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1.
J Org Chem ; 89(16): 11593-11606, 2024 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-39083794

RESUMEN

Chiral oxygen-containing heterocyclic compounds are of great interest for the development of pharmaceuticals. Monoterpenes and their derivatives are naturally abundant precursors of novel synthetic chiral oxygen-containing heterocyclic compounds. In this study, acid catalyzed reactions of salicylic aldehydes with (-)-8-acetoxy-6-hydroxymethyllimonene, readily accessible from α-pinene, leads to the formation of chiral polycyclic products of various structural types. Three of the six isolated chiral heterocyclic products obtained from salicylic aldehyde contain previously unknown polycyclic ring types. Having carried out the reaction in the presence of Brønsted or Lewis acids (Amberlyst 15, trifluoromethanesulfonic acid, trifluoroacetic acid and boron trifluoride etherate) or aluminosilicates (montmorillonite K10, halloysite nanotubes), we found that the nature of products depends on the catalyst as well as the reaction conditions (reaction time, reactant ratio, presence or absence of solvent). Detailed mechanistic insight on the complex cascade reactions for product formation is provided with extensive experimental and quantum mechanical computational studies.

2.
Biochemistry (Mosc) ; 89(6): 1109-1121, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38981704

RESUMEN

At the Institute of Cytology and Genetics (Novosibirsk, Russia) for over 85 generations, gray rats have been selected for high aggression toward humans (aggressive rats) or its complete absence (tame rats). Aggressive rats are an interesting model for studying fear-induced aggression. Benzopentathiepin TC-2153 exerts an antiaggressive effect on aggressive rats and affects the serotonergic system: an important regulator of aggression. The aim of this study was to investigate effects of TC-2153 on key serotonergic-system enzymes - tryptophan hydroxylase 2 (TPH2) and monoamine oxidase A (MAOA) - in the brain of aggressive and tame rats. Either TC-2153 (10 or 20 mg/kg) or vehicle was administered once intraperitoneally to aggressive and tame male rats. TPH2 and MAOA enzymatic activities and mRNA and protein levels were assessed. The selection for high aggression resulted in upregulation of Tph2 mRNA in the midbrain, of the TPH2 protein in the hippocampus, and of proteins TPH2 and MAOA in the hypothalamus, as compared to tame rats. MAO enzymatic activity was higher in the midbrain and hippocampus of aggressive rats while TPH2 activity did not differ between the strains. The single TC-2153 administration decreased TPH2 and MAO activity in the hypothalamus and midbrain, respectively. The drug affected MAOA protein levels in the hypothalamus: upregulated them in aggressive rats and downregulated them in tame ones. Thus, this study shows profound differences in the expression and activity of key serotonergic system enzymes in the brain of rats selectively bred for either highly aggressive behavior toward humans or its absence, and the effects of benzopentathiepin TC-2153 on these enzymes may point to mechanisms of its antiaggressive action.


Asunto(s)
Agresión , Encéfalo , Monoaminooxidasa , Triptófano Hidroxilasa , Animales , Triptófano Hidroxilasa/metabolismo , Triptófano Hidroxilasa/genética , Monoaminooxidasa/metabolismo , Monoaminooxidasa/genética , Ratas , Masculino , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Agresión/efectos de los fármacos , Humanos , Serotonina/metabolismo
3.
Molecules ; 29(3)2024 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-38338326

RESUMEN

Deoxycholic acid derivatives containing various heterocyclic functional groups at C-3 on the steroid scaffold were designed and synthesized as promising dual tyrosyl-DNA phosphodiesterase 1 and 2 (TDP1 and TDP2) inhibitors, which are potential targets to potentiate topoisomerase poison antitumor therapy. The methyl esters of DCA derivatives with benzothiazole or benzimidazole moieties at C-3 demonstrated promising inhibitory activity in vitro against TDP1 with IC50 values in the submicromolar range. Furthermore, methyl esters 4d-e, as well as their acid counterparts 3d-e, inhibited the phosphodiesterase activity of both TDP1 and TDP2. The combinations of compounds 3d-e and 4d-e with low-toxic concentrations of antitumor drugs topotecan and etoposide showed significantly greater cytotoxicity than the compounds alone. The docking of the derivatives into the binding sites of TDP1 and TDP2 predicted plausible binding modes of the DCA derivatives.


Asunto(s)
Inhibidores de Fosfodiesterasa , Hidrolasas Diéster Fosfóricas , Inhibidores de Fosfodiesterasa/química , Hidrolasas Diéster Fosfóricas/metabolismo , Modelos Moleculares , Ácido Desoxicólico/farmacología , Relación Estructura-Actividad
4.
Molecules ; 29(18)2024 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-39339493

RESUMEN

The novel antiparkinsonian agent PA-96 is the focus of our research. PA-96 supported the survival of cultured naïve dopamine neurons, alleviated motor deficits in MPTP and haloperidol-based mice models of Parkinson's disease, and increased the density of tyrosine hydroxylase positive neurons and dopamine concentration in the midbrain of an MPTP-damaged brain. In this work, an HPLC-MS/MS method was developed and validated, and the pharmacokinetics of the agent was investigated in mice after a single or multiple oral administration (p.o.) and intravenous injection (i.v.) at various doses. The dose proportionality was also evaluated after a single p.o. administration of three ascending doses (1, 5, and 10 mg/kg) and a single i.v. injection of two doses (1 and 10 mg/kg); also, the bioavailability was estimated. The disproportionality of pharmacokinetic parameters could be explained by the saturation of active centres of enzymes or receptors binding the substance: at low doses, part of the compound is bound, leaving a small amount circulating in blood, and rapidly metabolised and/or bound too. The bioavailability of PA-96 was c.a. 7 and 35% for the doses of 5 and 10 mg/kg, correspondingly.


Asunto(s)
Antiparkinsonianos , Animales , Ratones , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/química , Masculino , Triazoles/farmacocinética , Triazoles/administración & dosificación , Espectrometría de Masas en Tándem , Relación Dosis-Respuesta a Droga , Disponibilidad Biológica , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Administración Oral , Cromatografía Líquida de Alta Presión , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad
5.
Int J Mol Sci ; 24(9)2023 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-37175662

RESUMEN

The DNA repair system plays a crucial role in maintaining the integrity of the genome [...].


Asunto(s)
Enzimas Reparadoras del ADN , Reparación del ADN , Enzimas Reparadoras del ADN/metabolismo , Genoma , Preparaciones Farmacéuticas , Daño del ADN
6.
Int J Mol Sci ; 24(6)2023 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-36982914

RESUMEN

Parkinson's disease is the second most common neurodegenerative disease. Unfortunately, there is still no definitive disease-modifying therapy. In our work, the antiparkinsonian potential of trans-epoxide (1S,2S,3R,4S,6R)-1-methyl-4-(prop-1-en-2-yl)-7-oxabicyclo [4.1.0]heptan-2,3-diol (E-diol) was analyzed in a rotenone-induced neurotoxicity model using in vitro, in vivo and ex vivo approaches. It was conducted as part of the study of the mitoprotective properties of the compound. E-diol has been shown to have cytoprotective properties in the SH-SY5Y cell line exposed to rotenone, which is associated with its ability to prevent the loss of mitochondrial membrane potential and restore the oxygen consumption rate after inhibition of the complex I function. Under the conditions of rotenone modeling of Parkinson's disease in vivo, treatment with E-diol led to the leveling of both motor and non-motor disorders. The post-mortem analysis of brain samples from these animals demonstrated the ability of E-diol to prevent the loss of dopaminergic neurons. Moreover, that substance restored functioning of the mitochondrial respiratory chain complexes and significantly reduced the production of reactive oxygen species, preventing oxidative damage. Thus, E-diol can be considered as a new potential agent for the treatment of Parkinson's disease.


Asunto(s)
Neuroblastoma , Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , Rotenona/toxicidad , Rotenona/metabolismo , Monoterpenos/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Línea Celular Tumoral , Neuroblastoma/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Mitocondrias/metabolismo , Fenotipo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/metabolismo
7.
Int J Mol Sci ; 24(2)2023 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-36674499

RESUMEN

The Bdnf (brain-derived neurotrophic factor) gene contains eight regulatory exons (I-VIII) alternatively spliced to the protein-coding exon IX. Only exons I, II, IV, and VI are relatively well studied. The BDNF system and brain serotonergic system are tightly interconnected and associated with aggression. The benzopentathiepine TC-2153 affects both systems and exerts antiaggressive action. Our aim was to evaluate the effects of TC-2153 on the Bdnf exons I-IX's expressions and serotonin receptors' mRNA levels in the brain of rats featuring high aggression toward humans (aggressive) or its absence (tame). Aggressive and tame adult male rats were treated once with vehicle or 10 or 20 mg/kg of TC-2153. mRNA was quantified in the cortex, hippocampus, hypothalamus, and midbrain with real-time PCR. Selective breeding for high aggression or its absence affected the serotonin receptors' and Bdnf exons' transcripts differentially, depending on the genotype (strain) and brain region. TC-2153 had comprehensive effects on the Bdnf exons' expressions. The main trend was downregulation in the hypothalamus and midbrain. TC-2153 increased 5-HT1B receptor hypothalamusc mRNA expression. For the first time, an influence of TC-2153 on the expressions of Bdnf regulatory exons and the 5-HT1B receptor was shown, as was an association between Bdnf regulatory exons and fear-induced aggression involving genetic predisposition.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Receptor de Serotonina 5-HT1B , Humanos , Ratas , Animales , Masculino , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Receptor de Serotonina 5-HT1B/genética , Receptor de Serotonina 5-HT1B/metabolismo , Encéfalo/metabolismo , Miedo/fisiología , ARN Mensajero/análisis , Hipocampo/metabolismo , Agresión/fisiología
8.
Int J Mol Sci ; 24(11)2023 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-37298694

RESUMEN

Novel monoterpene-based hydroxamic acids of two structural types were synthesized for the first time. The first type consisted of compounds with a hydroxamate group directly bound to acyclic, monocyclic and bicyclic monoterpene scaffolds. The second type included hydroxamic acids connected with the monoterpene moiety through aliphatic (hexa/heptamethylene) or aromatic linkers. An in vitro analysis of biological activity demonstrated that some of these molecules had powerful HDAC6 inhibitory activity, with the presence of a linker area in the structure of compounds playing a key role. In particular, it was found that hydroxamic acids containing a hexa- and heptamethylene linker and (-)-perill fragment in the Cap group exhibit excellent inhibitory activity against HDAC6 with IC50 in the submicromolar range from 0.56 ± 0.01 µM to 0.74 ± 0.02 µM. The results of the study of antiradical activity demonstrated the presence of moderate ability for some hydroxamic acids to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2ROO• radicals. The correlation coefficient between the DPPH radical scavenging activity and oxygen radical absorbance capacity (ORAC) value was R2 = 0.8400. In addition, compounds with an aromatic linker based on para-substituted cinnamic acids, having a monocyclic para-menthene skeleton as a Cap group, 35a, 38a, 35b and 38b, demonstrated a significant ability to suppress the aggregation of the pathological ß-amyloid peptide 1-42. The 35a lead compound with a promising profile of biological activity, discovered in the in vitro experiments, demonstrated neuroprotective effects on in vivo models of Alzheimer's disease using 5xFAD transgenic mice. Together, the results obtained demonstrate a potential strategy for the use of monoterpene-derived hydroxamic acids for treatment of various aspects of Alzheimer's disease.


Asunto(s)
Enfermedad de Alzheimer , Animales , Ratones , Enfermedad de Alzheimer/tratamiento farmacológico , Ácidos Hidroxámicos/química , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Inhibidores de Histona Desacetilasas/química , Ratones Transgénicos , Péptidos beta-Amiloides , Relación Estructura-Actividad
9.
Int J Mol Sci ; 24(4)2023 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-36835244

RESUMEN

Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a promising target for antitumor therapy; the use of TDP1 inhibitors with a topoisomerase 1 poison such as topotecan is a potential combination therapy. In this work, a novel series of 3,5-disubstituted thiazolidine-2,4-diones was synthesized and tested against TDP1. The screening revealed some active compounds with IC50 values less than 5 µM. Interestingly, compounds 20d and 21d were the most active, with IC50 values in the submicromolar concentration range. None of the compounds showed cytotoxicity against HCT-116 (colon carcinoma) and MRC-5 (human lung fibroblasts) cell lines in the 1-100 µM concentration range. Finally, this class of compounds did not sensitize cancer cells to the cytotoxic effect of topotecan.


Asunto(s)
Inhibidores de Fosfodiesterasa , Hidrolasas Diéster Fosfóricas , Tiazolidinedionas , Humanos , Modelos Moleculares , Monoterpenos/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Topotecan/farmacología , Tiazolidinedionas/farmacología
10.
Int J Mol Sci ; 24(16)2023 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-37628818

RESUMEN

The utility of sterically hindered phenols (SHPs) in drug design is based on their chameleonic ability to switch from an antioxidant that can protect healthy tissues to highly cytotoxic species that can target tumor cells. This work explores the biological activity of a family of 45 new hybrid molecules that combine SHPs equipped with an activating phosphonate moiety at the benzylic position with additional urea/thiourea fragments. The target compounds were synthesized by reaction of iso(thio)cyanates with C-arylphosphorylated phenols containing pendant 2,6-diaminopyridine and 1,3-diaminobenzene moieties. The SHP/urea hybrids display cytotoxic activity against a number of tumor lines. Mechanistic studies confirm the paradoxical nature of these substances which combine pronounced antioxidant properties in radical trapping assays with increased reactive oxygen species generation in tumor cells. Moreover, the most cytotoxic compounds inhibited the process of glycolysis in SH-SY5Y cells and caused pronounced dissipation of the mitochondrial membrane of isolated rat liver mitochondria. Molecular docking of the most active compounds identified the activator allosteric center of pyruvate kinase M2 as one of the possible targets. For the most promising compounds, 11b and 17b, this combination of properties results in the ability to induce apoptosis in HuTu 80 cells along the intrinsic mitochondrial pathway. Cyclic voltammetry studies reveal complex redox behavior which can be simplified by addition of a large excess of acid that can protect some of the oxidizable groups by protonations. Interestingly, the re-reduction behavior of the oxidized species shows considerable variations, indicating different degrees of reversibility. Such reversibility (or quasi-reversibility) suggests that the shift of the phenol-quinone equilibrium toward the original phenol at the lower pH may be associated with lower cytotoxicity.


Asunto(s)
Neuroblastoma , Fenoles , Humanos , Animales , Ratas , Fenoles/farmacología , Antioxidantes/farmacología , Fenol , Urea , Especies Reactivas de Oxígeno , Simulación del Acoplamiento Molecular , Apoptosis
11.
Int J Mol Sci ; 24(16)2023 Aug 18.
Artículo en Inglés | MEDLINE | ID: mdl-37629115

RESUMEN

Respiratory syncytial virus (RSV) is known to cause annual epidemics of respiratory infections; however, the lack of specific treatment options for this disease poses a challenge. In light of this, there has been a concerted effort to identify small molecules that can effectively combat RSV. This article focuses on the mechanism of action of compound K142, which was identified as a primary screening leader in the earlier stages of the project. The research conducted demonstrates that K142 significantly reduces the intensity of virus penetration into the cells, as well as the formation of syncytia from infected cells. These findings show that the compound's interaction with the surface proteins of RSV is a key factor in its antiviral activity. Furthermore, pharmacological modeling supports that K142 effectively interacts with the F-protein. However, in vivo studies have shown only weak antiviral activity against RSV infection, with a slight decrease in viral load observed in lung tissues. As a result, there is a need to enhance the bioavailability or antiviral properties of this compound. Based on these findings, we hypothesize that further modifications of the compound under study could potentially increase its antiviral activity.


Asunto(s)
Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Infecciones del Sistema Respiratorio , Humanos , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Antivirales/farmacología , Disponibilidad Biológica
12.
Int J Mol Sci ; 24(11)2023 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-37298106

RESUMEN

Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is an important enzyme in the DNA repair system. The ability of the enzyme to repair DNA damage induced by a topoisomerase 1 poison such as the anticancer drug topotecan makes TDP1 a promising target for complex antitumor therapy. In this work, a set of new 5-hydroxycoumarin derivatives containing monoterpene moieties was synthesized. It was shown that most of the conjugates synthesized demonstrated high inhibitory properties against TDP1 with an IC50 in low micromolar or nanomolar ranges. Geraniol derivative 33a was the most potent inhibitor with IC50 130 nM. Docking the ligands to TDP1 predicted a good fit with the catalytic pocket blocking access to it. The conjugates used in non-toxic concentration increased cytotoxicity of topotecan against HeLa cancer cell line but not against conditionally normal HEK 293A cells. Thus, a new structural series of TDP1 inhibitors, which are able to sensitize cancer cells to the topotecan cytotoxic effect has been discovered.


Asunto(s)
Antineoplásicos , Topotecan , Humanos , Topotecan/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Inhibidores de Fosfodiesterasa/química , Relación Estructura-Actividad , Hidrolasas Diéster Fosfóricas/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral
13.
Molecules ; 28(21)2023 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-37959723

RESUMEN

Two approaches to the synthesis of para-menthene epoxide ((1S,5S,6R)-4) are developed. The first approach includes a reaction between chlorohydrin 7 and NaH in THF. The second involves the formation of epoxide in the reaction of corresponding diacetate 6 with sodium tert-butoxide. One possible mechanism of this reaction is proposed to explain unexpected outcomes in the regio- and stereospecificity of epoxide (1S,5S,6R)-4 formation. The epoxide ring in (1S,5S,6R)-4 is then opened by various S- and O-nucleophiles. This series of reactions allows for the stereoselective synthesis of diverse derivatives of the monoterpenoid Prottremine 1, a compound known for its antiparkinsonian activity, including promising antiparkinsonian properties.

14.
Molecules ; 28(6)2023 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-36985645

RESUMEN

Respiratory syncytial virus (RSV) causes annual epidemics of respiratory infection. Usually harmless to adults, the RSV infection can be dangerous to children under 3 years of age and elderly people over 65 years of age, often causing serious problems, even death. At present, there are no vaccines and specific chemotherapeutic agents for the treatment of this disease, so the search for low-molecular weight compounds to combat RSV is a challenge. In this work, we have shown, for the first time, that monoterpene-substituted arylcoumarins are efficient RSV replication inhibitors at low micromolar concentrations. The most active compound has a selectivity index of about 200 and acts most effectively at the early stages of infection. The F protein of RSV is a potential target for these compounds, which is also confirmed by molecular docking and molecular dynamics simulation data.


Asunto(s)
Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Niño , Humanos , Preescolar , Anciano , Simulación del Acoplamiento Molecular , Anticuerpos Antivirales , Proteínas Virales de Fusión , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Replicación Viral
15.
Bioorg Med Chem Lett ; 73: 128909, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-35907608

RESUMEN

Tyrosyl-DNA phosphodiesterase 1(TDP1) is a promising target for a new therapy in oncological disease as an adjunct to topoisomerase 1 (TOP1) drugs. In this paper, novel thiazolidin-4-one derivatives with a benzyl and monoterpene substituents were synthesized. Compounds with a monoterpene fragment attached via a phenyloxy linker were active against TDP1 with IC50 values in the 1 ÷ 3 µM range, while direct attachment of monoterpene moiety to the thiazolidin-4-one fragment had no activity. Molecular modelling predicted two plausible binding modes of the active compounds both effectively blocking access to the catalytic site of TDP. At non-toxic concentrations the active ligands potentiated the efficacy of the TOP1 poison topotecan in human cervical cancer HeLa cells, but not in non-cancerous HEK293A cells.


Asunto(s)
Inhibidores de Fosfodiesterasa , Hidrolasas Diéster Fosfóricas , Esterasas/metabolismo , Células HeLa , Humanos , Monoterpenos/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Relación Estructura-Actividad
16.
Molecules ; 27(24)2022 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-36557798

RESUMEN

Natural and synthetic coumarins are often considered privileged scaffolds for obtaining pharmacological agents with hypoglycemic activity. Chemical modification of coumarins often leads to antidiabetic agents with greater efficacy. In the present work, twenty monoterpene-substituted 7-hydroxycoumarins were synthesized. A new approach using the Mitsunobu reaction was shown to be effective for the synthesis of target compounds. All of the synthesized compounds were evaluated in an oral glucose tolerance test, and two of them containing geranyl and (-)-myrtenyl substituents showed in vivo hypoglycemic action. A possible mechanism of action of these compounds may include inhibition of DPP IV, which was proved in an in vitro test.


Asunto(s)
Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Humanos , Hipoglucemiantes/química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Prueba de Tolerancia a la Glucosa , Dipeptidil Peptidasa 4/química , Glucemia
17.
Molecules ; 27(17)2022 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-36080227

RESUMEN

Alzheimer's disease (AD) is a neurodegenerative disease associated with memory impairment and other central nervous system (CNS) symptoms. Two myrtenal-adamantane conjugates (MACs) showed excellent CNS potential against Alzheimer's models. Adamantane is a common pharmacophore for drug design, and myrtenal (M) demonstrated neuroprotective effects in our previous studies. The aim of this study is to evaluate the MACs' neuroprotective properties in dementia. METHODS: Scopolamine (Scop) was applied intraperitoneally in Wistar rats for 11 days, simultaneously with MACs or M as a referent, respectively. Brain acetylcholine esterase (AChE) activity, noradrenaline and serotonin levels, and oxidative brain status determination followed behavioral tests on memory abilities. Molecular descriptors and docking analyses for AChE activity center affinity were performed. RESULTS: M derivatives have favorable physicochemical parameters to enter the CNS. Both MACs restored memory damaged by Scop, showing significant AChE-inhibitory activity in the cortex, in contrast to M, supported by the modeling analysis. Moderate antioxidant properties were manifested by glutathione elevation and catalase activity modulation. MACs also altered noradrenaline and serotonin content in the hippocampus. CONCLUSION: For the first time, neuroprotective properties of two MACs in a rat dementia model were observed. They were stronger than the natural M effects, which makes the substances promising candidates for AD treatment.


Asunto(s)
Adamantano , Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Acetilcolinesterasa/metabolismo , Adamantano/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Monoterpenos Bicíclicos , Aprendizaje por Laberinto , Enfermedades Neurodegenerativas/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Norepinefrina , Estrés Oxidativo , Ratas , Ratas Wistar , Escopolamina/farmacología , Serotonina/metabolismo
18.
Molecules ; 27(23)2022 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-36500381

RESUMEN

Parkinson's disease (PD) is the most common age-related movement disorder characterized by the progressive loss of nigrostriatal dopaminergic neurons. To date, PD treatment strategies are mostly based on dopamine replacement medicines, which can alleviate motor symptoms but do not slow down the progression of neurodegeneration. Thus, there is a need for disease-modifying PD therapies. The aim of this work was to evaluate the neuroprotective effects of the novel compound PA96 on dopamine neurons in vivo and in vitro, assess its ability to alleviate motor deficits in MPTP- and haloperidol-based PD models, as well as PK profile and BBB penetration. PA96 was synthesized from (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl) cyclohex-3-ene-1,2-diol (Prottremin) using the original three-step stereoselective procedure. We found that PA96: (1) supported the survival of cultured näive dopamine neurons; (2) supported the survival of MPP+-challenged dopamine neurons in vitro and in vivo; (3) had chemically appropriate properties (synthesis, solubility, etc.); (4) alleviated motor deficits in MPTP- and haloperidol-based models of PD; (5) penetrated the blood-brain barrier in vivo; and (6) was eliminated from the bloodstream relative rapidly. In conclusion, the present article demonstrates the identification of PA96 as a lead compound for the future development of this compound into a clinically used drug.


Asunto(s)
Intoxicación por MPTP , Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Ratones , Humanos , Neuronas Dopaminérgicas , Intoxicación por MPTP/tratamiento farmacológico , Monoterpenos/farmacología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Haloperidol/farmacología , Sustancia Negra
19.
Molecules ; 27(11)2022 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-35684313

RESUMEN

Inhibiting tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising strategy for increasing the effectiveness of existing antitumor therapy since it can remove the DNA lesions caused by anticancer drugs, which form covalent complexes with topoisomerase 1 (TOP1). Here, new adamantane-monoterpene conjugates with a 1,2,4-triazole or 1,3,4-thiadiazole linker core were synthesized, where (+)-and (-)-campholenic and (+)-camphor derivatives were used as monoterpene fragments. The campholenic derivatives 14a-14b and 15a-b showed activity against TDP1 at a low micromolar range with IC50 ~5-6 µM, whereas camphor-containing compounds 16 and 17 were ineffective. Surprisingly, all the compounds synthesized demonstrated a clear synergy with topotecan, a TOP1 poison, regardless of their ability to inhibit TDP1. These findings imply that different pathways of enhancing topotecan toxicity other than the inhibition of TDP1 can be realized.


Asunto(s)
Adamantano , Antineoplásicos , Adamantano/farmacología , Antineoplásicos/farmacología , Alcanfor , Monoterpenos/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Topotecan/farmacología
20.
Bioorg Med Chem Lett ; 31: 127677, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33171219

RESUMEN

We synthesized fluoro- and hydroxy-containing octahydro-2H-chromenes by the Prins reaction starting from a monoterpenoid (-)-isopulegol and a wide range of aromatic aldehydes in the presence of the BF3∙Et2O/H2O system acting as both an acid catalyst and a fluorine source. Activity of the produced compounds against the influenza A/Puerto Rico/8/34 (H1N1) virus was studied. The highest activity was demonstrated by fluoro- (11i) and hydroxy-containing (10i) derivatives of 2,4,6-trimethoxybenzaldehyde. The most pronounced virus-inhibiting effect of compounds 10i and 11i was observed at an early stage of infection. These compounds were supposed to be capable of binding to viral hemagglutinin, which is an agreement with data on the effect of compounds 10i and 11i on the viral fusogenic activity as well as by molecular docking studies.


Asunto(s)
Antivirales/farmacología , Benzopiranos/farmacología , Monoterpenos Ciclohexánicos/farmacología , Virus de la Influenza A/efectos de los fármacos , Animales , Antivirales/síntesis química , Antivirales/química , Benzopiranos/síntesis química , Benzopiranos/química , Células CACO-2 , Muerte Celular/efectos de los fármacos , Monoterpenos Ciclohexánicos/síntesis química , Monoterpenos Ciclohexánicos/química , Perros , Relación Dosis-Respuesta a Droga , Humanos , Células de Riñón Canino Madin Darby/efectos de los fármacos , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad
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