RESUMEN
In the present study, a series of chalcones and their B-aryl analogues were prepared and evaluate as inhibitors of myeloperoxidase (MPO) chlorinating activity, using in vitro and ex vivo assays. Among these, B-thiophenyl chalcone (analogue 9) demonstrated inhibition of in vitro and ex vivo MPO chlorinating activity, exhibiting IC50 value of 0.53 and 19.2 µM, respectively. Potent ex vivo MPO inhibitors 5, 8 and 9 were not toxic to human neutrophils at 50 µM, as well as displayed weak 2,2-diphenyl-1-pycrylhydrazyl radical (DPPHâ¢) and hypochlorous acid (HOCl) scavenger abilities. Docking simulations indicated binding mode of MPO inhibitors, evidencing hydrogen bonds between the amino group at 4'position (ring A) of chalcones with Gln91, Asp94, and Hys95 MPO residues. In this regard, the efficacy and low toxicity promoted aminochalcones and arylic analogues to the rank of hit compounds in the search for new non-steroidal anti-inflammatory compounds.
Asunto(s)
Chalconas/síntesis química , Chalconas/farmacología , Peroxidasa/antagonistas & inhibidores , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Depuradores de Radicales Libres , Humanos , Modelos Moleculares , Simulación de Dinámica Molecular , Estructura Molecular , Neutrófilos/efectos de los fármacos , Conformación ProteicaRESUMEN
Considering that cancer continues to be an important cause of death worldwide, several conventional anticancer treatments are widely used. However, most of them display low selectivity against malignant cells and induce many adverse side effects. Among these, the use of therapies based on 5-Fluorouracil (5-FU) has been one of the most efficient, with a broad-spectrum. Due to these circumstances, various modifications of 5-FU have been developed to improve drug delivery and reduce side effects. Among the optimization strategies, modifications of 5-FU at N1 or N3 position are made, usually including the incorporation of pharmacologically active compounds with anticancer activity (called hybrid molecule) and functionalization with other groups of compounds (called conjugates). Several studies have been conducted in the search for new alternative therapies against cancer. Many of them have evidenced that hybrid compounds exhibit good anticancer activity, which has emerged as a promising strategy in this field of drug discovery and development. Furthermore, the binding of 5-FU to amino acids, peptides, phospholipids, polymers, among others, improves metabolic stability and absorption. This review highlights the potential of hybrids and derivatives based on 5-FU as a scaffold for the development of antitumor agents. Besides, it also presents a detailed description of the different strategies employed to design and synthesized these compounds, together with their biological activities and structure-activity relationship (SAR) analysis.
Asunto(s)
Antineoplásicos , Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Descubrimiento de Drogas , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
Malaria is still a life-threatening public health issue, and the upsurge of resistant strains requires continuous generation of active molecules. In this work, 35 sulfonylhydrazone derivatives were synthesized and evaluated against Plasmodium falciparum chloroquine-sensitive (3D7) and resistant (W2) strains. The most promising compound, 5b, had an IC50 of 0.22 µM against W2 and was less cytotoxic and 26-fold more selective than chloroquine. The structure-activity relationship model, statistical analysis and molecular modeling studies suggested that antiplasmodial activity was related to hydrogen bond acceptor count, molecular weight and partition coefficient of octanol/water and displacement of frontier orbitals to the heteroaromatic ring beside the imine bond. This study demonstrates that the synthesized molecules with a simple scaffold allow the hit-to-lead process for new antimalarials to commence.
Asunto(s)
Antimaláricos/farmacología , Hidrazonas/química , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cloroquina/farmacología , Cloroquina/uso terapéutico , Resistencia a Medicamentos/efectos de los fármacos , Humanos , Hidrazonas/farmacología , Estadios del Ciclo de Vida/efectos de los fármacos , Aprendizaje Automático , Malaria/tratamiento farmacológico , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/crecimiento & desarrollo , Teoría Cuántica , Relación Estructura-ActividadRESUMEN
Aim: Compounds that block enzyme activity can kill pathogens and help develop effective and safe drugs for Chagas disease and leishmaniasis. Materials & methods: A library of nonpeptidic nitrile-based compounds was synthesized and had their inhibitory affinity tested against cruzain, Leishmania mexicana cysteine protease B and cathepsin L. Isothermal titration calorimetry experiments and molecular simulations were performed for selected compounds to obtain thermodynamic fingerprints and identify main interactions and putative modes of binding with cruzain. Results: The derivatives provided increased affinity against all enzymes compared with the lead, and thermodynamic and computational studies showed improved thermodynamic properties and a possible different mode of binding. Conclusion: Our studies culminated in 1b, a compound 60-fold more potent in cruzain than its lead that also showed entropic and enthalpic contributions favorable to Gibbs binding energy.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Cisteína Endopeptidasas/metabolismo , Inhibidores de Cisteína Proteinasa/síntesis química , Flúor/química , Leishmaniasis/tratamiento farmacológico , Nitrilos/síntesis química , Catepsina L/metabolismo , Inhibidores de Cisteína Proteinasa/farmacología , Descubrimiento de Drogas , Humanos , Leishmania mexicana/metabolismo , Modelos Moleculares , Nitrilos/farmacología , Proteínas Protozoarias/metabolismo , Relación Estructura-Actividad , TermodinámicaRESUMEN
BACKGROUND: Moniliophthora perniciosa (Stahel) Aime & Phillips-Mora is the causal agent of witches' broom disease (WBD) of cocoa (Theobroma cacao L.) and a threat to the chocolate industry. The membrane-bound enzyme alternative oxidase (AOX) is critical for M. perniciosa virulence and resistance to fungicides, which has also been observed in other phytopathogens. Notably AOX is an escape mechanism from strobilurins and other respiration inhibitors, making AOX a promising target for controlling WBD and other fungal diseases. RESULTS: We present the first study aimed at developing novel fungal AOX inhibitors. N-Phenylbenzamide (NPD) derivatives were screened in the model yeast Pichia pastoris through oxygen consumption and growth measurements. The most promising AOX inhibitor (NPD 7j-41) was further characterized and displayed better activity than the classical AOX inhibitor SHAM in vitro against filamentous fugal phytopathogens, such as M. perniciosa, Sclerotinia sclerotiorum and Venturia pirina. We demonstrate that 7j-41 inhibits M. perniciosa spore germination and prevents WBD symptom appearance in infected plants. Finally, a structural model of P. pastoris AOX was created and used in ligand structure-activity relationships analyses. CONCLUSION: We present novel fungal AOX inhibitors with antifungal activity against relevant phytopathogens. We envisage the development of novel antifungal agents to secure food production. © 2018 Society of Chemical Industry.
Asunto(s)
Agaricales/efectos de los fármacos , Agaricales/fisiología , Benzamidas/síntesis química , Benzamidas/farmacología , Cacao/microbiología , Proteínas Mitocondriales/antagonistas & inhibidores , Oxidorreductasas/antagonistas & inhibidores , Enfermedades de las Plantas/microbiología , Proteínas de Plantas/antagonistas & inhibidores , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Benzamidas/química , Técnicas de Química Sintética , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Relación Estructura-ActividadRESUMEN
Tuberculosis is an infection caused mainly by Mycobacterium tuberculosis. A first-line antimycobacterial drug is pyrazinamide (PZA), which acts partially as a prodrug activated by a pyrazinamidase releasing the active agent, pyrazinoic acid (POA). As pyrazinoic acid presents some difficulty to cross the mycobacterial cell wall, and also the pyrazinamide-resistant strains do not express the pyrazinamidase, a set of pyrazinoic acid esters have been evaluated as antimycobacterial agents. In this work, a QSAR approach was applied to a set of forty-three pyrazinoates against M. tuberculosis ATCC 27294, using genetic algorithm function and partial least squares regression (WOLF 5.5 program). The independent variables selected were the Balaban index (J), calculated n-octanol/water partition coefficient (ClogP), van-der-Waals surface area, dipole moment, and stretching-energy contribution. The final QSAR model (N = 32, r2 = 0.68, q2 = 0.59, LOF = 0.25, and LSE = 0.19) was fully validated employing leave-N-out cross-validation and y-scrambling techniques. The test set (N = 11) presented an external prediction power of 73%. In conclusion, the QSAR model generated can be used as a valuable tool to optimize the activity of future pyrazinoic acid esters in the designing of new antituberculosis agents.