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1.
Chem Biodivers ; 21(5): e202400056, 2024 May.
Article in English | MEDLINE | ID: mdl-38472742

ABSTRACT

N-Arylenaminones are highly versatile compounds which can be synthesized in relatively simple ways. In this work we explored the synthesis of the four monosubstituted N-(4-R-phenyl)enaminones 3 a (R=NO2), 3 b (R=F), 3 c (R=H), and 3 d (R=OMe) with the goal of determining the influence of the substituents' electronic effects on tautomer stability and biological activity. These compounds were analyzed by means of Density Functional Theory calculations (DFT), to evaluate the relative stability of the possible tautomers. We found that the enaminone structure is the most stable with respect to the ketoimine and iminoenol forms. In addition, all four compounds display anticonvulsant activity, with 3 d being the one that mostly increased latency and mostly decreased the number of convulsions with respect to the control group. The suggested mechanism of action involves blockage of the voltage-dependent Na+ channels, considering that these molecules meet the structural characteristics needed to block the receptor, as is the case of the positive control molecules phenytoin (PHT) and valproic acid (VPA).


Subject(s)
Anticonvulsants , Density Functional Theory , Anticonvulsants/pharmacology , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Animals , Seizures/drug therapy , Structure-Activity Relationship , Mice , Molecular Structure
2.
ACS Omega ; 8(23): 20611-20620, 2023 Jun 13.
Article in English | MEDLINE | ID: mdl-37332815

ABSTRACT

Pseudo-C2-symmetric dodecaheterocyclic structures, which possess two acyl/aroyl groups disposed on either a cis- or trans-relative configuration, were prepared from the naturally occurring (-)-(1R)-myrtenal. Addition of Grignard reagents (RMgX) to the diastereoisomeric mixture of these compounds unexpectedly showed that nucleophilic additions to the two prochiral carbonyl centers gave the same stereochemical result in both cis/trans diastereoisomers, making unnecessary the separation of this mixture. Noticeably, both carbonyl groups showed different reactivity because one of them is attached to an acetalic carbon and the other to a thioacetalic carbon. Furthermore, addition of RMgX to the carbonyl attached to the former carbon takes place through the re face, while addition to the second one proceeds through the si face, thus affording the corresponding carbinols in a highly diastereoselective process. This structural feature allowed the sequential hydrolysis of both carbinols, yielding separately (R)- and (S)-1,2-diols after reduction with NaBH4. The mechanism of the asymmetric Grignard addition was explained by density functional theory calculations. This approach contributes to the development of the divergent synthesis of structurally and/or configurationally different chiral molecules.

3.
Molecules ; 27(9)2022 Apr 28.
Article in English | MEDLINE | ID: mdl-35566162

ABSTRACT

A representative number of decalin and hydrindane derivatives 2a-l were prepared in 11-91% yield by means of a cascade reaction of cyclohexanone/cyclopentanone enolates and methyl acrylate through a Michael-Michael ring closure (MIMIRC) process. The relative stereochemistry of the four stereogenic centers formed in all products was determined by analyzing the vicinal coupling constants from the 1H NMR and X-ray crystallography. Such a stereochemical outcome was corroborated by conformational analysis supported by DFT calculations and simulating the 1H NMR spectra of representative products. All products showed the same relative stereochemistry at C-1 and C-8a, while at C-3 and bridgehead carbon C-4a, configurational changes were observed. The present results provide some insights about the scope and limitations of the triple cascade reaction between cycloalkanone enolates with methyl acrylate. This synthetic protocol is still a simple and very practical alternative to generate decalin and hydrindane derivatives with great structural diversity.


Subject(s)
Stereoisomerism , Crystallography, X-Ray , Magnetic Resonance Spectroscopy , Molecular Conformation
4.
Med Chem ; 17(9): 1023-1045, 2021.
Article in English | MEDLINE | ID: mdl-32998678

ABSTRACT

BACKGROUND: Anticonvulsants are drugs used in the treatment of seizures; their pharmacology includes promoters of brain inhibition and inhibitors of brain activity. Of the latter, voltagedependent sodium channel blockers (VGSCB) are the most widely used in therapeutics. OBJECTIVE: The study aimed at proposing the structural requirements of VGSC blockers through a quantitative structure-activity relationship analysis of drugs with proven activity. METHODS: IC50 values of anticonvulsant drugs on VGSCs were considered under similar experimental conditions; some physicochemical properties of the molecules that were correlated with their biological activity were determined in silico. RESULTS: Relationships were observed between the dipole moment, pKa, EHOMO, and MR with the biological activity, which infers that between greater polarity and basicity of the drugs, their activity as blockers will increase. Subsequently, the structural subclassification of the drugs was carried out, based on the urea derivation, the groups of which were: Group 1 (direct and bioisostere derivatives) and Group 2 (homologue and vinylogue derivatives of urea). CONCLUSION: The biological activity depends on the polarity, basicity, and electronic density of the drugs. The derivation of urea is essential, which is present in its original substituted form or a bioisosteric form. Urea can be in the form of a homologue or a vinylogue at the ends of the molecule. Aromatic substitution to the urea portion is necessary.


Subject(s)
Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Quantitative Structure-Activity Relationship , Voltage-Gated Sodium Channel Blockers/chemistry , Voltage-Gated Sodium Channel Blockers/pharmacology , Epilepsy/metabolism , Humans , Voltage-Gated Sodium Channel Blockers/metabolism
5.
Chirality ; 31(9): 719-749, 2019 09.
Article in English | MEDLINE | ID: mdl-31318100

ABSTRACT

Enantiopure 3-((R)- and 3-((S)-1-phenylethyl)-4-oxazoline-2-ones were evaluated as chiral building blocks for the divergent construction of heterocycles with stereogenic quaternary centers. The N-(R)- or N-(S)-1-phenylethyl group of these compounds proved to be an efficient chiral auxiliary for the asymmetric induction of the 4- and 5-positions of the 4-oxazolin-2-one ring through thermal and MW-promoted nucleophilic conjugated addition to Michael acceptors and alkyl halides. The resulting adducts were transformed via a cascade process into fused six-membered carbo- and heterocycles. The structure of the reaction products depended on the electrophiles and reaction conditions used. Alternative isomeric 4-methylene-2-oxazolidinones served as chiral precursors for a versatile and divergent approach to highly substituted cyclic carbamates. DFT quantum calculations showed that the formation of bicyclic pyranyl compounds was generated by a diastereoselective concerted hetero-Diels-Alder cycloaddition.

6.
J Org Chem ; 83(10): 5347-5364, 2018 05 18.
Article in English | MEDLINE | ID: mdl-29697257

ABSTRACT

An efficient and alternative synthesis of exo-imidazolidin-2-one dienes is described. A condensation reaction was carried out with bis-imino derivatives, diacetyl, and triphosgene, affording symmetrically N, N-disubstituted dienes. The use of alkyl methyl α-diketones led to the formation of nonsymmetrical dienes, which underwent isomerization to provide more stable inner-outer-ring dienes under Lewis acid conditions. Evaluation was made of the reactivity as well as regio- and stereoselectivity of these dienes in Diels-Alder reactions. They proved to be highly reactive and selective. DFT calculations of the transition states accounted for their behavior.

7.
J Enzyme Inhib Med Chem ; 29(6): 884-94, 2014 Dec.
Article in English | MEDLINE | ID: mdl-24517366

ABSTRACT

Herein we introduce the derivation of a mathematical expression to evaluate the dissociation constant of a mixture of stereoisomers in equal amounts (KdMIX), when the corresponding dissociation constants (Kd) or medium response (MR50) of the pure stereoisomers are known; the final equation takes the form of the harmonic mean. In order to validate the equation, we carried out a bibliographic search of experimental data of enantiomeric molecules with biological activity, considering the Kd's or MR50's of the isolated enantiomers as well as that of the racemate. The comparisons between the experimental dissociation constants of the mixtures (KdEXP or MR50EXP) and the calculated values (KdMIX or MR50MIX) were consistent; the similarity between these values is supported through statistical analyses of group comparison and simple linear correlation. The equation we obtained, which corresponds to the harmonic mean, was used to predict the values of KdMIX (or MR50MIX) or Kd (or MR50) in systems when only two of the experimental values are known: either the dissociation constants of both enantiomers or the Kd (or MR50) of one of the enantiomers and dissociation constant of the racemate.


Subject(s)
Biological Products/chemistry , Eukaryotic Cells/drug effects , Models, Statistical , Receptors, Cell Surface/metabolism , Animals , Biological Products/pharmacology , Eukaryotic Cells/metabolism , Humans , Inhibitory Concentration 50 , Kinetics , Receptors, Cell Surface/agonists , Receptors, Cell Surface/antagonists & inhibitors , Stereoisomerism
8.
Nat Prod Res ; 27(19): 1749-56, 2013.
Article in English | MEDLINE | ID: mdl-23480643

ABSTRACT

A short and efficient total synthesis of naturally occurring carbazole clauraila A (1) is described. The approach is designed on the basis of the key regioselective Diels-Alder reaction of the properly substituted exo-2-oxazolidinone diene 3 with acrolein (4) to give the corresponding adduct 2. The latter is converted to functionalised diarylamine 8, which is cyclised to the desired carbazole 1 through a Pd-promoted or -catalysed double C-H bond activation process in a fairly good overall yield.


Subject(s)
Carbazoles/chemical synthesis , Alkaloids/chemical synthesis , Alkaloids/chemistry , Carbazoles/chemistry , Catalysis , Magnetic Resonance Spectroscopy , Molecular Structure , Stereoisomerism
9.
Chem Cent J ; 7(1): 20, 2013 Jan 31.
Article in English | MEDLINE | ID: mdl-23363878

ABSTRACT

BACKGROUND: The proton at position 5 of imidazo[1,2-a]pyridines substituted with an angular electron withdrawing group (EWG) at position 3, shows an unusual downfield chemical shift, which is usually explained in terms of a peri effect. However usage of this term is sometimes confusing. In this investigation, it is proposed that the aforementioned shift is in fact a combination of several factors: Anisotropy, long-distance mesomerism and an attractive intramolecular interaction of the electrostatic hydrogen bond type. RESULTS: Theoretical calculations were performed aimed to obtain evidence of the existence of an intramolecular non-bonding interaction between H-5 and the oxygen atom of the EWG. Results derived from conformational and vibrational analysis at the DFT B3LYP/6-311++G(d,p) level of theory, the determination of Bond Critical Points derived from AIM theory, and the measurement of some geometrical parameters, support the hypothesis that the higher stability of the prevailing conformation in these molecules (that in which the oxygen of the EWG is oriented towards H-5) has its origin in an intramolecular interaction. CONCLUSION: Computational calculations predicted correctly the conformational preferences in angular 3-π-EWG-substituted imidazo[1,2-a]pyridines. The existence of an electrostatic hydrogen bond between H-5 and the oxygen atom of the π-EWG was supported by several parameters, including X-ray crystallography. The existence of such structural array evidently impacts the H-5 chemical shift.

10.
Molecules ; 17(12): 13864-78, 2012 Nov 22.
Article in English | MEDLINE | ID: mdl-23174902

ABSTRACT

The Weinreb amides 2a,b were prepared from the α,α-dimethoxyacetic acids 1c,d. A number of representative nucleophilic additions (RMgX and RLi) on 2 afforded α-ketoacetals 3a-j in 70-99% yield. These compounds represent a versatile arrangement of functional groups of significant synthetic value, as demonstrated in the synthesis of (±)-salbutamol.


Subject(s)
Albuterol/chemical synthesis , Amides/chemical synthesis , Ketones/chemical synthesis , Molecular Structure , Stereoisomerism
11.
J Org Chem ; 77(4): 1640-52, 2012 Feb 17.
Article in English | MEDLINE | ID: mdl-22217094

ABSTRACT

Benzoyl-S,O-acetals 1a and 1b were used as chiral auxiliaries to achieve the diastereoselective preparation of both enantiomers of 2-methoxy-2-phenylpent-3-ynoic acids (MPPAs). The latter were condensed with several chiral secondary alcohols and some primary amines to evaluate their potential as chiral derivatizing agents (CDAs). The (1)H NMR spectra of the corresponding esters and amides showed strong consistency with the absolute configuration of the carbinol and amine moieties, whose observed ΔδL(1) and ΔδL(2) values were in the ranges of 0.1-0.4 and 0.02-0.12 ppm, respectively.


Subject(s)
Acetals/chemistry , Alcohols/chemistry , Amines/chemistry , Pentanoic Acids/chemical synthesis , Amides/chemistry , Esters/chemistry , Magnetic Resonance Spectroscopy , Methanol/chemistry , Models, Molecular , Molecular Structure , Pentanoic Acids/chemistry , Stereoisomerism , Thermodynamics
12.
MEDISUR ; 4(1)abr. 2006.
Article in Spanish | CUMED | ID: cum-30494

ABSTRACT

En la actualidad la mayoría de las personas conoce sobre el virus de inmunodeficiencia humana, la hipertensión y otras enfermedades. Conocen de qué se trata y cómo combatirlas. Gracias a las campañas de los medios de comunicación y el accionar de los médicos de la familia, son pocas las enfermedades trasmisibles, como las no trasmisibles de las cuales la población no tiene referencia. Mas, existe una enfermedad de la que se habla poco y se desconoce casi todo; sin embargo cada día se incrementa el número de las personas que la padecen y las consecuencias de padecerla. Esta enfermedad muy poco conocida se denomina: osteoporosis y constituye el motivo del presente trabajo(AU)


Subject(s)
Humans , Osteoporosis , Climacteric , Bone and Bones , Osteoporosis, Postmenopausal
13.
MEDISUR ; 3(3)dic. 6, 2005.
Article in Spanish | CUMED | ID: cum-30502

ABSTRACT

Fundamento: Uno de los propósitos más importantes de la cirugía moderna es la pronta recuperación del enfermo y su integración a la sociedad. Este anhelo se limita frecuentemente por la persistencia del dolor, fundamentalmente en etapa posoperatoria. El desarrollo de una analgesia efectiva para el dolor posoperatorio es entonces una prioridad de la medicina moderna. Objetivo: Caracterizar los resultados obtenidos con la aplicación de analgesia preventiva infiltrando la herida operatoria sin restringir el uso de otros analgésicos si fuera necesario. Métodos: Estudio prospectivo descriptivo en una serie de 30 pacientes atendidos por del Servicio de Ortopedia del Hospital Universitario “Dr. Gustavo Aldereguía Lima” de Cienfuegos en el período de septiembre de 2004 a marzo de 2005. Se les aplicó una infiltración anestésica en el área quirúrgica una vez finalizada la intervención, con bupivacaína al 0,125 porciento en un volumen de 20 ml y 2 gotas de epinefrina sin restringir el uso de otros analgésicos. Resultados: Comprobamos que 13 enfermos no presentaron dolor dentro de las primeras 24-48 horas posoperatorias, seguido por otro grupo formado por 9 en que existió alivio entre las 12 y 23 horas. Conclusiones: En la serie de pacientes estudiados se comprobaron los beneficios de la infiltración anestésica en el área quirúrgica con fines analgésicos, al proporcionar ausencia de dolor en un período mayor de 24 horas en gran número de pacientes. La bupivacaína presentó buenos resultados por proporcionar una analgesia posoperatoria y la aplicación temprana de la rehabilitación en buen número de casos(AU)


Subject(s)
Humans , Pain, Postoperative/therapy , Anesthesia, Local , Bupivacaine/therapeutic use , Bupivacaine , Epinephrine/therapeutic use , Epinephrine/administration & dosage
14.
MEDISUR ; 3(2)Nov 4, 2005.
Article in Spanish | CUMED | ID: cum-27890

ABSTRACT

Se presenta el caso de un paciente de 10 años de edad que mientras jugaba fútbol sufrió una caída que le produjo epifisiolisis de la cúpula radial según el mecanismo de lesión descrito por Jeffrey. Se expone el cuadro clínico y la conducta tomada ante la lesión del paciente


Subject(s)
Epiphyses, Slipped
15.
J Org Chem ; 69(7): 2348-54, 2004 Apr 02.
Article in English | MEDLINE | ID: mdl-15049629

ABSTRACT

Diels-Alder reactions of the masked o-benzoquinone (MOB) 2 with vinylene carbonate (3), the bicyclic derivatives 4, 5, and 6, and the intramolecular version of the 2-hydroxymethylfuran-MOB Diels-Alder reaction are described. In addition, a theoretical study of the Diels-Alder reactions of MOBs with enol and thioenol ethers is presented.

16.
Rev. cuba. med. gen. integr ; 14(4): 311-5, jul.-ago. 1998. tab
Article in Spanish | CUMED | ID: cum-17894

ABSTRACT

Resumen: Se analizan 96 niños de 3 a 5 años y de ambos sexos del Círculo Infantil "Sueños de Martí" del municipio Cienfuegos, para observar el comportamiento de las deformidades podálicas y la atención en los afectados. Se realiza un examen físico ortopédico con enfásis en las deformidades podálicas. Se toman en consideración algunos aspectos de interés como: edad, sexo, deformidades podálicas, deformidades asociadas y atención ortopédica anterior. Estas afecciones se presentaron en el 80,7 porciento de la muestra; el pie plano fue la deformidad más frecuente y predominó en el sexo masculino; el genus valgus fue la deformidad asociada más encontrada. Se observa que más del 70 porciento de los afectados carecían de atención ortopédica anterior. Se impuso tratamiento a los niños con ejercicios correctores, y se confeccionó un esquema de ejercicios al efecto, el cual fue incluido en las actividades programadas en el círculo infantil de referencia(AU)


Subject(s)
Humans , Child, Preschool , Male , Female , Foot Deformities/epidemiology , Schools, Nursery , Physical Examination
17.
Rev. cuba. med. gen. integr ; 14(4): 311-5, jul.-ago. 1998. tab
Article in Spanish | LILACS | ID: lil-274791

ABSTRACT

Resumen: Se analizan 96 niños de 3 a 5 años y de ambos sexos del Círculo Infantil "Sueños de Martí" del municipio Cienfuegos, para observar el comportamiento de las deformidades podálicas y la atención en los afectados. Se realiza un examen físico ortopédico con enfásis en las deformidades podálicas. Se toman en consideración algunos aspectos de interés como: edad, sexo, deformidades podálicas, deformidades asociadas y atención ortopédica anterior. Estas afecciones se presentaron en el 80,7 porciento de la muestra; el pie plano fue la deformidad más frecuente y predominó en el sexo masculino; el genus valgus fue la deformidad asociada más encontrada. Se observa que más del 70 porciento de los afectados carecían de atención ortopédica anterior. Se impuso tratamiento a los niños con ejercicios correctores, y se confeccionó un esquema de ejercicios al efecto, el cual fue incluido en las actividades programadas en el círculo infantil de referencia


Subject(s)
Humans , Child, Preschool , Male , Female , Child Day Care Centers , Foot Deformities/epidemiology , Physical Examination
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