Resumen La dopamina 1, está implicada en trastornos neurodegenerativos que afectan al sistema nervioso central (SNC) tales como la enfermedad de Parkinson, entre otros. Aunque no se dispone aún de ningún fármaco capaz de prevenir, detener o curar la progresión de estas enfermedades, son numerosos los compuestos que han sido diseñados, sintetizados y evaluados farmacológicamente, que han aportado las generalizaciones farmacofóricas del receptor dopaminérgico, necesarias para la búsqueda de un fármaco capaz de mejorar o curar estas patologías. Los derivados 2-aminoindano-N-aralquílicos han mostrado tener actividad selectiva en el sistema dopaminérgico central, de modo tal que los compuestos clorhidratos de N-[(2,4-diclorofenil)-1-metil- etil]-2-aminoindano 2 y N-[(3,4-diclorofenil)-1-metil-etil]-2-aminoindano 3 demostraron tener actividad agonística mediada por mecanismos dopaminérgicos centrales. Con el propósito de contribuir en la búsqueda de nuevos fármacos que permitan restablecer la homeostasis de la transmisión dopaminérgica en la enfermedad de Parkinson, el compuesto N-2,6-dicloro-aralquil-2-aminoindano 4 fue diseñado a través de estrategias de la química medicinal, que contienen las aproximaciones farmacofóricas de los profármacos. La evaluación farmacológica del compuesto 4, en la conducta estereotipada en ratas macho de la cepa Sprague Dawley, demostró tener actividad agonística a través de la activación de los mecanismos dopaminérgicos centrales y mostró mayor selectividad en las respuestas de conductas estereotipadas propias de los ganglios basales sobre las respuestas conductuales propias de las estructuras límbicas.
Abstract Dopamine 1 is involved in neurodegenerative disorders affecting the central nervous system (CNS), such as Parkinson's disease. Despite the absence of some available drugs capable of preventing, stopping or curing the progression of such diseases, there are numerous compounds designed, synthesized, and pharmacologically tested which give rise to pharmacophoric generalizations about the dopaminergic receptor required for the search of a drug able to improve or cure those pathologies. N-aralkyl-2-aminoindane derivatives have shown selective activity in the central dopaminergic system. Both the N-[(2,4-dichlorophenyl)-1-methyl-ethyl]-2-aminoindane hydrochloride 2 and N-[(3,4-dichlorophenyl)-1-methyl-ethyl]-2-aminoindane hydrochloride 3 showed an agonistic activity mediated by central dopaminergic mechanisms. To contribute to the search of new drugs able to re-establish homeostasis in the dopaminergic transmission in Parkinson's disease, the compound N-2,6- dichloro-aralkyl-2-aminoindane 4 was designed through medicinal chemistry strategies that contain pharmacophoric approximations of prodrugs. The pharmacological evaluation of compound 4 in the stereotyped behavior of male Sprague Dawley rats showed agonistic activity through the activation of central dopaminergic mechanisms and a higher selectivity in the responses of stereo- typed behavior characteristic of the basal ganglia over the typical responses from limbic structures.
A series of heterocyclic chloroquine hybrids containing either a ß-phenethylamine fragment or a 2-aminoindane moiety were synthesized and screened in vitro as inhibitors of ß-hematin formation and in vivo for their antimalarial activity against chloroquine-sensitive strains of Plasmodium berghei ANKA. Although these new compounds were not found to be more active than chloroquine in vivo, all new compounds significantly reduced heme crystallization with IC50 values < 1 µM. Compounds 12 and 13 were able to inhibit heme crystallization with IC50 values of 0.39 ± 0.09 and 0.48 ± 0.02 µM, respectively, and these values were comparable to that of chloroquine with an IC50 value of 0.18 ± 0.03. It was also determined that the physicochemical and pharmacokinetic properties were moderately favorable after in silico evaluation, derivatives 8 and 10 did not present hepatotoxicity, and the in vitro hemolytic activity against red blood cells was found to be low. Spectral (infrared, nuclear magnetic resonance, and elemental analysis) data for all final compounds were consistent with the proposed structures.
Antimalarials , Malaria , Antimalarials/therapeutic use , Chloroquine/therapeutic use , Humans , Malaria/drug therapy , Plasmodium berghei , Plasmodium falciparum
This study describes the direct synthesis of 2-amino-4-(phenylsubstituted)-5H-indeno[1,2-b]pyridine-3-carbonitrile derivatives 5-21, through sequential multicomponent reaction of aromatic aldehydes, malononitrile, and 1-indanone in the presence of ammonium acetate and acetic acid (catalytic). The biological study showed that compound 10 significantly impeded proliferation of the cell lines PC-3, LNCaP, and MatLyLu. The antimetastatic effects of compound 10 could be related with inhibition of MMP9 in the PC-3 and LNCaP human cell lines. On the basis of a study of the structure-activity relationship of these compounds, we propose that the presence of two methoxy groups at positions 6 and 7 of the indeno nucleus and a 4-hydroxy-3-methoxy phenyl substitution pattern at position 4 of the pyridine ring is decisive for these types of molecules to exert very good antiproliferative and antimetastatic activities.
Antineoplastic Agents/pharmacology , Indenes/pharmacology , Prostatic Neoplasms/drug therapy , Pyridines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Indenes/chemical synthesis , Indenes/chemistry , Male , Neoplasm Metastasis/prevention & control , PC-3 Cells , Prostatic Neoplasms/pathology , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship
Resumen Justificación: alrededor del mundo las cardiopatías congénitas ocupan las primeras causas de mortalidad infantil. En Costa Rica son el grupo de defectos congénitos más frecuentes, con una prevalencia de 6 x 1000 nacimientos (IC95 % 5 -7 x 1000 nacimientos), que representan cerca del 13 % de la mortalidad infantil. El objetivo del estudio fue analizar la supervivencia a cinco años de edad de los niños nacidos con defectos cardiacos en Costa Rica. Métodos: se analizó una cohorte retrospectiva de 543 niños nacidos con cardiopatías congénitas entre enero de 2006 y junio de 2007 en Costa Rica; utilizando los registros médicos y la base nacional de defunciones se brindó un seguimiento mínimo de 5 años en todos los casos. Se obtuvo estimados de supervivencia de Kaplan-Meier al mes, año y cinco años de vida, y se evaluaron factores pronóstico empleando el modelo de riesgos proporcionales de Cox. Se estimaron riesgos relativos crudos y ajustados con su respectivo intervalo de confianza del 95 %. Resultados: la prevalencia de cardiopatías congénitas fue de 5,14 por 1000 nacimientos (IC95 % 4,73-5,60; n: 543) para el período de estudio. La mortalidad fue del 27,9 % (IC 95 % = 24,21- 31,73; n: 152). La supervivencia acumulada al año y cinco años fue del 76,1 % y el 72,4 %, respectivamente, frente al 99,1 % y 98,8 % sobrevivencia de la cohorte de nacimientos nacional (con y sin cardiopatía) de la misma edad. La edad temprana al diagnóstico, severidad, cardiopatías congénitas múltiples y la asociación de defectos congénitos mayores se asociaron significativamente (p≤0,05) a una menor probabilidad de supervivencia. Conclusiones: la cohorte de niños con cardiopatías congénitas estudiada presentó una alta mortalidad al año y cinco años. El peor pronóstico de supervivencia fue para aquellos que necesitaban una cirugía cardíaca a temprana edad.
Abstract Background: Around the world, congenital heart defects occupy the first causes of infant mortality. In Costa Rica heart malformations are the most frequent group of birth defects, with a prevalence of 6 x 1000 births (95% CI 5-7 x 1000 births). They represent about 13% of infant mortality and are. the leading cause of death due to birth defects. The objective of this study is to analyze the survival of children with CC in Costa Rica. Methods: A retrospective cohort of 543 children born with CC between January 2006 and June 2007 in Costa Rica was analyzed. Using medical records and the national database of deaths, a minimum follow-up of 5 years was given in all cases. Kaplan-Meier survival estimates were obtained at month, year and five years of life. Prognostic factors were assessed using the Cox proportional hazards model. Raw and adjusted relative risks were estimated with their respective 95% confidence interval. Results: The prevalence of CC was 5.14 per 1000 births (95% CI: 4.73-5.60; n: 543) for the study period. Mortality was 27.9% (95% CI: 24.21-31.73; n: 152). Cumulative survival at one year and five years was 76.1% and 72.4%, respectively, compared to 99.1% and 98.8% of survival in the same national birth cohort (with and without CC), at the same age. Early age at diagnosis, severity, multiple CC and the association of major BD were significantly associated (p≤0.05) with a lower probability of survival. Conclusions: The cohort of children with congenital heart disease studied had a high mortality rate at one year and five years. The worst prognosis of survival was for those who needed cardiac surgery at an early age.
Infant, Newborn , Infant , Child, Preschool , Child , Costa Rica , Heart Defects, Congenital/mortality
A series of E-2-quinolinylbenzocycloalcanones 5-21 were prepared and evaluated for their activity to inhibit beta-hematin formation and the hydrolysis of hemoglobin in vitro. Positive compounds for both assays were also tested for their efficacy in rodent Plasmodium berghei. Compounds 6, 16, 19, and 20, were the most promising. Inhibition of beta-hematin formation was minimal when a hydrogen or methoxy groups were present on the position 8 of the quinoline and position 4' of the indanone ring as it appeared for compounds 5, 7-15, 17, 18, and 21, and greatest with compounds (52%) and (90%) with a substitution of methoxy on position 6 and 7 or methyl on position 8 of the quinoline nucleus and methoxy or methyl groups on position 4' of the indanone. The most active compound to emerge from this study is 2-chloro-8-methyl-3-[(4'-methoxy-1'-indanoyl)-2'-methyliden]-quinoline 20 effective as antimalarial that target beta-hematin formation and the inhibition of the hydrolysis of hemoglobin in vitro together with a good survival in a murine malaria model, which should help delay the rapid onset of resistance to drugs acting at only a single site. Results with these assays suggest that quinolinylbenzocycloalcanones exert their antimalarial activity via multiple mechanisms.
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/pharmacology , Malaria/drug therapy , Plasmodium berghei/drug effects , Animals , Antimalarials/chemistry , Disease Models, Animal , Hemeproteins/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Hydrolysis/drug effects , Male , Mice , Mice, Inbred BALB C , Parasitic Sensitivity Tests , Plasmodium berghei/chemistry , Quinolinium Compounds/chemistry , Quinolinium Compounds/metabolism , Quinolinium Compounds/pharmacology , Structure-Activity Relationship , Survival Rate
