RESUMEN
Polycyclic polyprenylated acylphloroglucinols (PPAPs) comprise a large group of compounds of mostly plant origin. The best-known compound is hyperforin from St. John's wort with its antidepressant, antitumor and antimicrobial properties. The chemical synthesis of PPAP variants allows the generation of compounds with improved activity and compatibility. Here, we studied the antimicrobial activity of two synthetic PPAP-derivatives, the water-insoluble PPAP23 and the water-soluble sodium salt PPAP53. In vitro, both compounds exhibited good activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Both compounds had no adverse effects on Galleria mellonella wax moth larvae. However, they were unable to protect the larvae from infection with S. aureus because components of the larval coelom neutralized the antimicrobial activity; a similar effect was also seen with serum albumin. In silico docking studies with PPAP53 revealed that it binds to the F1 pocket of human serum albumin with a binding energy of -7.5 kcal/mol. In an infection model of septic arthritis, PPAP23 decreased the formation of abscesses and S. aureus load in kidneys; in a mouse skin abscess model, topical treatment with PPAP53 reduced S. aureus counts. Both PPAPs were active against anaerobic Gram-positive gut bacteria such as neurotransmitter-producing Clostridium, Enterococcus or Ruminococcus species. Based on these results, we foresee possible applications in the decolonization of pathogens.
Asunto(s)
Cetonas , Staphylococcus aureus Resistente a Meticilina , Compuestos de Espiro , Animales , Humanos , Ratones , Antibacterianos/farmacología , Antibacterianos/química , Enterococcus faecium/efectos de los fármacos , Cetonas/química , Cetonas/farmacología , Larva/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Mariposas Nocturnas/efectos de los fármacos , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Infecciones Estafilocócicas/tratamiento farmacológicoRESUMEN
Hippuristanol is a marine derived steroidal natural product with promising anticancer activity. However, instability at low pH has precluded its development as an efficient therapy. We addressed this limitation by replacing one of the oxygen atoms of the spiroketal moiety with a carbon atom. Key steps in the synthesis include a Meyer-Schuster/Nazarov cascade, a hypoiodite mediated oxyfunctionalization, and the late-stage installation of a hydroxyl group on the C-ring of the steroid.
Asunto(s)
Productos Biológicos , Estructura Molecular , Productos Biológicos/química , Productos Biológicos/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/síntesis química , Esteroides/química , Esteroides/síntesis química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacologíaRESUMEN
Twelve spiro thiazolidinone compounds (A-L) were synthesized via either conventional thermal or ultrasonication techniques using Fe2O3 nanoparticles. The modification of the traditional procedure by using Fe2O3 nanoparticles led to enhancement of the yield of the desired candidates to 78-93% in approximately half reaction time compared with 58-79% without catalyst. The products were fully characterized using different analytical and spectroscopic techniques. The structure of the two derivatives 4-phenyl-1-thia-4-azaspirodecan-3-one (A) and 4-(p-tolyl)-1-thia-4-azaspirodecan-3-one (B) were also determined using single crystal X-ray diffraction and Hirshfeld surface analysis. The two compounds (A and B) were crystallized in the orthorhombic system with Pbca and P212121 space groups, respectively. In addition, the crystal packing of compounds revealed the formation of supramolecular array with a net of intermolecular hydrogen bonding interactions. The energy optimized geometries of some selected derivatives were performed by density functional theory (DFT/B3LYP). The reactivity descriptors were also calculated and correlated with their biological properties. All the reported compounds were screened for antimicrobial inhibitions. The two derivatives, F and J, exhibited the highest levels of bacterial inhibition with an inhibition zone of 10-17 mm. Also, the two derivatives, F and J, displayed the most potent fungal inhibition with an inhibition zone of 15-23 mm. Molecular docking investigations of some selected derivatives were performed using a B-DNA (PDB: 1BNA) as a macromolecular target. Structure and activity relationship of the reported compounds were correlated with the data of antimicrobial activities and the computed reactivity parameters.
Asunto(s)
Simulación del Acoplamiento Molecular , Tiazolidinas , Catálisis , Tiazolidinas/química , Tiazolidinas/síntesis química , Tiazolidinas/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Cristalografía por Rayos X/métodos , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Teoría Funcional de la Densidad , Pruebas de Sensibilidad Microbiana , Compuestos Férricos/química , Enlace de HidrógenoRESUMEN
There is an urgent unmet need for more targeted and effective treatments for advanced epithelial ovarian cancer (EOC). The emergence of drug resistance is a particular challenge, but small molecule covalent inhibitors have promise for difficult targets and appear less prone to resistance. Michael acceptors are covalent inhibitors that form bonds with cysteines or other nucleophilic residues in the target protein. However, many are categorized as pan-assay interference compounds (PAINS) and considered unsuitable as drugs due to their tendency to react non-specifically. Targeting RPN13/ADRM1-mediated substrate recognition and deubiquitination by the proteasome 19S Regulatory Particle (RP) is a promising treatment strategy. Early candidate RPN13 inhibitors (iRPN13) produced a toxic accumulation of very high molecular weight polyubiquitinated substrates, resulting in therapeutic activity in mice bearing liquid or solid tumor models, including ovarian cancer; however, they were not drug-like (PAINS) because of their central piperidone core. Up284 instead has a central spiro-carbon ring. We hypothesized that adding a guanidine moiety to the central ring nitrogen of Up284 would produce a compound, RA475, with improved drug-like properties and therapeutic activity in murine models of ovarian cancer. RA475 produced a rapid accumulation of high molecular polyubiquitinated proteins in cancer cell lines associated with apoptosis, similar to Up284 although it was 3-fold less cytotoxic. RA475 competed binding of biotinylated Up284 to RPN13. RA475 shows improved solubility and distinct pharmacodynamic properties compared to Up284. Specifically, tetraubiquitin firefly luciferase expressed in leg muscle was stabilized in mice more effectively upon IP treatment with RA475 than with Up284. However, pharmacologic analysis showed that RA475 was more rapidly cleared from the circulation, and less orally available than Up284. RA475 shows reduced ability to cross the blood-brain barrier and in vitro inhibition of HERG. Treatment of mice with RA475 profoundly inhibited the intraperitoneal growth of the ID8-luciferase ovarian tumor model. Likewise, RA475 treatment of immunocompetent mice inhibited the growth of spontaneous genetically-engineered peritoneal tumor, as did weekly cisplatin dosing. The combination of RA475 and cisplatin significantly extended survival compared to individual treatments, consistent with synergistic cytotoxicity in vitro. In sum, RA475 is a promising candidate covalent RPN13i with potential utility for treatment of patients with advanced EOC in combination with cisplatin.
Asunto(s)
Neoplasias Ováricas , Femenino , Animales , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/metabolismo , Ratones , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/uso terapéutico , Compuestos de Espiro/química , Ensayos Antitumor por Modelo de Xenoinjerto , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Guanidinas/farmacología , Guanidinas/uso terapéutico , Guanidinas/química , Péptidos y Proteínas de Señalización IntracelularRESUMEN
Overexpression of carboxyl/cholinesterase (CCE) genes has been reported to be associated with many cases of pesticide resistance in arthropods. However, it has been rarely documented that CCE genes participate in spirodiclofen resistance in Panonychus citri. In previous research, we found that spirodiclofen resistance is related to increased P450 and CCE enzyme activities in P. citri. In this study, we identified two CCE genes, PcCCE3 and PcCCE5, which were significantly upregulated in spirodiclofen-resistant strain and after exposure to spirodiclofen. RNA interference of PcCCE3 and PcCCE5 increased the spirodiclofen susceptibility in P. citri. In vitro metabolism indicated that PcCCE3 and PcCCE5 could interact with spirodiclofen, but metabolites were detected only in the PcCCE3 treatment. Our results indicated that PcCCE3 participates in spirodiclofen resistance through direct metabolism, and PcCCE5 may be involved in the spirodiclofen resistance by passive binding and sequestration, which provides new insights into spirodiclofen resistance in P. citri.
Asunto(s)
Proteínas de Artrópodos , Compuestos de Espiro , Animales , Compuestos de Espiro/farmacología , Compuestos de Espiro/metabolismo , Compuestos de Espiro/química , Proteínas de Artrópodos/genética , Proteínas de Artrópodos/metabolismo , Proteínas de Artrópodos/química , Resistencia a Medicamentos/genética , Carboxilesterasa/genética , Carboxilesterasa/metabolismo , 4-Butirolactona/análogos & derivados , 4-Butirolactona/metabolismo , 4-Butirolactona/farmacologíaRESUMEN
We recently developed a series of nalfurafine analogs (TK10, TK33, and TK35) that may serve as non-addictive candidate analgesics. These compounds are mixed-action agonists at the kappa and delta opioid receptors (KOR and DOR, respectively) and produce antinociception in a mouse warm-water tail-immersion test while failing to produce typical mu opioid receptor (MOR)-mediated side effects. The warm-water tail-immersion test is an assay of pain-stimulated behavior vulnerable to false-positive analgesic-like effects by drugs that produce motor impairment. Accordingly, this study evaluated TK10, TK33, and TK35 in a recently validated assay of pain-related behavioral depression in mice that are less vulnerable to false-positive effects. For comparison, we also evaluated the effects of the MOR agonist/analgesic hydrocodone (positive control), the neurokinin 1 receptor (NK1R) antagonist aprepitant (negative control), nalfurafine as a selective KOR agonist, SNC80 as a selective DOR agonist, and a nalfurafine/SNC80 mixture. Intraperitoneal injection of dilute lactic acid (IP lactic acid) served as a noxious stimulus to depress vertical and horizontal locomotor activity in male and female ICR mice. IP lactic acid-induced locomotor depression was alleviated by hydrocodone but not by aprepitant, nalfurafine, SNC80, the nalfurafine/SNC80 mixture, or the KOR/DOR agonists. These results suggest that caution is warranted in advancing mixed-action KOR/DOR agonists as candidate analgesics.
Asunto(s)
Dolor , Receptores Opioides delta , Receptores Opioides kappa , Animales , Receptores Opioides delta/agonistas , Receptores Opioides delta/metabolismo , Ratones , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/metabolismo , Dolor/tratamiento farmacológico , Dolor/metabolismo , Masculino , Depresión/tratamiento farmacológico , Depresión/etiología , Morfinanos/farmacología , Conducta Animal/efectos de los fármacos , Analgésicos Opioides/farmacología , Compuestos de Espiro/farmacología , Compuestos de Espiro/químicaRESUMEN
This review describes novel organocatalytic methods for the enantioselective construction of spiroindans and spirochromans and the application of the methods to the total synthesis of natural products. We developed an intramolecular Friedel-Craftstype 1,4-addition in which the substrates were a resorcinol derivative and 2-cyclohexenone linked by an alkyl chain. The reaction proceeded smoothly in the presence of a cinchonidine-based primary amine (30 mol%) with water and p-bromophenol as additives. A variety of spiroindanes were obtained with high enantioselectivity under these conditions. The reaction was applied in the first total synthesis of the unusual proaporphine alkaloid (-)-misramine, which included the key steps of enantioselective spirocyclization and double reductive amination of the keto-aldehyde to form a piperidine ring toward the end of the synthesis. The total synthesis of misrametine was achieved by selective demethylation of the methoxy group from the precursor to misramine. Next, a method for highly enantioselective organocatalytic construction of spirochromans containing a tetrasubstituted stereocenter was developed. An intramolecular oxy-Michael addition was catalyzed by a bifunctional cinchona alkaloid thiourea catalyst. A variety of spirochroman compounds containing a tetrasubstituted stereocenter were obtained with excellent enantioselectivity of up to 99% enantiomeric excess. The reaction was applied to the asymmetric formal synthesis of (-)-(R)-cordiachromene.
Asunto(s)
Productos Biológicos , Catálisis , Productos Biológicos/síntesis química , Productos Biológicos/química , Estereoisomerismo , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Alcaloides de Cinchona/química , Ciclohexanonas/síntesis química , Ciclohexanonas/química , Fenómenos Químicos Orgánicos , Preparaciones Farmacéuticas/síntesis química , Preparaciones Farmacéuticas/química , Aminas/química , Aminas/síntesis química , Tiourea/química , Tiourea/síntesis química , Resorcinoles/síntesis química , Resorcinoles/química , Indanos/síntesis química , Indanos/químicaRESUMEN
Highly functionalized spirobisnaphthalenes, preussomerins N (1) and O (2), and simpler compounds, such as 2,3-α-epoxypalmarumycin CP18 (3), 3α-hydroxy-CJ-12,372 (4), and 16 known structurally related congeners, were isolated from a culture broth of Roussoella sp. KT4147. Structural analysis revealed that 1 was a dimer of preussomerin G (6), connected by a nitrogen atom, and 2 was a derivative of 6 with a macommelin substructure. Preussomerin N (1) was considered to be biosynthetically derived via the Michael-type 1,4-addition of ammonia to 6, followed by another Michael addition to another molecule of 6. Contrarily, 2 was suggested to be derived through an endo-Diels-Alder cycloaddition between a diene derived from the (E)-enol form of macommelinal via an ene-reaction and dienophile 6. Compounds 1 and 2 exhibited potent cytotoxicity against COLO-201 human colorectal cancer cells.
Asunto(s)
Naftalenos , Compuestos de Espiro , Humanos , Estructura Molecular , Compuestos de Espiro/química , Compuestos de Espiro/aislamiento & purificación , Compuestos de Espiro/farmacología , Naftalenos/química , Naftalenos/farmacología , Naftalenos/aislamiento & purificación , Ensayos de Selección de Medicamentos Antitumorales , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Reacción de Cicloadición , Línea Celular TumoralRESUMEN
A series of 21 new 7'H-spiro[azetidine-3,5'-furo [3,4-d]pyrimidine]s substituted at the pyrimidine ring second position were synthesized. The compounds showed high antibacterial in vitro activity against M. tuberculosis. Two compounds had lower minimum inhibitory concentrations against Mtb (H37Rv strain) compared with isoniazid. The novel spirocyclic scaffold shows excellent properties for anti-tuberculosis drug development.
Asunto(s)
Antituberculosos , Azetidinas , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis , Nitrofuranos , Compuestos de Espiro , Mycobacterium tuberculosis/efectos de los fármacos , Antituberculosos/farmacología , Antituberculosos/química , Antituberculosos/síntesis química , Azetidinas/química , Azetidinas/farmacología , Nitrofuranos/farmacología , Nitrofuranos/química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/síntesis química , Relación Estructura-Actividad , Estructura MolecularRESUMEN
OBJECTIVE: Polymerization shrinkage poses a significant challenge in dental resin composites. The objective of this study is to introduce spiroorthocarbonate monomer 3,9-dimethylene-1,3,5,7-tetraoxa-spiro[5,5]undecane (BMSOC) and epoxy resin monomer 3,4-epoxycyclohexylmethyl-3,4-epoxycyclohexane carboxylate (ECHM-ECHC) into bisphenol-S-bis(3-methacrylato-2-hydroxy propyl)ether (BisS-GMA) based resin composites to develop composites with reduced shrinkage properties. METHODS: BMSOC and BisS-GMA were synthesized and thoroughly mixed with ECHM-ECHC, followed by inorganic fillers and photoinitiators. Based on the composition of the resin matrix, five groups of experimental composites were prepared, with traditional bisphenol A-dimethacrylate glycidyl ester (Bis-GMA)/triethylene glycol dimethacrylate (TEGDMA) based composite serving as the control. The polymerization properties, including degree of conversion (DC) and polymerization shrinkage (PS), as well as marginal microleakage, wettability, flexural strength (FS), flexural modulus (FM), and biocompatibility were evaluated. RESULTS: The results demonstrated that compared with the control group, the PS of BisS-GMA based composites containing BMSOC and ECHM-ECHC were significantly reduced (P < 0.05), and the lowest PS (0.96 ± 0.08 %) was observed when the ratio of BisS-GMA: (Epoxy + BMSOC) was 4:6. Additionally, the experimental composites also exhibited improved DC, minimal microleakage, low hydrophilicity, enhanced mechanical properties, qualified in vivo biocompatibility, and slight/moderate in vitro biocompatibility. SIGNIFICANCE: The resin composites incorporating multiple modified low-shrink monomers are promising for dental applications to prevent various clinical problems caused by PS and extend restoration longevity.
Asunto(s)
Resinas Compuestas , Ensayo de Materiales , Polimerizacion , Resinas Compuestas/química , Luces de Curación Dental , Polietilenglicoles/química , Curación por Luz de Adhesivos Dentales , Ácidos Polimetacrílicos/química , Bisfenol A Glicidil Metacrilato/química , Propiedades de Superficie , Poliuretanos/química , Compuestos de Espiro/química , Metacrilatos/química , Módulo de ElasticidadRESUMEN
A Quantitative structure-retention relationship (QSRR) analysis has been carried out on the chromatography parameters of lipophilicity of selected spirohydantoins. Multiple linear regression (MLR) was applied for construct the QSRR models. The chromatographic parameters of lipophilicity were determined by reversed-phase thin-layer chromatography. Chromatographic analyses were performed on C-18 modified silica gel with a two-component mobile phase consisting of water and protic organic solvent (ethanol, n-propanol, i-propanol, or t-butanol) in different ratios. QSRR models were built and for additional four aqueous mobile phases: acetone-water, acetonitrile-water, tetrahydrofuran-water, and 1,4-dioxane-water (results published before). In total, chromatographic lipophilicity parameters obtained for two types of organic solvents was subject of the QSRR. The predictive ability of each model was defined by an internal validation coefficient. The best QSRR model for predicting the chromatographic parameter of lipophilicity was obtained for tetrahydrofuran as an organic solvent.
Asunto(s)
Hidantoínas , Cromatografía en Capa Delgada , Hidantoínas/química , Relación Estructura-Actividad Cuantitativa , Compuestos de Espiro/química , Solventes/química , Modelos Lineales , DioxanosRESUMEN
We report herein the design and discovery of novel allosteric HIV-1 integrase inhibitors. Our design concept utilized the spirocyclic moiety to restrain the flexibility of the conformation of the lipophilic part of the inhibitor. Compound 5 showed antiviral activity by binding to the nuclear lens epithelium-derived growth factor (LEDGF/p75) binding site of HIV-1 integrase (IN). The introduction of a lipophilic amide substituent into the central benzene ring resulted in a significant increase in antiviral activity against HIV-1 WT X-ray crystallography of compound 15 in complex with the integrase revealed the presence of a hydrogen bond between the oxygen atom of the amide of compound 15 and the hydroxyl group of the T125 side chain. Chiral compound 17 showed high antiviral activity, good bioavailability, and low clearance in rats.
Asunto(s)
Diseño de Fármacos , Inhibidores de Integrasa VIH , Integrasa de VIH , VIH-1 , Compuestos de Espiro , Inhibidores de Integrasa VIH/farmacología , Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/química , Integrasa de VIH/metabolismo , VIH-1/efectos de los fármacos , Cristalografía por Rayos X , Ratas , Relación Estructura-Actividad , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/síntesis química , Animales , Humanos , Regulación Alostérica/efectos de los fármacos , Estructura Molecular , Modelos Moleculares , Sitios de UniónRESUMEN
Spirotryprostatins are representative members of medicinally interesting bioactive molecules of the spirooxindole natural products. In this communication, we present a novel enantioselective total synthesis of the spirooxindole alkaloid dihydrospirotryprostatin B. The synthesis takes advantage of copper-catalyzed tandem reaction of o-iodoanilide chiral sulfinamide derivatives with alkynone to rapidly construct the key quaternary carbon stereocenter of the natural product dihydrospirotryprostatin B.
Asunto(s)
Compuestos de Espiro , Estereoisomerismo , Estructura Molecular , Compuestos de Espiro/química , Compuestos de Espiro/síntesis química , Productos Biológicos/síntesis química , Productos Biológicos/química , Catálisis , Cobre/química , Alcaloides/síntesis química , Alcaloides/químicaRESUMEN
Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants, the elderly, and immune-compromised patients. While a half-life extended monoclonal antibody and 2 vaccines have recently been approved for infants and the elderly, respectively, options to prevent disease in immune-compromised patients are still needed. Here, we describe spiro-azetidine oxindoles as small molecule RSV entry inhibitors displaying favorable potency, developability attributes, and long-acting PK when injected as an aqueous suspension, suggesting their potential to prevent complications following RSV infection over a period of 3 to 6 months with 1 or 2 long-acting intramuscular (IM) or subcutaneous (SC) injections in these immune-compromised patients.
Asunto(s)
Antivirales , Azetidinas , Oxindoles , Infecciones por Virus Sincitial Respiratorio , Compuestos de Espiro , Humanos , Infecciones por Virus Sincitial Respiratorio/prevención & control , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Animales , Oxindoles/química , Oxindoles/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/administración & dosificación , Antivirales/farmacología , Antivirales/química , Antivirales/administración & dosificación , Azetidinas/química , Azetidinas/farmacología , Azetidinas/administración & dosificación , Azetidinas/farmacocinética , Profilaxis Pre-Exposición/métodos , Inyecciones Intramusculares , Indoles/química , Indoles/administración & dosificación , Indoles/farmacología , Inyecciones Subcutáneas , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Internalización del Virus/efectos de los fármacosRESUMEN
As a typical RNA virus, the genetic information on HIV-1 is entirely stored in RNA. The reverse transcription activity of HIV-1 reverse transcriptase (RT) plays a crucial role in the replication and transmission of the virus. Non-nucleoside RT inhibitors (NNRTIs) block the function of RT by binding to the RNA binding site on RT, with very few targeting viral RNA. In this study, by transforming planar conjugated ligands into a spiro structure, we convert classical Ru(II) DNA intercalators into a nonintercalator. This enables selective binding to HIV-1 transactivation response (TAR) RNA on the outer side of nucleic acids through dual interactions involving hydrogen bonds and electrostatic attraction, effectively inhibiting HIV-1 RT and serving as a selective fluorescence probe for TAR RNA.
Asunto(s)
Transcriptasa Inversa del VIH , VIH-1 , Inhibidores de la Transcriptasa Inversa , Rutenio , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/metabolismo , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/metabolismo , Ligandos , VIH-1/enzimología , VIH-1/efectos de los fármacos , Rutenio/química , Rutenio/farmacología , ARN Viral/metabolismo , ARN Viral/química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/metabolismo , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Sustancias Intercalantes/química , Sustancias Intercalantes/farmacología , Estructura Molecular , Humanos , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Duplicado del Terminal Largo de VIH , Sitios de UniónRESUMEN
A novel series of 5'-benzylidene-3'-phenylspiro[indoline-3,2'-thiazolidine]-2,4'(1H)-diones 6a-d and spiro[indoline-3,2'-thiazolo[5,4-e]pyrimido[1,2-a]pyrimidin]-2(1H)-one 9a-d derivatives have been synthesized. All the newly synthesized compounds were evaluated for antifungal and anti-candidiasis activity by using Disc Diffusion and Modified Microdilution methods. The antimicrobial experiments have shown that the synthesized compounds demonstrated broad-spectrum antifungal activity in vitro. Among them, compounds 9a-9d had stronger antifungal activity against Trichophyton rubrum, Trichophyton mentagrophytes, and Candida albicans; compounds 6a-d also showed significant antifungal activity against selected fungal strains as compared to ketoconazole, the reference antifungal drug. The evaluation of antifungal activity against drug-resistant fungal variants showed that the designed compounds had significant antifungal activity against the tested variants. The combination of compounds (6a-d) and (9a-d) exhibited that the synthesized compounds had synergistic effects or additive effects. These results demonstrated that the synthesized compounds were putative chitin synthase inhibitors exhibiting broad spectrum antifungal activities. The present results indicate that novel spiro pyrimidine derivatives can be used as an active pharmaceutical ingredient for novel drug candidate for treatment of dermatophytosis and other fungal agents.
Asunto(s)
Antifúngicos , Arthrodermataceae , Candida albicans , Pirimidinas , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/síntesis química , Candida albicans/efectos de los fármacos , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Arthrodermataceae/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Compuestos de Espiro/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/síntesis química , Trichophyton/efectos de los fármacos , HumanosRESUMEN
We have devised a supported-amine-catalyzed efficient synthesis of spiro-thiazolone-tetrahydrothiophenes via a sulfa-Michael/aldol cascade approach. The catalyst demonstrated sustained efficacy over 21 cycles. These derivatives were found to exhibit excellent binding abilities with purified human serum albumin as indicated by both in silico and in vitro-based experiments.
Asunto(s)
Aminas , Tiofenos , Humanos , Catálisis , Tiofenos/química , Tiofenos/síntesis química , Aminas/química , Aminas/síntesis química , Albúmina Sérica Humana/química , Albúmina Sérica Humana/metabolismo , Unión Proteica , Compuestos de Espiro/química , Compuestos de Espiro/síntesis química , Estructura Molecular , Tiazoles/química , Tiazoles/síntesis química , Simulación del Acoplamiento MolecularRESUMEN
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra, resulting in motor dysfunction. Current treatments are primarily centered around enhancing dopamine signaling or providing dopamine replacement therapy and face limitations such as reduced efficacy over time and adverse side effects. To address these challenges, we identified selective dopamine receptor subtype 4 (D4R) antagonists not previously reported as potential adjuvants for PD management. In this study, a library screening and artificial neural network quantitative structure-activity relationship (QSAR) modeling with experimentally driven library design resulted in a class of spirocyclic compounds to identify candidate D4R antagonists. However, developing selective D4R antagonists suitable for clinical translation remains a challenge.
Asunto(s)
Diseño Asistido por Computadora , Relación Estructura-Actividad Cuantitativa , Humanos , Receptores de Dopamina D4/antagonistas & inhibidores , Receptores de Dopamina D4/metabolismo , Compuestos de Espiro/farmacología , Compuestos de Espiro/química , Antagonistas de Dopamina/farmacología , Redes Neurales de la Computación , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Diseño de FármacosRESUMEN
Cyclin-dependent kinase 2 (CDK2) regulates cell cycle checkpoints in the synthesis and mitosis phases and plays a pivotal role in cancerous cell proliferation. The activation of CDK2, influenced by various protein signaling pathways, initiates the phosphorylation process. Due to its crucial role in carcinogenesis, CDK2 is a druggable hotspot target to suppress cancer cell proliferation. In this context, several studies have identified spirooxindoles as an effective class of CDK2 inhibitors. In the present study, three spirooxindoles (SOI1, SOI2, and SOI3) were studied to understand their inhibitory mechanism against CDK2 through a structure-based approach. Molecular docking and molecular dynamics (MD) simulations were performed to explore their interactions with CDK2 at the molecular level. The calculated binding free energy for the spirooxindole-based CDK2 inhibitors aligned well with experimental results regarding CDK2 inhibition. Energy decomposition (ED) analysis identified key binding residues, including I10, G11, T14, R36, F82, K89, L134, P155, T158, Y159, and T160, in the CDK2 active site and T-loop phosphorylation. Molecular mechanics (MM) energy was identified as the primary contributor to stabilizing inhibitor binding in the CDK2 protein structure. Furthermore, the analysis of binding affinity revealed that the inhibitor SOI1 binds more strongly to CDK2 compared to the other inhibitors under investigation. It demonstrated a robust interaction with the crucial residue T160 in the T-loop phosphorylation site, responsible for kinase activation. These insights into the inhibitory mechanism are anticipated to contribute to the development of potential CDK2 inhibitors using the spirooxindole scaffold.
Asunto(s)
Quinasa 2 Dependiente de la Ciclina , Indoles , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Oxindoles , Inhibidores de Proteínas Quinasas , Compuestos de Espiro , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 2 Dependiente de la Ciclina/química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Humanos , Oxindoles/química , Oxindoles/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Indoles/química , Indoles/farmacología , Termodinámica , Relación Estructura-Actividad , Estructura Molecular , Unión Proteica , EspirooxindolesRESUMEN
Despite the availability of numerous pain medications, the current array of Food and Drug Administration-approved options falls short in adequately addressing pain states for numerous patients and consequently worsens the opioid crisis. Thus, it is imperative for basic research to develop novel and nonaddictive pain medications. Toward addressing this clinical goal, nalfurafine (NLF) was chosen as a lead and its structure-activity relationship (SAR) systematically studied through design, syntheses, and in vivo characterization of 24 analogues. Two analogues, 21 and 23, showed longer durations of action than NLF in a warm-water tail immersion assay, produced in vivo effects primarily mediated by KOR and DOR, penetrated the blood-brain barrier, and did not function as reinforcers. Additionally, 21 produced fewer sedative effects than NLF. Taken together, these results aid the understanding of NLF SAR and provide insights for future endeavors in developing novel nonaddictive therapeutics to treat pain.