net/10366/168755 The deficit of effective treatments for Chagas disease has led to searching for new substances with therapeutic potential. Natural products possess a wide variety of chemical structural motifs and are thus a valuable source of diverse lead compounds for the development of new drugs. Castanedia santamartensis is endemic to Colombia, and local indigenous communities often use it to treat skin sores from leishmaniasis; however, its mechanism of action against the infective form of Trypanosoma cruzi has not been determined. Thus, we performed chemical and biological studies of two alcoholic leaf extracts of C. santamartensis to identify their active fractions and relate them to a trypanocidal effect and evaluate their mechanism of action. Alcoholic extracts were obtained through cold maceration at room temperature and fractionated using classical column chromatography. Both ethanolic and methanolic extracts displayed activity against T. cruzi. Chemical studies revealed that kaurenoic acid was the major component of one fraction of the methanolic extract and two fractions of the ethanolic extract of C. santamartensis leaves. Moreover, caryophyllene oxide, kaurenol, taraxasterol acetate, pentadecanone, and methyl and ethyl esters of palmitate, as well as a group of phenolic compounds, including ferulic acid, caffeic acid, chlorogenic acid, myricetin, quercitrin, and cryptochlorogenic acid were identified in the most active fractions. Kaurenoic acid and the most active fractions CS400 and CS402 collapsed the mitochondrial membrane potential in trypomastigotes, demonstrating for the first time the likely mechanism against T. cruzi, probably due to interactions with other components of the fractions. Fri, 15 Apr 2022 00:00:00 GMT http://hdl.handle.net/10366/168755 2022-04-15T00:00:00Z http://hdl.handle.net/10366/168744 Gastrointestinal nematode infections are the main diseases in herds of small ruminants. Resistance to the main established drugs has become a worldwide problem. The purpose of this study is to obtain and evaluate the in vitro ovicidal and larvicidal activity of some 2-phenylbenzimidazole derivatives on susceptible and resistant strains of Teladorsagia circumcincta. Compounds were prepared by known procedures from substituted o-phenylenediamines and arylaldehydes or intermediate sodium 1-hydroxyphenylmethanesulfonate derivatives. Egg Hatch Test (EHT), Larval Mortality Test (LMT) and Larval Migration Inhibition Test (LMIT) were used in the initial screening of compounds at 50 μM concentration, and EC50 values were determined for the most potent compounds. Cytotoxicity evaluation of compounds was conducted on human Caco-2 and HepG2 cell lines to calculate their Selectivity Indexes (SI). At 50 μM concentration, nine out of twenty-four compounds displayed more than 98% ovicidal activity on a susceptible strain, and four of them showed more than 86% on one resistant strain. The most potent ovicidal benzimidazole (BZ) 3 showed EC50 = 6.30 μM, for the susceptible strain, while BZ 2 showed the lowest EC50 value of 14.5 μM for the resistant strain. Docking studies of most potent compounds in a modelled Teladorsagia tubulin indicated an inverted orientation for BZ 1 in the colchicine binding site, probably due to its fair interaction with glutamic acid at codon 198, which could justify its inactivity against the resistant strain of T. circumcincta. Tue, 15 Dec 2020 00:00:00 GMT http://hdl.handle.net/10366/168744 2020-12-15T00:00:00Z http://hdl.handle.net/10366/168231 Introduction: Drug development has traditionally used mathematical models to predict formulation behavior. Objective: Building artificial neural networks for the drug release evaluation of drug delivery systems using sustained-release metronidazole-coated colonic hydrophilic matrices as a model. Methods: The technological factors associated with the biopharmaceutical performance of hydrophilic metronidazole matrices were evaluated using a quality by design approach (QbD). The developed neural network includes variables related to the technological process for producing the matrices. These are related to the materials used, such as the type and viscosity of core polymers, the type of coating agent, or the matrix production process, such as the mixing time of core materials or the percentage of the coating agent. The output variables of the neural network were the percentages of drug released in vitro at 1, 6, 12, and 24 h and the mean dissolution time of the matrix. An iterative quasi-Newton method was used to train the artificial neural network. Results: A neural network with excellent prediction capacity allows selecting the technological variables with the greatest influence on the % of drug dissolved: the type of coating agent used and the percentage of the total weight increase after coating for 1 h and 6 h of drug release and also the viscosity of the HPMC for 12 and 24 h. Conclusions: The optimized neural network demonstrated an excellent predictive capacity for in vitro drug dissolution profiles, allowing the use of this type of methodology based on artificial intelligence methods in the optimization of drug delivery systems. Mon, 10 Nov 2025 00:00:00 GMT http://hdl.handle.net/10366/168231 2025-11-10T00:00:00Z http://hdl.handle.net/10366/166972 Natural products are the ideal basis for the design of novel efficient molecular entities. Podophyllotoxin, a naturally occurring cyclolignan, is an example of natural product which displays a high versatility from a biological activity point of view. Based on its unique chemical structure, different derivatives have been synthesized presenting the original antitumoral properties associated with the compound, i.e., the tubulin polymerization inhibition and arising anti-topoisomerase II activity from structural modifications on the cyclolignan skeleton. In this report, we present a novel conjugate or hybrid which chemically combines both biological activities in one single molecule. Chemical design has been planned based in our lead compound, podophyllic aldehyde, as an inhibitor of tubulin polymerization, and in etoposide, an approved antitumoral drug targeting topoisomerase II. The cytotoxicity and selectivity of the novel synthetized hybrid has been evaluated in several cell lines of different solid tumors. In addition, these dual functional effects of the novel compound have been also evaluated by molecular docking approaches. Wed, 01 Jan 2020 00:00:00 GMT http://hdl.handle.net/10366/166972 2020-01-01T00:00:00Z http://hdl.handle.net/10366/166971 Podophyllotoxin is a naturally occurring cyclolignan isolated from rhizomes of Podophyllum sp. In the clinic, it is used mainly as an antiviral; however, its antitumor activity is even more interesting. While podophyllotoxin possesses severe side effects that limit its development as an anticancer agent, nevertheless, it has become a good lead compound for the synthesis of derivatives with fewer side effects and better selectivity. Several examples, such as etoposide, highlight the potential of this natural product for chemomodulation in the search for new antitumor agents. This review focuses on the recent chemical modifications (2017–mid-2023) of the podophyllotoxin skeleton performed mainly at the C-ring (but also at the lactone D-ring and at the trimethoxyphenyl E-ring) together with their biological properties. Special emphasis is placed on hybrids or conjugates with other natural products (either primary or secondary metabolites) and other molecules (heterocycles, benzoheterocycles, synthetic drugs, and other moieties) that contribute to improved podophyllotoxin bioactivity. In fact, hybridization has been a good strategy to design podophyllotoxin derivatives with enhanced bioactivity. The way in which the two components are joined (directly or through spacers) was also considered for the organization of this review. This comprehensive perspective is presented with the aim of guiding the medicinal chemistry community in the design of new podophyllotoxin-based drugs with improved anticancer properties. Sun, 01 Jan 2023 00:00:00 GMT http://hdl.handle.net/10366/166971 2023-01-01T00:00:00Z