RESUMEN
First synthesis of novel coumarin-trioxane hybrids is reported. The synthesis was achieved via condensation of ß-hydroxyhydroperoxides with coumarinic-aldehydes in presence of p-toluenesulfonic acid in good yields and the novel hybrids were evaluated for their antimalarial activity both in vitro and in vivo.
Asunto(s)
Antimaláricos/síntesis química , Cumarinas/química , Compuestos Heterocíclicos/química , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Plasmodium yoelii/efectos de los fármacos , Aldehídos/química , Animales , Antimaláricos/farmacología , Bencenosulfonatos/química , Cumarinas/farmacología , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Compuestos Heterocíclicos/farmacología , Humanos , Concentración 50 Inhibidora , Malaria Falciparum/parasitología , Ratones , Peróxidos/química , Plasmodium falciparum/parasitología , Plasmodium yoelii/parasitología , Relación Estructura-ActividadRESUMEN
The high potential of quinoline containing natural products and their derivatives in medicinal chemistry led us to discover novel series of 25 compounds for the development of new antileishmanial agents. A series of triazolyl 2-methyl-4-phenylquinoline-3-carboxylate derivatives has been synthesized via click chemistry inspired molecular hybridization approach and evaluated against Leishmania donovani. Most of the screened derivatives exhibited significant in vitro anti-leishmanial activity against promastigote (IC50 ranging from 2.43 to 45.75⯵M) and intracellular amastigotes (IC50 ranging from 7.06 to 34.9⯵M) than the control, miltefosine (IC50â¯=â¯8.4⯵M), with less cytotoxicity in comparison to the standard drugs. Overall results revealed that prototype signify a new structural lead for antileishmanial chemotherapy.
Asunto(s)
Antiprotozoarios/farmacología , Leishmania donovani/efectos de los fármacos , Quinolinas/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Relación Dosis-Respuesta a Droga , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-ActividadRESUMEN
A series of novel indole-chalcone fibrates were synthesized and their hypolipidemic activity was evaluated in triton WR-1339 induced hyperlipidemic rat model. Preliminary studies indicated that the hybrids 19, 24 and 29 exhibited potent in vitro antioxidant and significant in vivo antidyslipidemic effects. Our results suggest that these new hybrid architectures may serve as promising leads for the development of next generation lipid lowering agents.
Asunto(s)
Antioxidantes/farmacología , Chalcona/farmacología , Diseño de Fármacos , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/farmacología , Indoles/farmacología , Animales , Antioxidantes/síntesis química , Antioxidantes/química , Chalcona/química , Modelos Animales de Enfermedad , Hiperlipidemias/inducido químicamente , Hipolipemiantes/síntesis química , Hipolipemiantes/química , Indoles/química , Lipoproteínas/sangre , Lipoproteínas HDL/sangre , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/sangre , Lipoproteínas LDL/metabolismo , Masculino , Estructura Molecular , Polietilenglicoles/administración & dosificación , RatasRESUMEN
In the search for effective multifunctional agents for the treatment of Alzheimer's disease (AD), a series of novel hybrids incorporating benzofuran and chalcone fragments were designed and synthesized. These hybrids were screened by using a transgenic Caenorhabditis elegans model that expresses the human ß-amyloid (Aß) peptide. Among the hybrids investigated, (E)-3-(7-methyl-2-(4-methylbenzoyl)benzofuran-5-yl)-1-phenylprop-2-en-1-one (4 f), (E)-3-(2-benzoyl-7-methylbenzofuran-5-yl)-1-phenylprop-2-en-1-one (4 i), and (E)-3-(2-benzoyl-7-methylbenzofuran-5-yl)-1-(thiophen-2-yl)prop-2-en-1-one (4 m) significantly decreased Aß aggregation and increased acetylcholine (ACh) levels along with the overall availability of ACh at the synaptic junction. These compounds were also found to decrease acetylcholinesterase (AChE) levels, reduce oxidative stress in the worms, lower lipid content, and to provide protection against chemically induced cholinergic neurodegeneration. Overall, the multifunctional effects of these hybrids qualify them as potential drug leads for further development in AD therapy.
Asunto(s)
Antioxidantes/síntesis química , Benzofuranos/química , Chalcona/química , Chalconas/química , Tiofenos/química , Acetilcolina/metabolismo , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Animales Modificados Genéticamente/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Benzofuranos/farmacología , Benzofuranos/uso terapéutico , Sitios de Unión , Caenorhabditis elegans/metabolismo , Chalconas/farmacología , Chalconas/uso terapéutico , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Humanos , Microscopía Fluorescente , Conformación Molecular , Simulación del Acoplamiento Molecular , Estrés Oxidativo/efectos de los fármacos , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Tiofenos/farmacología , Tiofenos/uso terapéuticoRESUMEN
A novel series of amide based fibrates were synthesized and evaluated for antidyslipidemic activity in triton induced hyperlipidemic rats. Interestingly, the compound 13 produced striking reduction in serum levels of total cholesterol (TC), phospholipids (PL) and triglycerides (TG). In addition, it exhibited improved lipoprotein lipase activity and found to possess moderate radical scavenging potential. The results of the above studies shows that the compounds synthesized on fibrate based pharmacophores might result in identification of new lead for dyslipidemia.