RESUMEN
Herein a new azobenzene-substituted porphyrin molecule was synthesized, characterized and its optoelectronic properties were investigated by combining the high optoelectronic properties of porphyrin with the photosensitive properties of azobenzene. The carboxylic acid of azobenzene was covalently connected to -OH group of the porphyrin ring by using Steglich esterification. Molecular structure of the obtained azobenzene-porphyrin (8), was elucidated, by FTIR, 1 H and 13 C NMR and HRMS. After structural characterization absorption and emission, characteristics were determined in solvents that have different. And also, optical and fluorescence behaviors in the range of different acid pH with trans-cis photoisomerization behaviors were investigated in aqueous-THF solution in acid media.
RESUMEN
A Rh2(OAc)4 catalyzed three-component reaction of vinyl diazosuccinimides with alcohols and isatins has been reported, which provides a practical assess to the direct assembly of succinimide and isatin hybrid molecules in good-to-high yields with excellent stereoselectivity. The antiproliferation activity of these synthesized succinimide and isatin hybrid products has been tested via the CCK8 assay in different cancer cell lines, and compounds 4g (SJSA-1, IC50 = 3.82 µM) and 4r (HCT-116, IC50 = 9.02 µM) exhibit higher anticancer potency than other tested compounds.
Asunto(s)
Antineoplásicos , Isatina , Isatina/farmacología , Estructura Molecular , Antineoplásicos/farmacología , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Succinimidas/farmacología , Relación Estructura-Actividad , Línea Celular TumoralRESUMEN
A series of dihydrofuran-3-one and 9,10-phenanthrenequinone hybrid compounds were synthetized through a one-pot gold-catalyzed oxidative cyclization and Aldol-type addition cascade reaction of homopropargylic alcohols with 9,10-phenanthrenequinone. The cytotoxicity of newly synthesized compounds was evaluated in CCK8 assay against different human cancer cells, showing significantly antiproliferative activity against tested tumor cell lines with a lowest IC50 value of 0.92 µM over HCT-116. Further investigation revealed that the treatment of HCT-116 cell line with the promising compound 4c induced cell death as a selective Akt inhibitor. In addition, controlled experiments and molecular docking study suggested that the significant antitumor activity might be attributed to the unique hybrid structure, which implied the promising potential of this dual heterocycle hybrid method in the discovery of novel bioactive molecules with structural diversity.
Asunto(s)
Antineoplásicos , Neoplasias del Colon , Humanos , Estructura Molecular , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , Proteínas Proto-Oncogénicas c-akt , Antineoplásicos/química , Proliferación Celular , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Ensayos de Selección de Medicamentos Antitumorales , Relación Dosis-Respuesta a Droga , Diseño de FármacosRESUMEN
A novel donepezil-caffeic acid (DP-CA) hybrid molecule was designed, synthesis, and investigated by molecular modeling. Its biological activity and protective effect were investigated by the IR spectroscopy, 1H and 13C NMR spectroscopy, and mass spectrometry. DP-CA was highly active against acetylcholine esterase and inhibited it at the micromolar concentrations. Fluorescence and UV-Vis spectroscopy studies showed strong binding of DP-CA to DNA. Moreover, DP-CA exhibited protective effects against H2O2-induced toxicity in U-118 MG glioblastoma cells. Finally, molecular docking showed a high affinity of DP-CA in all concentrations, and the active 4EY7 site exhibited essential residues with polar and apolar contacts. Taken together, these findings indicate that DP-CA could be a prospective multifunctional agent for the treatment of neurodegenerative diseases.
Asunto(s)
Acetilcolinesterasa , Peróxido de Hidrógeno , Donepezilo/farmacología , Donepezilo/química , Simulación del Acoplamiento Molecular , Estudios Prospectivos , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacologíaRESUMEN
In this work, we carried out the design and synthesis of new chimeric compounds from the natural cytotoxic chalcone 2',4'-dihydroxychalcone (2',4'-DHC, A) in combination with cinnamic acids. For this purpose, a descriptive and predictive quantitative structure-activity relationship (QSAR) model was developed to study the chimeric compounds' anti-cancer activities against human breast cancer MCF-7, relying on the presence or absence of structural motifs in the chalcone structure, like in a Free-Wilson approach. For this, we used 207 chalcone derivatives with a great variety of structural modifications over the α and ß rings, such as halogens (F, Cl, and Br), heterocyclic rings (piperazine, piperidine, pyridine, etc.), and hydroxyl and methoxy groups. The multilinear equation was obtained by the genetic algorithm technique, using logIC50 as a dependent variable and molecular descriptors (constitutional, topological, functional group count, atom-centered fragments, and molecular properties) as independent variables, with acceptable statistical parameter values (R2 = 86.93, Q2LMO = 82.578, Q2BOOT = 80.436, and Q2EXT = 80.226), which supports the predictive ability of the model. Considering the aromatic and planar nature of the chalcone and cinnamic acid cores, a structural-specific QSAR model was developed by incorporating geometrical descriptors into the previous general QSAR model, again, with acceptable parameters (R2 = 85.554, Q2LMO = 80.534, Q2BOOT = 78.186, and Q2EXT = 79.41). Employing this new QSAR model over the natural parent chalcone 2',4'-DHC (A) and the chimeric compound 2'-hydroxy,4'-cinnamate chalcone (B), the predicted cytotoxic activity was achieved with values of 55.95 and 17.86 µM, respectively. Therefore, to corroborate the predicted cytotoxic activity compounds A and B were synthesized by two- and three-step reactions. The structures were confirmed by 1H and 13C NMR and ESI+MS analysis and further evaluated in vitro against HepG2, Hep3B (liver), A-549 (lung), MCF-7 (breast), and CasKi (cervical) human cancer cell lines. The results showed IC50 values of 11.89, 10.27, 56.75, 14.86, and 29.72 µM, respectively, for the chimeric cinnamate chalcone B. Finally, we employed B as a molecular scaffold for the generation of cinnamate candidates (C-K), which incorporated structural motifs that enhance the cytotoxic activity (pyridine ring, halogens, and methoxy groups) according to our QSAR model. ADME/tox in silico analysis showed that the synthesized compounds A and B, as well as the proposed chalcones C and G, are the best candidates with adequate drug-likeness properties. From all these results, we propose B (as a molecular scaffold) and our two QSAR models as reliable tools for the generation of anti-cancer compounds over the MCF-7 cell line.
Asunto(s)
Antineoplásicos , Chalcona , Chalconas , Humanos , Células MCF-7 , Chalcona/farmacología , Chalconas/química , Cinamatos/farmacología , Antineoplásicos/química , Piridinas/farmacología , Proliferación Celular , Relación Estructura-Actividad , Línea Celular Tumoral , Estructura Molecular , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
Vinca alkaloids are well-known microtubule targeting agents, which are used against some types of cancer. Vindoline is one of the monomeric Vinca alkaloids which does not have anti-tumor effect, although its derivatives have serious impact on the field of these indole alkaloids. Chrysin is a secondary plant metabolite, which has broad-spectrum biological activity, among others anticancer activity. Chrysin had shown synergic effect with several antiproliferative compounds (e. g., doxorubicin, cisplatin and ciglitazone), therefore, we attempted the synthesis of a novel vindoline-chrysin hybrid molecule. However, in the first case a diphenylamine structure was isolated. The mechanism of the unexpected reaction was studied, and then the originally targeted hybrid was synthesized by a reverse route coupling. A further hybrid was produced using a different site of the molecule. The antitumor activities were determined against 60 human tumor cell lines (NCI60), where the aimed hybrid showed low micromolar GI50 values on most of the cell lines.
Asunto(s)
Antineoplásicos/síntesis química , Flavonoides/química , Vinblastina/análogos & derivados , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Alcaloides Indólicos/química , Relación Estructura-Actividad , Vinblastina/químicaRESUMEN
Malaria is still considered as the major parasitic disease and the development of artemisinin resistance does not improve this alarming situation. Based on the recent identification of relevant malaria targets in the artemisinin resistance context, novel drug combinations were evaluated against artemisinin-sensitive and artemisinin-resistant Plasmodium falciparum parasites. Corresponding hybrid molecules were also synthesized and evaluated for comparison with combinations and individual pharmacophores (e.g. atovaquone, mefloquine or triclosan). Combinations and hybrids showed remarkable antimalarial activity (IC50 = 0.6 to 1.1 nM for the best compounds), strong selectivity, and didn't present any cross-resistance with artemisinin. Moreover, the combination triclosan + atovaquone showed high activity against artemisinin-resistant parasites at the quiescent stage but the corresponding hybrid lost this pharmacological property. This result is essential since only few molecules active against quiescent artemisinin-resistant parasites are reported. Our promising results highlight the potential of these combinations and paves the way for pharmacomodulation work on the best hybrids.
Asunto(s)
Antimaláricos/farmacología , Artemisininas/farmacología , Atovacuona/farmacología , Mefloquina/farmacología , Plasmodium falciparum/efectos de los fármacos , Triclosán/farmacología , Antimaláricos/síntesis química , Antimaláricos/química , Artemisininas/química , Atovacuona/síntesis química , Atovacuona/química , Relación Dosis-Respuesta a Droga , Resistencia a Medicamentos/efectos de los fármacos , Humanos , Malaria Falciparum/tratamiento farmacológico , Mefloquina/síntesis química , Mefloquina/química , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Triclosán/síntesis química , Triclosán/químicaRESUMEN
Due to the increasing problem of bacterial resistance worldwide, the demand for new antibiotics is becoming increasingly urgent. We wished to: (a) prepare hybrid molecules by linking different pharmacophores by chemical bonds; (b) investigate the antib acterial activity of these hybrids using drug-sensitive and drug-resistant pathogens in vitro and vivo. A series of hybrid molecules with a diester structure were designed and synthesized that linked amoxicillin and derivatives of benzoic acid via a methylene bridge. Synthesized compounds were evaluated for activities against Gram-positive bacteria (Staphylococcus aureus American Type Culture Collection [ATCC] 29213, ATCC 11632; methicillin-resistant S. aureus [MRSA] 11; Escherichia coli ATCC 25922) and Gram-negative bacteria (Salmonella LS677, GD836, GD828, GD3625) by microdilution of broth. Synthesized compounds showed good activity against Gram-positive and Gram-negative bacteria in vitro. In particular, amoxicillin-p-nitrobenzoic acid (6d) showed good activity against Salmonella species and had better activity against methicillin-resistant S. aureus (minimum inhibitory concentration [MIC] = 64 µg/ml) than the reference drug, amoxicillin (MIC = 128 µg/ml). Amoxicillin-p-methoxybenzoic acid (6b) had the best antibacterial activity in vivo (ED50 = 13.2496 µg/ml). The hybrid molecules of amoxicillin and derivatives of benzoic acid synthesized based on a diester structure can improve the activity of amoxicillin against Salmonella species and even improve the activity against MRSA.
Asunto(s)
Amoxicilina/síntesis química , Antibacterianos/síntesis química , Ácido Benzoico/síntesis química , Química Farmacéutica/métodos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Salmonella enterica/efectos de los fármacos , Amoxicilina/farmacología , Animales , Antibacterianos/farmacología , Ácido Benzoico/farmacología , Farmacorresistencia Bacteriana Múltiple/fisiología , Femenino , Ratones , Ratones Endogámicos ICR , Salmonella enterica/fisiologíaRESUMEN
Primary sulfonamide derivatives with various heterocycles represent the most widespread group of potential human carbonic anhydrase (hCA) inhibitors with high affinity and selectivity towards specific isozymes from the hCA family. In this work, new 4-aminomethyl- and aminoethyl-benzenesulfonamide derivatives with 1,3,5-triazine disubstituted with a pair of identical amino acids, possessing a polar (Ser, Thr, Asn, Gln) and non-polar (Ala, Tyr, Trp) side chain, have been synthesized. The optimized synthetic, purification, and isolation procedures provided several pronounced benefits such as a short reaction time (in sodium bicarbonate aqueous medium), satisfactory yields for the majority of new products (20.6-91.8%, average 60.4%), an effective, well defined semi-preparative RP-C18 liquid chromatography (LC) isolation of desired products with a high purity (>97%), as well as preservation of green chemistry principles. These newly synthesized conjugates, plus their 4-aminobenzenesulfonamide analogues prepared previously, have been investigated in in vitro inhibition studies towards hCA I, II, IV and tumor-associated isozymes IX and XII. The experimental results revealed the strongest inhibition of hCA XII with low nanomolar inhibitory constants (Kis) for the derivatives with amino acids possessing non-polar side chains (7.5-9.6 nM). Various derivatives were also promising for some other isozymes.
Asunto(s)
Aminoácidos/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/farmacología , Sulfonamidas/química , Triazinas/química , Antígenos de Neoplasias , Anhidrasa Carbónica I/antagonistas & inhibidores , Anhidrasa Carbónica II/antagonistas & inhibidores , Anhidrasa Carbónica IV/antagonistas & inhibidores , Anhidrasa Carbónica IX/antagonistas & inhibidores , Anhidrasas Carbónicas/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , BencenosulfonamidasRESUMEN
Genetic mutations and aberrant epigenetic alterations are the triggers for carcinogenesis. The emergence of the drugs targeting epigenetic aberrations has provided a better outlook for cancer treatment. Histone deacetylases (HDACs) are epigenetic modifiers playing critical roles in numerous key biological functions. Inappropriate expression of HDACs and dysregulation of PI3K signaling pathway are common aberrations observed in human diseases, particularly in cancers. Histone deacetylase inhibitors (HDACIs) are a class of epigenetic small-molecular therapeutics exhibiting promising applications in the treatment of hematological and solid malignancies, and in non-neoplastic diseases. Although HDACIs as single agents exhibit synergy by inhibiting HDAC and the PI3K pathway, resistance to HDACIs is frequently encountered due to activation of compensatory survival pathway. Targeted simultaneous inhibition of both HDACs and PI3Ks with their respective inhibitors in combination displayed synergistic therapeutic efficacy and encouraged the development of a single HDAC-PI3K hybrid molecule via polypharmacology strategy. This review provides an overview of HDACs and the evolution of HDACs-based epigenetic therapeutic approaches targeting the PI3K pathway.
Asunto(s)
Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinogénesis/genética , Epigénesis Genética , Humanos , Ratones , Morfolinas/farmacología , Polifarmacología , Pirimidinas/farmacologíaRESUMEN
An environment friendly synthesis of novel hybrid pharmacophores derived from synergism of nalidixic acid and 1,3-diphenylprop-2-en-1-ones is described. Percent yield and reaction times of microwave assisted reactions have been compared with the reactions carried out under conventional reaction conditions which show marked decrease in reaction times and significant increase in yields. Besides, anti-oxidant potential of the synthesized hybrid compounds was evaluated and some of the compounds showed marked ascorbic acid equivalence Ferric reducing anti-oxidant power (FRAP) and metal chelating capacities. Crystal study of one representative of the synthesized series is also presented.
Asunto(s)
Antioxidantes/farmacología , Naftiridinas/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Microondas , Modelos Moleculares , Estructura Molecular , Naftiridinas/síntesis química , Naftiridinas/química , Relación Estructura-ActividadRESUMEN
In this study, a series of carbazole-rhodanine conjugates was synthesized and evaluated for their Topoisomerase II inhibition potency as well as cytotoxicity against a panel of four human cancer cell lines. Among these thirteen compounds, 3a, 3b, 3g, and 3h possessed Topoisomerase II inhibition potency at 20⯵M. Mechanism study revealed that these compounds may function as Topo II catalytic inhibitors. It was found that the electron-withdrawing groups on the phenyl ring of compounds played an important role on enhancing both enzyme inhibition and cytotoxicity.
Asunto(s)
Antineoplásicos/farmacología , Carbazoles/farmacología , ADN-Topoisomerasas de Tipo II/metabolismo , Rodanina/análogos & derivados , Rodanina/farmacología , Inhibidores de Topoisomerasa II/farmacología , Antineoplásicos/síntesis química , Carbazoles/síntesis química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Etopósido/farmacología , Humanos , Sustancias Intercalantes/síntesis química , Sustancias Intercalantes/farmacología , Rodanina/síntesis química , Inhibidores de Topoisomerasa II/síntesis químicaRESUMEN
Peroxisome proliferator-activated receptors (PPARs) are important drug targets for treatment of dyslipidemia, type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and great efforts have been made to develop novel PPAR ligands. However, most existing PPAR ligands contain a carboxylic acid (CA) or thiazolidinedione (TZD) structure (acidic head group) that is essential for activity. We recently discovered non-CA/TZD class PPARα/δ partial agonists, which contain an acetamide moiety and adjacent methyl group, linked to a 1,2,4-oxadiazole ring ("fragment a"). We hypothesized that the acetamide structure might interact with the CA/TZD-binding pocket. To test this idea, we firstly replaced fragment a in one of our compounds with the α-alkoxy-CA structure often found in PPAR agonists. Secondly, we replaced the α-alkoxy-CA head group of several reported PPAR agonists with our acetamide-based fragment a. The agonistic activities of the synthesized hybrid compounds toward PPARs (PPARα, PPARγ and PPARδ) were evaluated by means of cell-based reporter gene assays. All the hybrid molecules showed PPAR-agonistic activities, but replacement of the α-alkoxy-CA head group altered the maximum efficacy and the subtype-specificity. The acetamide-based hybrid molecules showed partial agonism toward PPARα and PPARδ, whereas the α-alkoxy-CA-based molecules were generally selective for PPARα and PPARγ, with relatively high activation efficacies. Thus, the fragment replacement strategy appears promising for the development of novel acetamide-based PPARα/δ dual agonists.
Asunto(s)
PPAR alfa/agonistas , PPAR delta/agonistas , Acetamidas/síntesis química , Acetamidas/química , Acetamidas/metabolismo , Sitios de Unión , Genes Reporteros , Células HEK293 , Humanos , Ligandos , PPAR alfa/metabolismo , PPAR delta/metabolismo , Unión Proteica , Estereoisomerismo , Tiazolidinedionas/químicaRESUMEN
The design, synthesis, and investigation of antitumor and anti-lipase activities of some coumarin-triazole hybrid molecules are reported. The synthesis of these hybrid molecules was performed under microwave irradiation and conventional heating procedures. The newly synthesized hybrid molecules were investigated as inhibitors against four tumor cell lines (BT20 human breast carcinoma, SK-Mel 128 melanoma, DU-145 prostate carcinoma, and A549 lung carcinoma) and porcine pancreatic lipase (PPL). Most of these compounds showed notable antitumor activities against the tested tumor cell lines, and compounds 8i and 8l showed the best anti-lipase activity of 99.30 ± 0.56% and 99.85 ± 1.21%, respectively, at a concentration of 10 µM.
Asunto(s)
Antineoplásicos/farmacología , Cumarinas/farmacología , Inhibidores Enzimáticos/farmacología , Triazoles/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Cumarinas/síntesis química , Cumarinas/química , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Calor , Humanos , Lipasa/antagonistas & inhibidores , Microondas , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Relación Estructura-Actividad , Porcinos , Triazoles/síntesis química , Triazoles/químicaRESUMEN
Vascular endothelial cells cover the luminal surface of blood vessels and contribute to the prevention of vascular disorders such as atherosclerosis. Metallothionein (MT) is a low molecular weight, cysteine-rich, metal-binding, inducible protein, which protects cells from the toxicity of heavy metals and active oxygen species. Endothelial MT is not induced by inorganic zinc. Adequate tools are required to investigate the mechanisms underlying endothelial MT induction. In the present study, we found that an organoantimony compound, tris(pentafluorophenyl)stibane, induces gene expression of MT-1A and MT-2A, which are subisoforms of MT in bovine aortic endothelial cells. The data reveal that MT-1A is induced by activation of both the MTF-1-MRE and Nrf2-ARE pathways, whereas MT-2A expression requires only activation of the MTF-1-MRE pathway. The present data suggest that the original role of MT-1 is to protect cells from heavy metal toxicity and oxidative stress in the biological defense system, while that of MT-2 is to regulate intracellular zinc metabolism.
Asunto(s)
Aorta/citología , Células Endoteliales/metabolismo , Hidrocarburos Clorados/farmacología , Metalotioneína/genética , Animales , Bovinos , Proteínas de Unión al ADN/genética , Células Endoteliales/efectos de los fármacos , Glutamato-Cisteína Ligasa/genética , Hemo-Oxigenasa 1/genética , Factor 2 Relacionado con NF-E2/genética , Isoformas de Proteínas/genética , Factores de Transcripción/genética , Transcripción Genética/efectos de los fármacos , Transcripción Genética/genética , Factor de Transcripción MTF-1RESUMEN
In order to expand the structural diversity of Bcr-Abl inhibitors, twenty hybrids (series E and P) have been synthesized and characterized based on Imatinib and GNF-2. Their biological activities were evaluated in vitro against human leukemia cells. Most compounds exhibited potent antiproliferative activity against K562 cells, especially for compounds E4, E5 and E7. Furthermore, these new hybrids were also screened for Abl kinase inhibitory activity, and some of them inhibited Abl kinase with low micromolar IC50 values. In particular, compound P3 displayed the most potent activity with IC50 value of 0.017 µM comparable with that of Imatinib. Molecular docking studies indicated that these novel hybrids fitted well with the active site of Bcr-Abl. These results suggested the great potential of these compounds as novel Bcr-Abl inhibitors.
Asunto(s)
Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Mesilato de Imatinib/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Mesilato de Imatinib/síntesis química , Mesilato de Imatinib/química , Células K562 , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
An efficient method for the preparation of kojic acid based α-amino acid derivatives by alkylation of glycinate schiff base with bromokojic acids have been described. Using this method, mono as well as di alkylated kojic acid-amino acid conjugates have been prepared. This is the first synthesis of C-linked kojic acid-amino acid conjugate where kojic acid is directly linked to amino acid through a C-C bond.
Asunto(s)
Aminoácidos/síntesis química , Pironas/química , Aminoácidos/química , Estructura MolecularRESUMEN
One of the most viable options to tackle the growing resistance to the antimalarial drugs is hybrid molecules. It involves combination of different scaffolds in one frame that may lead to compounds with diverse biological profiles. In this context, new hybrids of three different scaffolds viz pyrazole, pyrazoline and thiosemicarbazone moiety were incorporated into one single compound and evaluated for their in vitro schizontocidal activity against the CQ-sensitive 3D7 strain of Plasmodium falciparum. Compounds with significant in vitro antimalarial activity were further evaluated for cytotoxicity against VERO cell lines. The best active compound 48 exhibited an IC50 of 1.13 µM. The in vitro results were further validated by quantitative structure-activity relationship (QSAR).
Asunto(s)
Antimaláricos/farmacología , Pirazoles/farmacología , Tioamidas/química , Animales , Antimaláricos/síntesis química , Antimaláricos/química , Plasmodium falciparum/efectos de los fármacos , Pirazoles/química , Relación Estructura-Actividad CuantitativaRESUMEN
In recent years, G protein-coupled receptor (GPCR) ligands have not only been modified by conducting structure-activity relationship studies of leads and known ligands, but several new approaches have emerged in which GPCR ligands were connected or merged with other biologically active molecules. Identical or related ligands were combined to bivalent ones. Orthosteric ligands were combined with allosteric ligands, sometimes leading to dualsteric ones, and also chemical structures were merged to dual-acting or multifunctional compounds. In this article, we want to present some representative examples for these approaches at different GPCRs, showing the versatility of this approach, with a focus on our own work and references to related articles and reviews.
Asunto(s)
Diseño de Fármacos , Preparaciones Farmacéuticas , Receptores Acoplados a Proteínas G/efectos de los fármacos , Animales , Sitios de Unión , Humanos , Ligandos , Terapia Molecular Dirigida , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/metabolismo , Unión Proteica , Conformación Proteica , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly. Contemporary treatments can only relieve symptoms but fail to delay disease progression. Curcumin is a naturally derived compound that has demonstrated significant therapeutic effects in AD treatment. Recently, molecular hybridization has been utilized to combine the pharmacophoric groups present in curcumin with those of other AD drugs, resulting in a series of novel compounds that enhance the therapeutic efficacy through multiple mechanisms. In this review, we firstly provide a concise summary of various pathogenetic hypotheses of AD and the mechanism of action of curcumin in AD, as well as the concept of molecular hybridization. Subsequently, we focus on the recent development of hybrid molecules derived from curcumin, summarizing their structures and pharmacological activities, including cholinesterase inhibitory activity, Aß aggregation inhibitory activity, antioxidant activity, and other activities. The structure-activity relationships were further discussed.