The Organic Chemistry of Drug Synthesis

Lednicer, Daniel; Mitscher, Lester A.

doi:10.1002/9780470180679

Cited by 183 publications

(172 citation statements)

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“…Fue creado por el grupo de investigadores de la compañía Boots en 1 960 (Lednicer, 2008), demostrando ser más efectivo que sus predecesores y, que a su vez, causa menos efectos secundarios. El ibuprofeno pertenece a la familia de los derivados del ácido propiónico.…”

Section: Introductionunclassified

Modelamiento molecular de la interacción de ibuprofeno con las enzimas Ciclooxigenasa 1, 2 y el Citocromo P450 2C9

Meneses¹,

Pilaquinga²,

H³

2017

REMCB

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RESUMEN.-En esta investigación, se presenta el modelamiento computacional de la interacción de ibuprofeno con las enzimas Ciclooxigenasa 1, Ciclooxigenasa 2 y Citocromo P450 2C9. El objetivo fue comprobar la aplicabilidad de métodos de acoplamiento molecular en la determinación de nuevos ligandos y la localización de sitios activos en las enzimas, así como también tener un mejor entendimiento del mecanismo de acción farmacológica de ibuprofeno. Para el estudio se aplicaron métodos de dinámica molecular, para modelar la interacción de la molécula de ibuprofeno con las enzimas, determinando el sitio activo de éstas. Se utilizaron los programas Autodock 4 y Autodock VINA. En el modelamiento molecular, los mejores resultados se lograron con el programa Autodock VINA, por lo que éstos fueron comparados con resultados experimentales obtenidos mediante cristalografía de rayos X. Los métodos computacionales de acoplamiento molecular son totalmente comparables con resultados obtenidos experimentalmente, demostrando ser bastante exactos. Esto comprueba la aplicabilidad de estos métodos en el proceso de síntesis y diseño de nuevos fármacos. PALABRAS CLAVES: acoplamiento, autodock, ciclooxigenasa, citocromo P450, ibuprofeno ABSTRACT.-In this research, a computational modeling of the interaction of ibuprofen with the enzymes Cyclooxygenase 1, Cyclooxygenase 2 and Cytochrome P450 2C9 is presented. The aim of this study was to test the applicability of molecular docking methods in the identification of new ligands and the location of active sites in enzymes; also to have a better understanding of the action mechanism of ibuprofen. The research encompasses modeling the interaction of the ibuprofen molecule with the enzymes through molecular dynamics methods. AutoDock 4 and AutoDock VINA software were used. In the molecular modeling, the best results were achieved with AutoDock VINA, so those results were compared with experimental data obtained by X-ray crystallography. Computational docking methods are fully comparable with experimental results proving to be quite accurate. This demonstrates the applicability of these methods in the synthesis and design of new drugs.

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Section: Introductionunclassified

Modelamiento molecular de la interacción de ibuprofeno con las enzimas Ciclooxigenasa 1, 2 y el Citocromo P450 2C9

Meneses¹,

Pilaquinga²,

H³

2017

REMCB

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“…Coronaridine and voacangine are indole alkaloids that have antileishmanial, antitumor, diuretic and hypoglycemic activities (Camila, Paulo, Meireles, 2007). The indole moiety has been incorporated as a core skeleton to access active sites, implicated in enzyme inhibitions (Lednicer, 2007). Some indole derivatives are also identified as good inhibitors of 5-lipoxygenase (LOX) (Hutchinson et al, 1995;Yar et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Convergent synthesis of new N -substituted 2-{[5-(1H -indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]sulfanyl}acetamides as suitable therapeutic agents

Rubab

Abbasi

Aziz-Ur-Rehman

et al. 2015

Braz. J. Pharm. Sci.

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A series of N-substituted 2-{[5-(1H-indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]sulfanyl}acetamides (8a-w) was synthesized in three steps. The first step involved the sequential conversion of 2-(1H-indol-3-yl) acetic acid (1) to ester (2) followed by hydrazide (3) formation and finally cyclization in the presence of CS 2 and alcoholic KOH yielded 5-(1H-indole-3-yl-methyl)-1,3,4-oxadiazole-2-thiol (4). In the second step, aryl/aralkyl amines (5a-w) were reacted with 2-bromoacetyl bromide (6) in basic medium to yield 2-bromo-N-substituted acetamides (7a-w). In the third step, these electrophiles (7a-w) were reacted with 4 to afford the target compounds (8a-w). Structural elucidation of all the synthesized derivatives was done by 1 H-NMR, IR and EI-MS spectral techniques. Moreover, they were screened for antibacterial and hemolytic activity. Enzyme inhibition activity was well supported by molecular docking results, for example, compound 8q exhibited better inhibitory potential against α-glucosidase, while 8g and 8b exhibited comparatively better inhibition against butyrylcholinesterase and lipoxygenase, respectively. Similarly, compounds 8b and 8c showed very good antibacterial activity against Salmonella typhi, which was very close to that of ciprofloxacin, a standard antibiotic used in this study. 8c and 8l also showed very good antibacterial activity against Staphylococcus aureus as well. Almost all compounds showed very slight hemolytic activity, where 8p exhibited the least. Therefore, the molecules synthesized may have utility as suitable therapeutic agents.sulfanyl}acetamides/antibacterial activity. N-substituted 2-{[5-(1H-indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]sulfanyl} acetmides/hmolytic activity. α-Glicosidase. Butirylcholinesterase. Lipoxygenase.Uma série de acetamidas 2-{[5-(1H-indol-3-ilmetil)-1,3,4-oxadiazol-2-il]sulfanila} N-substituídas (8a-w) foi sintetizada em três fases. A primeira etapa envolveu a conversão sequencial de ácido 2-(1H-indol-3-il) acético (1) a éster (2), seguido por hidrazida (3) e, finalmente, a e ciclização na presença de CS 2 e KOH alcoólico produziu 5-(1H-indol-3-il-metil)-1,3,4-oxadiazole-2-tiol (4). Na segunda etapa, aminas arílicas/ aralquílicas(5a-w) reagiram com brometo de 2-bromoacetila (6 ), em meio básico, para se obter acetamidas 2-bromo-N-substituídas (7a-w). Na terceira etapa, estes eletrófilos (7a-w) reagiram com 4, para se obter os compostos alvo (8a-w). A elucidação estrutural de todos os derivados sintetizados foi realizada por 1 H-NMR, IR e técnicas de espectrometria de EI-MS. Além disso, eles foram submetidos a triagem de atividade antibacteriana e hemolítica. Análise da inibição enzimática foi bem apoiada pelos resultados de docking molecular. Por exemplo, o composto 8q exibiu melhor potencial inibitório contra α-glicosidase,e os compostos 8g e 8b exibiram, comparativamente, melhor inibição contra butirilcolinesterase (BChE) elipoxigenase (LOX), respectivamente. Do mesmo modo os compostos 8b e 8c mostraram excelente potencial antibacteriano contra SalmonellaTyphi...

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“…Fue creado por el grupo de científicos de la compañía Boots en 1960, demostrando ser más efectivo que sus predecesores y, que a su vez, causa menos efectos secundarios (Lednicer, 2008). El ibuprofeno pertenece a la familia de los derivados del áci-do propiónico.…”

Section: Introductionunclassified

Estudio espectroscópico experimental y computacional de Ibuprofeno y sus precursores de síntesis

Cuesta¹,

Meneses²

2015

lgr

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Manuscrito recibido el 21 de enero de 2015. Aceptado, tras revisión, el 5 de mayo de 2015. ResumenSe presenta un estudio comparativo de los espectros infrarrojo (IR) y ultravioleta/visible (UV/VIS) de ibuprofeno, isobutilbenceno y 4-isobutilacetofenona obtenidos experimentalmente, con los calculados computacionalmente. La investigación constó de dos etapas. En la primera se realizó la síntesis experimental de ibuprofeno, donde se aislaron los precursores para el análisis. En la segunda fase, se utilizó el programa de modelamiento electrónico estructural GAUSSIAN 03, donde se obtuvo una optimización molecular de todas las estructuras de interés y sus propiedades espectroscópicas. Los espectros experimentales fueron comparados con los computacionales, obteniéndose ligeras diferencias, con porcentajes de error en bandas específicas, entre 2 y 28 % en los dos tipos de espectroscopía. La principal causa, puede ser el distinto estado de agregación en la que se encuentran las moléculas: estado líquido y sólido en el caso de los espectros experimentales, y estado gaseoso en el caso de los espectros computacionales. Los espectros computacionales son comparables con los obtenidos experimentalmente, demostrando ser bastante exactos. Esto comprueba la aplicabilidad de los métodos computacionales, en el proceso de síntesis y diseño de nuevos fármacos.Palabras claves: Ibuprofeno, síntesis, espectroscopia, métodos computacionales. AbstractIn this research, infrared (IR) and ultraviolet/visible spectra (UV/VIS) of ibuprofen, 4-isobutylacetophenone and isobutylbenzene obtained experimentally were compared with the spectra obtained computationally. The research comprises of two stages. In the first one, ibuprofen was experimentally synthetized and its precursors isolated. In the second phase, the electronic structural modeling program GAUSSIAN 03 was used in order to obtain molecular optimization of all structures of interest and their spectroscopic properties. The experimental spectra were compared with the computational ones, obtaining error rates between 2 and 28 % in both spectroscopy methods. The main difference was due to the aggregation state in which the spectra were obtained, liquid and solid in the case of the experimental spectra, and gaseous for computational spectra. Computational spectra are fully comparable with those obtained experimentally proving to be quite accurate. This proves the applicability of the computational methods in the synthesis and design of new drugs.

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The Organic Chemistry of Drug Synthesis

Cited by 183 publications

References 1 publication

Modelamiento molecular de la interacción de ibuprofeno con las enzimas Ciclooxigenasa 1, 2 y el Citocromo P450 2C9

Modelamiento molecular de la interacción de ibuprofeno con las enzimas Ciclooxigenasa 1, 2 y el Citocromo P450 2C9

Convergent synthesis of new N -substituted 2-{[5-(1H -indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]sulfanyl}acetamides as suitable therapeutic agents

Estudio espectroscópico experimental y computacional de Ibuprofeno y sus precursores de síntesis

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