RESUMEN
Ηypercholesterolemia/hyperlipidemia in conjunction with oxidative stress and inflammatory processes contribute synergistically to the pathogenesis of atherosclerosis. We hereby evaluated the antiatherosclerotic effect of the multi-target derivative 4-methyl-2-(10H-phenothiazin-3-yl)morpholin-2-ol hydrobromide 1 in apoE-/- mice; compound 1 is a potent antihyperlipidemic agent acting through Squalene Synthase inhibition, while it has exhibited an outstanding antioxidant and anti-inflammatory activity in various experimental animal models. The new analogue was evaluated in terms of its antiatherosclerotic/antioxidant effect in the ApoE-/- transgenic mouse model. Its toxicity profile was also assessed by measuring the levels of four sensitive indicators of liver toxicity. Prolonged administration of 1 in ApoE-/- mice fed with a western-type (wt) diet efficiently reduced the aortic atheromatic lesions, an effect that took place through a cholesterol lowering independent manner. In addition, 1 displayed a significant reduction not only of glucose but also of oxidative stress levels, while it did not cause any toxicity. To the best of our knowledge this is the first time that the antiatherosclerotic effect of a Squalene Synthase inhibitor is studied in this specific atherosclerosis mouse model. As a result, compound 1 may serve as a promising starting point towards developing new bioactive analogues against the onset and subsequent development of atherosclerosis.
Asunto(s)
Aterosclerosis , Farnesil Difosfato Farnesil Transferasa , Ratones , Animales , Escualeno , Aterosclerosis/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Apolipoproteínas E/genética , Ratones Transgénicos , Antioxidantes/farmacología , Ratones NoqueadosRESUMEN
Even though non-steroidal anti-inflammatory drugs are the most effective treatment for inflammatory conditions, they have been linked to negative side effects. A promising approach to mitigating potential risks, is the development of new compounds able to combine anti-inflammatory with antioxidant activity to enhance activity and reduce toxicity. The implication of reactive oxygen species in inflammatory conditions has been extensively studied, based on the pro-inflammatory properties of generated free radicals. Drugs with dual activity (i.e., inhibiting inflammation related enzymes, e.g., LOX-3 and scavenging free radicals, e.g., DPPH) could find various therapeutic applications, such as in cardiovascular or neurodegenerating disorders. The challenge we embarked on using deep learning was the creation of appropriate classification and regression models to discriminate pharmacological activity and selectivity as well as to discover future compounds with dual activity prior to synthesis. An accurate filter algorithm was established, based on knowledge from compounds already evaluated in vitro, that can separate compounds with low, moderate or high activity. In this study, we constructed a customized highly effective one dimensional convolutional neural network (CONV1D), with accuracy scores up to 95.2%, that was able to identify dual active compounds, being LOX-3 inhibitors and DPPH scavengers, as an indication of simultaneous anti-inflammatory and antioxidant activity. Additionally, we created a highly accurate regression model that predicted the exact value of effectiveness of a set of recently synthesized compounds with anti-inflammatory activity, scoring a root mean square error value of 0.8. Eventually, we succeeded in observing the manner in which those newly synthesized compounds differentiate from each other, regarding a specific pharmacological target, using deep learning algorithms.
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This study was designed to evaluate the chemical fingerprints and the antioxidant, anti-inflammatory and hypolipidemic activity of selected Crepis species collected in Greece, namely, C. commutata, C. dioscoridis, C. foetida, C. heldreichiana, C. incana, C. rubra, and Phitosia crocifolia (formerly known as Crepis crocifolia). For the phytochemical analyses, sample measurements were carried out by using nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography coupled with mass spectrometry (LC-MS). Τhe extracts were evaluated both in vitro (radical scavenging activity: DPPH assay and total phenolic content: Folin-Ciocalteu) and in vivo (paw edema reduction and hypolipidemic activity: experimental mouse protocols). Among the tested extracts, C. incana presented the highest gallic acid equivalents (GAE) (0.0834 mg/mL) and the highest antioxidant activity (IC50 = 0.07 mg/mL) in vitro, as well as the highest anti-inflammatory activity with 32% edema reduction in vivo. Moreover, in the hypolipidemic protocol, the same extract increased plasma total antioxidant capacity (TAC) by 48.7%, and decreased cholesterol (41.3%) as well as triglycerides (37.2%). According to fractionation of the extract and the phytochemical results, this biological effect may be associated with the rich phenolic composition; caffeoyl tartaric acid derivatives (cichoric and caftaric acid) are regarded as the most prominent bioactive specialized metabolites. The present study contributes to the knowledge regarding the phytochemical and pharmacological profile of Crepis spp.
Asunto(s)
Antioxidantes , Crepis , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antioxidantes/química , Colesterol , Edema/tratamiento farmacológico , Ácido Gálico , Ratones , Fitoquímicos/análisis , Fitoquímicos/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacología , TriglicéridosRESUMEN
Multifactorial diseases exhibit a complex pathophysiology with several factors contributing to their pathogenesis and development. Examples of such disorders are neurodegenerative (e. g. Alzheimer's, Parkinson's) and cardiovascular diseases (e. g. atherosclerosis, metabolic syndrome, diabetes II). Traditional therapeutic approaches with single-target drugs have been proven, in many cases, unsatisfactory for the treatment of multifactorial diseases such as diabetes II. The well-established by now strategy of multitarget drugs is constantly gaining interest and momentum, as a more effective approach. The development of pharmacomolecules able to simultaneously modulate multiple relevant-to-the-disease targets has already several successful examples in various fields and has, as such, inspired the design of multitarget antidiabetic agents; this review highlights the design aspect and efficacy of this approach for improved antidiabetics by presenting several examples of successful pharmacophore combinations in (multitarget) agents that modulate two or more molecular targets involved in diabetes II, resulting in a superior antihyperglycemic profile.
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Diabetes Mellitus , Hipoglucemiantes , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéuticoRESUMEN
Oxidative stress and inflammation are two conditions that coexist in many multifactorial diseases such as atherosclerosis and neurodegeneration. Thus, the design of multifunctional compounds that can concurrently tackle two or more therapeutic targets is an appealing approach. In this study, the basic NSAID structure was fused with the antioxidant moieties 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHB), its reduced alcohol 3,5-di-tert-butyl- 4-hydroxybenzyl alcohol (BHBA), or 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox), a hydrophilic analogue of α-tocopherol. Machine learning algorithms were utilized to validate the potential dual effect (anti-inflammatory and antioxidant) of the designed analogues. Derivatives 1-17 were synthesized by known esterification methods, with good to excellent yields, and were pharmacologically evaluated both in vitro and in vivo for their antioxidant and anti-inflammatory activity, whereas selected compounds were also tested in an in vivo hyperlipidemia protocol. Furthermore, the activity/binding affinity of the new compounds for lipoxygenase-3 (LOX-3) was studied not only in vitro but also via molecular docking simulations. Experimental results demonstrated that the antioxidant and anti-inflammatory activities of the new fused molecules were increased compared to the parent molecules, while molecular docking simulations validated the improved activity and revealed the binding mode of the most potent inhibitors. The purpose of their design was justified by providing a potentially safer and more efficient therapeutic approach for multifactorial diseases.
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Antioxidantes/química , Aterosclerosis/tratamiento farmacológico , Hiperlipidemias/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Inhibidores de la Lipooxigenasa/química , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/química , Antioxidantes/síntesis química , Antioxidantes/farmacología , Aterosclerosis/patología , Cromanos/química , Cromanos/farmacología , Diseño de Fármacos , Humanos , Hiperlipidemias/patología , Hipolipemiantes/síntesis química , Hipolipemiantes/química , Hipolipemiantes/farmacología , Inflamación/patología , Lipooxigenasa/química , Lipooxigenasa/efectos de los fármacos , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/farmacología , Simulación del Acoplamiento Molecular , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/patología , Estrés Oxidativo/efectos de los fármacos , Parabenos/química , Parabenos/farmacología , Relación Estructura-ActividadRESUMEN
Dyslipidemia is one of the most important cardiovascular disease (CVD) risk factors. Polyunsaturated fatty acids (FAs), and especially omega-3 FAs, could significantly contribute to the management of dyslipidemia and the prevention of CVD. The anti-hyperlipidemic effect of selected fish oils (eel, sardine, trout, cod liver) was comparatively evaluated in a high fat diet (HFD)-fed mouse model. At the end of 30 days on the HFD, all animals were hyperlipidemic and were switched to a diet consisting of 90% standard rodent chow plus 10% of oil from eel, sardine, cod liver, or trout. At the end of 60 days on these diets, blood glucose, total blood cholesterol, triglycerides (TGs), and high density lipoprotein (HDL) were quantitated. All diets, except sardine and standard rodent chow, showed statistically significant decreases in blood glucose from day 30 to 90. Total blood cholesterol decreased in all diets except the HFD group, which was continued on this diet until the end of the study. Eel and cod liver oil diets showed significant decreases in TGs. All dietary groups showed a decrease in HDL, but only the trout and standard chow groups exhibited statistically significant decreases. The fish oils tested here for effects on hyperlipidemia vary in per cent of omega-3 FAs and omega-6/-3 FA ratios as determined by gas chromatography Overall, smoked eel was the best source of omega-3 FA, with a balance of omega-6 FA, that ameliorated HFD-induced mixed hyperlipidemia.
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Ácidos Grasos Omega-3 , Hiperlipidemias , Animales , Anguilas , Aceites de Pescado , Hiperlipidemias/tratamiento farmacológico , Ratones , TruchaRESUMEN
Squalene synthase (SQS) inhibitors, mostly known as antihyperlipidemic agents for controlling blood cholesterol levels, have been increasingly used to study alterations of the cholesterol content in cell membranes. As such, SQS inhibitors have been demonstrated to control cellular activities related to cancer cell proliferation and migration, neuron degeneration, and parasite growth. While the mechanisms behind the effects of cellular cholesterol are still being revealed in detail, the evidence for SQS as a therapeutic target for several seemingly unrelated diseases is increasing. SQS inhibitors may be the next promising candidates targeting the three remaining primary therapeutic areas, beyond cardiovascular disease, which still need to be addressed; their application as anticancer, antimicrobial, and antineurodegenerative agents appears promising for new drug discovery projects underway.
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Inhibidores Enzimáticos/farmacología , Farnesil Difosfato Farnesil Transferasa/antagonistas & inhibidores , Hipolipemiantes/farmacología , Animales , Antiinfecciosos/farmacología , Antineoplásicos/farmacología , Colesterol/sangre , Colesterol/metabolismo , Descubrimiento de Drogas , Farnesil Difosfato Farnesil Transferasa/metabolismo , HumanosRESUMEN
Morpholine is a frequently used heterocycle in medicinal chemistry and a privileged structural component of bioactive molecules. This is mainly due to its contribution to a plethora of biological activities as well as to an improved pharmacokinetic profile of such bioactive molecules. The synthesis of morpholines is a subject of much study due to their biological and pharmacological importance, with the last such review being published in 2013. Here, an overview of the main approaches toward morpholine synthesis or functionalization is presented, emphasizing on novel work which has not been reviewed so far. This review is an update on synthetic strategies leading to easily accessible libraries of bioactives which are of interest for drug discovery projects.
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Morfolinas/síntesis química , Química Farmacéutica , Estructura Molecular , Morfolinas/químicaRESUMEN
Morpholine is a heterocycle featured in numerous approved and experimental drugs as well as bioactive molecules. It is often employed in the field of medicinal chemistry for its advantageous physicochemical, biological, and metabolic properties, as well as its facile synthetic routes. The morpholine ring is a versatile and readily accessible synthetic building block, it is easily introduced as an amine reagent or can be built according to a variety of available synthetic methodologies. This versatile scaffold, appropriately substituted, possesses a wide range of biological activities. There are many examples of molecular targets of morpholine bioactive in which the significant contribution of the morpholine moiety has been demonstrated; it is an integral component of the pharmacophore for certain enzyme active-site inhibitors whereas it bestows selective affinity for a wide range of receptors. A large body of in vivo studies has demonstrated morpholine's potential to not only increase potency but also provide compounds with desirable drug-like properties and improved pharamacokinetics. In this review we describe the medicinal chemistry/pharmacological activity of morpholine derivatives on various therapeutically related molecular targets, attempting to highlight the importance of the morpholine ring in drug design and development as well as to justify its classification as a privileged structure.
Asunto(s)
Química Farmacéutica , Morfolinas/química , Morfolinas/farmacología , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Terapia Molecular DirigidaRESUMEN
Among the causal risk factors directly promoting the development of coronary and peripheral atherosclerosis are reactive oxygen species and elevated low-density lipoprotein plasma levels. We hereby designed new potent squalene synthase (SQS) inhibitors that may simultaneously tackle the oxidative stress induced by lipid peroxidation. Using previously developed morpholine derivatives as a starting point, we conducted extensive structural changes by either substituting or modifying the morpholine ring, aiming at an optimal SQS-antioxidant pharmacological profile. Compounds 2, 3, and 7 emerged as the most potent bifunctional analogues, displaying IC50 values for SQS inhibition of 0.014, 0.16, and 0.51 µΜ, respectively, and further significantly decreasing lipid peroxidation of hepatic microsomal membranes. The aforementioned activities were also confirmed in vivo since the most promising derivative 2 exhibited a remarkable antihyperlipidemic and antioxidant effect. In conclusion, rational drug design accompanied by structure-activity relationship studies led to compounds combining improved antioxidant and antihyperlipidemic activity that may serve as multifunctional agents against atherosclerosis.
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For the treatment of multifactorial and complex diseases, it has become increasingly apparent that compounds acting at multiple targets often deliver superior efficacy compared to compounds with high specificity for only a single target. Based on previous studies demonstrating the important antioxidant and anti-hyperlipidemic effect of morpholine and 1,4-benzo(x/thi)azine derivatives (A-E), we hereby present the design, synthesis and pharmacological evaluation of novel dual-acting molecules as a therapeutic approach for atherosclerosis. Analogues 1-10 were rationally designed through structural modifications of their parent compounds (A-E) in order for structure-activity relationship studies to be carried out. Most compounds showed a significant inhibition against Squalene Synthase activity exhibiting at the same time a very potent multimodal antioxidant (against lipid peroxidation and as free-radical scavengers) effect, thus bringing to light the 2-aryl-1,4-benzo(x/thia)zin-2-ol scaffold as an outstanding pharmacophore for the design of potent antioxidants. Finally, the replacement of the octahydro-1,4-benzoxazine moiety of lead compound D with its respective 1,4-benzothiazine (compound 4), although conserved (anti-hypercholesterolemic) or even improved (anti-hyperlipidemic) activity, did not preserve the anti-diabetic effect of D.
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Aterosclerosis/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Farnesil Difosfato Farnesil Transferasa/antagonistas & inhibidores , Hipolipemiantes/farmacología , Animales , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Diabetes Mellitus Tipo 2/inducido químicamente , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Farnesil Difosfato Farnesil Transferasa/metabolismo , Humanos , Hipolipemiantes/síntesis química , Hipolipemiantes/química , Masculino , Ratones , Ratones Pelados , Estructura Molecular , Morfolinas/síntesis química , Morfolinas/química , Morfolinas/farmacología , Estrés Oxidativo/efectos de los fármacos , Ratas , Relación Estructura-Actividad , Tiazinas/síntesis química , Tiazinas/química , Tiazinas/farmacologíaRESUMEN
In line with our previous studies, novel morpholine and benzoxa(or thia)zine lead compounds have been developed through a rational design that modulate a multiplicity of targets against atherosclerosis. We have evaluated the most promising compounds for their efficiency to a) intercept and scavenge free radicals, b) inhibit the metal ion (Cu2+)- induced LDL oxidation c) act intracellularly as antioxidants in THP-1 monocytes from a leukemic patient and d) inhibit the pro-inflammatory enzymes cyclooxygenase-1 (COX-1) and -2 (COX-2) in vitro. Furthermore, two representative compounds were tested for their potential to decrease lipidemic parameters (TC, LDL and TG) in hyperlipidemic mice. Most derivatives indicated a remarkable antioxidant activity, while at the same time exhibited a significant in vitro anti-inflammatory activity, inhibiting COX-1 or/and COX-2 activity at 20 µΜ. In addition, after their long-term administration, compounds 6 and 8 afforded considerable activity in a chronic experimental animal model of hyperlipidemia (after high fat diet administration). The multifunctional pharmacological profile exhibited by the compounds of this study renders them interesting lead compounds for the development of novel agents against atherosclerosis.
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Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/farmacología , Aterosclerosis/tratamiento farmacológico , Hipolipemiantes/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Antioxidantes/química , Benzoxazinas/química , Benzoxazinas/farmacología , Humanos , Hipolipemiantes/química , Estructura Molecular , Morfolinas/química , Morfolinas/farmacología , Tiazinas/química , Tiazinas/farmacologíaRESUMEN
Drugs affecting more than one target could result in a more efficient treatment of multifactorial diseases as well as fewer safety concerns, compared to a one-drug one-target approach. Within our continued efforts towards the design of multifunctional molecules against atherosclerosis, we hereby report the synthesis of 17 new morpholine derivatives which structurally vary in terms of the aromatic substitution on the morpholine ring. These derivatives simultaneously suppress cholesterol biosynthesis through SQS inhibition (IC50 values of the most active compounds are between 0.7 and 5.5 µM) while exhibiting a significant protection of hepatic microsomal membranes against lipid peroxidation (with IC50 values for the most active compounds being between 73 and 200 µM). Further evaluation of these compounds was accomplished in vivo in an animal model of acute experimental hyperlipidemia, where it was observed that compounds reduced the examined lipidemic parameters (TC, TG and LDL) by 15-80%. In order to examine the mode of binding of these molecules in the active catalytic site of SQS, we also performed docking simulation studies. Our results indicate that some of the new compounds can be considered interesting structures in the search for new multifunctional agents of potential application in atherosclerosis.
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Antioxidantes/química , Farnesil Difosfato Farnesil Transferasa/antagonistas & inhibidores , Hipolipemiantes/química , Morfolinas/química , Animales , Antioxidantes/metabolismo , Antioxidantes/uso terapéutico , Sitios de Unión , Dominio Catalítico , Modelos Animales de Enfermedad , Farnesil Difosfato Farnesil Transferasa/metabolismo , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/patología , Hipolipemiantes/metabolismo , Hipolipemiantes/uso terapéutico , Concentración 50 Inhibidora , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Morfolinas/metabolismo , Morfolinas/uso terapéutico , RatasRESUMEN
New tetracyclic and pentacyclic azaphenothiazines containing one or two quinoline rings instead of benzene rings were obtained in the original reactions of isomeric diquinodithiins, dichlorodiquinolinyl sulfides, and disulfide with aromatic amines. The type of ring fusion in the azaphenothiazine system was concluded from the 1H NMR spectra. The obtained azaphenothiazines were evaluated in vitro for their antioxidant activity on rat hepatic microsomal membranes for protection of non-enzymatic lipid peroxidation promoted by the Fe2+/ascorbic acid redox system. Most compounds exhibited a very significant antioxidant activity with IC50 values between 1 and 23 µM. The degree of antioxidant activity depends on the lipophilicity and molecular size as well as the (non)substitution of the thiazine nitrogen atom and type of ring system fusion. It is the first time to our knowledge that azaphenothiazines are shown to exhibit such potent antioxidant activity.
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Excessive levels of reactive oxygen species (ROS) result in numerous pathologies including muscle disorders. In essence, skeletal muscle performance of daily activities can be severely affected by the redox imbalances occurring after muscular injuries, surgery, atrophy due to immobilization, dystrophy or eccentric muscle contraction. Therefore, research on the potential beneficial impact of antioxidants is of outmost importance. In this context, aiming at further exploring the mechanisms of action of our newly synthesized antioxidant compounds (AK1 and AK2) in a skeletal muscle experimental setting, we initially investigated their scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) and subsequently assessed their effect on the viability of C2 skeletal myoblasts in the presence of two pro-oxidants: H2O2 and curcumin (MTT assay). Interestingly, while both compounds reversed the detrimental effect of H2O2, only AK2 was cytoprotective in curcumin-treated C2 cells. We next confirmed the immediate activation of extracellular signal-regulated kinases (ERKs) and the more delayed activation profile of c-Jun NH2-terminal kinases (JNKs) in C2 skeletal myoblasts exposed to curcumin, by Western blotting. In correlation with the aforementioned results, only AK2 blocked the curcumin-induced activation of JNKs pathway. Furthermore, JNKs were revealed to mediate curcumin-induced apoptosis in C2 cells and only AK2 to effectively suppress it (by detecting its effect on poly(ADP-ribose) polymerase fragmentation). Overall, we have shown that two similar in structure novel antioxidants confer differential effects on C2 skeletal myoblasts viability under oxidative stress conditions. This result may be attributed to these antioxidants respective diverse mode of interaction with the signaling effectors involved in the observed responses. Future studies should further evaluate the mechanism of action of these compounds in order to support their potential application in therapeutic protocols against ROS-related muscle disorders.
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Antioxidantes/farmacología , Curcumina/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Mioblastos Esqueléticos/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Ratones , Mioblastos Esqueléticos/citología , Mioblastos Esqueléticos/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Because atherosclerosis is an inflammatory process involving a series of pathological events such as dyslipidemia, oxidative stress, and blood clotting mechanisms, we hereby report the synthesis and evaluation of novel compounds in which antioxidant, anti-inflammatory, and squalene synthase (SQS) inhibitory/hypolipidemic activities are combined in simple molecules through design. The coupling of two different pharmacophores afforded compounds 1-12, whose biological profile was markedly improved compared to those of parent lead structures (i.e., the hypolipidemic 2-hydroxy-2-aryl-(benzo)oxa(or thia)zine and the antioxidant phenothiazine). Most derivatives strongly inhibited in vitro microsomal lipid and LDL peroxidation, exhibiting potent free-radical scavenging activity. They further significantly inhibited SQS activity and showed remarkable antidyslipidemic activity in vivo in animal models of acute and high-fat-induced hyperlipidemia. Finally, several compounds showed anti-inflammatory activity in vitro, inhibiting cycloxygenase (COX-1/2) activity. The multimodal properties of the new compounds and especially their combined antioxidant/SQS/COX inhibitory activity render them interesting lead compounds for further evaluation against atherosclerosis.
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Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/síntesis química , Antioxidantes/farmacología , Hipolipemiantes/síntesis química , Hipolipemiantes/farmacología , Fenotiazinas/síntesis química , Fenotiazinas/farmacología , Animales , Aterosclerosis/tratamiento farmacológico , Compuestos de Bifenilo , Carragenina , Colesterol en la Dieta/farmacología , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/farmacología , Dieta Alta en Grasa , Diseño de Fármacos , Edema/inducido químicamente , Edema/prevención & control , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Farnesil Difosfato Farnesil Transferasa/antagonistas & inhibidores , Técnicas In Vitro , Indicadores y Reactivos , Peroxidación de Lípido/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Picratos , RatasRESUMEN
Oxidative stress, inflammation, and hyperlipidemia are common factors involved in the pathophysiology of atherosclerosis and type 2 diabetes. We have previously developed multifunctional antidyslipidemic derivatives with antioxidant and antiatherogenic properties. We now report the design, synthesis, and evaluation of two such novel derivatives that incorporate a structural moiety of the antidiabetic agent succinobucol. The new compounds exhibited a much improved in vitro antioxidant and squalene synthase inhibitory activity (at lower micromolar concentrations) as well as a significant antihyperlipidemic effect, reducing plasma total cholesterol, triglycerides, and MDA by 65-90%. Compound 2 also indicated a good anti-inflammatory activity, decreasing edema by 44%, while it was further evaluated for its antidiabetic activity using a type 2 diabetes experimental mouse model. After 7 weeks of administration, it produced a significant antihyperglycemic and antihyperlipidemic activity. In conclusion, rational drug design led to a compound combining improved antioxidant, antidyslipidemic, and antidiabetic action that may serve as a potential therapeutic strategy in metabolic syndrome disorders.
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Antioxidantes/farmacología , Hipoglucemiantes/farmacología , Hipolipemiantes/farmacología , Animales , Antioxidantes/síntesis química , Aterosclerosis/tratamiento farmacológico , Glucemia/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Farnesil Difosfato Farnesil Transferasa/antagonistas & inhibidores , Hiperlipidemias/tratamiento farmacológico , Hipoglucemiantes/síntesis química , Hipolipemiantes/síntesis química , Lipoproteínas LDL/metabolismo , Masculino , Ratones , Estrés Oxidativo/efectos de los fármacos , Probucol/análogos & derivados , Probucol/farmacología , RatasRESUMEN
Atherosclerosis is a multifactorial disease with several mechanisms participating in its manifestation. To address this disorder, we applied a strategy involving the design of a single chemical compound able to simultaneously modulate more than one target. We hereby present the development of novel benzoxazine and benzothiazine derivatives that significantly inhibit in vitro microsomal lipid peroxidation and LDL oxidation as well as squalene synthase activity (IC(50) of 5-16 µM). Further, these compounds show antidyslipidemic and antioxidant properties in vivo, decreasing total cholesterol, LDL, triglyceride, and MDA levels of hyperlipidemic rats by 26-74%. Finally, by determination of their in vivo concentration (up to 24 h) in target tissues (blood/liver), it is shown that compounds reach their targets in the low micromolar range. The new compounds seem to be interesting multifunctional molecules for the development of a new pharmacophore for disease-modifying agents useful in the treatment of atherosclerosis.
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Aterosclerosis/tratamiento farmacológico , Benzoxazinas/uso terapéutico , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Tiazinas/uso terapéutico , Animales , Antioxidantes/farmacología , Benzoxazinas/farmacocinética , LDL-Colesterol/química , LDL-Colesterol/efectos de los fármacos , Farnesil Difosfato Farnesil Transferasa/antagonistas & inhibidores , Humanos , Hipolipemiantes/farmacocinética , Peroxidación de Lípido/efectos de los fármacos , Ratones , Ratas , Tiazinas/farmacocinéticaRESUMEN
With the increasing realization that modulating a multiplicity of targets can be an asset in the treatment of multifactorial disorders, we hereby report the synthesis and evaluation of the first compounds in which antioxidant, anti-inflammatory as well as squalene synthase (SQS) inhibitory activities are combined by design, in a series of simple molecules, extending their potential range of activities against the multifactorial disease of atherosclerosis. The activity of the initially synthesized antihyperlipidemic morpholine derivatives (1-6), in which we combined several pharmacophore moieties, was evaluated in vitro (antioxidant, inhibition of SQS and lipoxygenase) and in vivo (anti-dyslipidemic and anti-inflammatory effect). We further compared the in vitro SQS inhibitory action of these derivatives with theoretically derived molecular interactions by performing an in silico docking study using the X-ray crystal structure of human SQS. Based on low energy preferred binding modes, we designed potentially more potent SQS ligands. We proceeded with synthesizing and evaluating these new structures (7-12) in vitro and in vivo, to show that the new derivatives were significantly more active than formerly developed congeners, both as SQS inhibitors (20-70-fold increase in activity) and antioxidants (4-30-fold increase in activity). A significant correlation between experimental activity [Log(1/IC(50))] and the corresponding binding free energy (ΔG(b)) of the docked compounds was shown. These results, taken together, show a promising alternative and novel approach for the design and development of multifunctional antiatherosclerosis agents.
Asunto(s)
Inhibidores Enzimáticos/química , Farnesil Difosfato Farnesil Transferasa/antagonistas & inhibidores , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Antioxidantes/farmacología , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Farnesil Difosfato Farnesil Transferasa/metabolismo , Humanos , Hipolipemiantes/síntesis química , Hipolipemiantes/química , Hipolipemiantes/farmacología , Lipooxigenasa/química , Lipooxigenasa/metabolismo , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/química , Inhibidores de la Lipooxigenasa/farmacología , Morfolinas/síntesis química , Morfolinas/química , Morfolinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
A series of 19 derivatives of 2,7-diazaphenothiazine was synthesized and evaluated for their antioxidant activity bearing in mind the structural similarity with "classical" phenothiazines several of which are considered powerful antioxidants. Among the new derivatives that inhibited in vitro Fe(2+)/ascorbate-induced lipid peroxidation of rat liver microsomal membranes, several exhibited significant antioxidant activity with IC(50 )values in the range of 64-125 microM. Although N-substitution led to a variable degree of antioxidant activity, the latter appears to correlate with the lipophilicity (expressed as clogP values) of the substituted derivatives. Reduced lipophilicity may also explain the relatively lower protection offered by these derivatives against lipid peroxidation when compared to their "classical" phenothiazine counterparts. Thus, modification of the phenothiazine structure by a substitution of two benzene rings with pyridine rings to form this new type of azaphenothiazines does not enhance antioxidant activity, although it retains it.