RESUMEN
The synthesis of novel triarylethylene analogs, designed based on well-known Selective Estrogen Receptor Modulators (SERMs), i.e., ospemifene and tamoxifen, as potential anti-breast cancer agents is described. The cytotoxic potential of these analogs against ER-positive (MCF-7) and ER-negative (MDA-MB-231) human breast cancer cell lines was determined and compared with the standards, ospemifene and tamoxifen. In initial screening, analogs 5, 14 and 15 were found to be much more effective than the standards against both the cell lines. The results showed that these novel analogs inhibit the expression of proteins involved in the migration and metastasis, compound 5 being most effective. Compound 5 inhibited the expression of MMP-9, c-Myc and Caveolin in both MCF-7 and MDA-MB-231 cells, and suppressed the invasion of ER-negative cells in a dose dependent manner. Finally, in silico docking simulations of the representative compounds in the binding sites of the estrogen receptors (ERs) indicated a good binding affinity of the compounds with the ERs, and supported their experimental toxicity against MCF-7 cancer cell lines.
Asunto(s)
Amidas/farmacología , Aminas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Diseño de Fármacos , Etilenos/química , Etilenos/farmacología , Amidas/química , Aminas/química , Antineoplásicos/química , Sitios de Unión/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Etilenos/síntesis química , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Estructura Molecular , Receptores de Estrógenos/química , Receptores de Estrógenos/metabolismo , Relación Estructura-ActividadRESUMEN
The synthesis of some novel Ospemifene derived analogs and their evaluation as anti-breast cancer agents against MCF-7 (ER-positive) and MDA-MB-231 (ER-negative) human breast cancer cell lines are described. Few of these analogs for instance, compounds 6, 7 and 8 are shown to be more effective than recent Selective Estrogen Receptor Modulators (SERMs) i.e. Ospemifene and Tamoxifen, against these cell lines. Compound 8 was relatively more cytotoxic to MCF-7 cells similar to Ospemifene and Tamoxifen, while most potent compounds 6 and 7 were equally effective in inhibiting growth of both ER-positive and ER-negative cell lines. The observed activity profiles were further supported by the docking studies performed against estrogen receptors (ERα and ERß). Compounds 6, 7 and 8 exhibited stronger binding affinities with both ERα and ERß compared to Ospemifene and Tamoxifen.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/patología , Diseño de Fármacos , Tamoxifeno/análogos & derivados , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células MCF-7 , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Tamoxifeno/síntesis química , Tamoxifeno/química , Tamoxifeno/farmacología , Células Tumorales CultivadasRESUMEN
The manuscript describes the synthesis of novel 1,2,3-triazole tethered ß-lactam-chalcone bifunctional hybrids via click chemistry approach utilizing azide-alkyne cycloaddition reactions and their evaluation as anticancer agents against four human cancer cell lines. The presence of a cyclohexyl substituent at N-1 of ß-lactam ring and methoxy substituents, preferably ortho on ring A and para on ring B on chalcones markedly improved the anticancer profiles of the synthesized scaffolds with the most potent of the test compound exhibiting an IC(50) value of <1, 67.1, <1 and 6.37 µM against A-549(lung), PC-3(prostate), THP-1(leukemia), and Caco-2(colon) cell lines, respectively.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Chalcona/química , Chalcona/farmacología , Triazoles/química , beta-Lactamas/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Chalcona/síntesis química , Humanos , Concentración 50 InhibidoraRESUMEN
1,2,3-Triazole tethered ß-lactam and 7-chloroquinoline bifunctional hybrids were synthesized and evaluated as potential antimalarial agents. Activity against cultured Plasmodium falciparum was dependent on the N-substituent of the ß-lactam ring as well as the presence of bis-triazole at the C-3 position. The observed activity profiles were further substantiated by docking studies via inhibition of P. falciparum dihydrofolate reductase (PfDHFR), a potential target for the development of new anti-malarials.
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/farmacología , Química Clic/métodos , beta-Lactamas/química , Algoritmos , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ligandos , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Mutación , Plasmodium falciparum/metabolismo , Quinolinas/química , beta-Lactamas/síntesis químicaRESUMEN
3-Azido-, 3-amino- and 3-(1,2,3-triazol-1-yl)-ß-lactams were synthesized and evaluated for their antiplasmodial activity against four strains of Plasmodium falciparum and KB cells for their cytotoxicity profiles. The presence of a cyclohexyl substituent at N-1 and a phenyl group on the triazole ring markedly improved the activity profiles of triazole-tethered ß-lactam exhibiting IC(50) values of 1.13, 1.21 and 1.00 µM against 3D7, K1 and W2 strains respectively.
Asunto(s)
Antimaláricos/química , Azetidinas/química , Antimaláricos/síntesis química , Antimaláricos/toxicidad , Azetidinas/síntesis química , Azetidinas/toxicidad , Línea Celular Tumoral , Humanos , Plasmodium falciparum/efectos de los fármacos , Triazoles/química , beta-Lactamas/químicaRESUMEN
Assisted by PASS predictions, the antidepressant activity of 1,3,4-trisubstituted monocyclic beta-lactams in seasonal affective disorders is described.
Asunto(s)
Antidepresivos/química , Antidepresivos/farmacología , Química Farmacéutica/métodos , Biología Computacional/métodos , Depresión/tratamiento farmacológico , Monobactamas/química , Trastorno Afectivo Estacional/tratamiento farmacológico , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Ratones , Modelos Químicos , Receptores de GABA/metabolismo , Serotonina/metabolismo , Programas InformáticosRESUMEN
Out of 400 virtually designed imidazoline N-oxides, five cyclic nitrones were selected on the basis of PASS prediction as potent nootropics and were evaluated for their biological activities in albino mice. The selected N-alkyl and aryl-substituted nitrones were found to be excellent nootropics. A series of lead compounds acting as cognition enhancers have been provided, which can be further exploited in search of such New Chemical Entities (NCEs).
Asunto(s)
Diseño de Fármacos , Óxidos de Nitrógeno/síntesis química , Óxidos de Nitrógeno/farmacología , Nootrópicos/síntesis química , Nootrópicos/farmacología , Animales , Conducta Animal , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Ratones , Óxidos de Nitrógeno/química , Nootrópicos/químicaRESUMEN
PURPOSE: The present study evaluates some azetidin-2-ones derivatives for their central nervous system (CNS) modulating activities. The compounds were chosen from a series (5a-o) which were previously synthesized and evaluated for hypolipidemic and antihyperglycemic activity based on the predictions made by the computer software "Prediction of Activity Spectra for Substances (PASS)". MATERIAL AND METHODS: The test compounds were predicted to have a variety of biological activities but those with the best potential for CNS modulating activity were selected for evaluation of a particular CNS activity as 5a for anti-anxiety, 5b, 5n and 5j for nootropic activity and compound 5c anti-catatonic and anti-dyskinetic activities. Test compound 5a was evaluated for anti-anxiety activity in mirrored chamber model and for pentobarbitone induced sleep potentiation in mice. Test compounds 5b, 5n and 5j were evaluated for nootropic activity in mice by examining the effect on transfer latency on elevated plus maze (EPM) in mice and compound 5c was tested for anti-catatonic activity in perphenazine-induced catatonia and anti-dyskinetic effects in reserpine induced orofacial dyskinesia in rats, respectively. RESULTS AND DISCUSSION: The test compound 5a showed significant anxiolytic activity in the mirror chamber paradigm and showed potentiation of the pentobarbitone-induced hypnosis, which was comparable to diazepam. The nootropic activity of compounds 5b, 5n and 5j were found to be significant in elevated and maze test. The test compound 5c significantly prevented the perphenazine-induced catalepsy in a dose dependent manner. Potentiation of anti-catatonic effect of sub-effective dose of L-dopa and reversal of sulpiride-induced catalepsy was also observed by compound 5c. It indicated that the test compound might be showing anticatatonic effect by dopaminergic stimulation probably through D2 dopaminergic receptors. Compound 5c significantly reduced the vacuous chewing movements, tongue protrusions and jaw tremors induced by reserpine. It further supports the dopaminergic agonism by the test compound as reserpine induces oral dyskinetic features by depleting catecholamine (dopamine and nor- epinephrine). CONCLUSION: It was concluded that azetidinones possess considerable CNS activities and can be further explored to find additional CNS active compounds.
Asunto(s)
Azetidinas/química , Azetidinas/farmacología , Fármacos del Sistema Nervioso Central/química , Fármacos del Sistema Nervioso Central/farmacología , Animales , Ansiedad/tratamiento farmacológico , Azetidinas/uso terapéutico , Fármacos del Sistema Nervioso Central/uso terapéutico , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Femenino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Valor Predictivo de las Pruebas , Ratas , Ratas Wistar , Sueño/efectos de los fármacosRESUMEN
Novel quinazolines, having interesting antibacterial activity have been prepared, characterized and tested against a panel of susceptible and resistant Gram positive and Gram negative organisms.
Asunto(s)
Antibacterianos/síntesis química , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Quinazolinas/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Farmacorresistencia Bacteriana , Pruebas de Sensibilidad Microbiana , Quinazolinas/química , Quinazolinas/farmacología , Relación Estructura-ActividadRESUMEN
Several 1-aryl-2-phenyl-4-piperidino-4-thioalkyl-1,3-diazabuta-1,3-dienes were prepared by the treatment of N-arylimino isothiocyanate with piperidine followed by S-alkylation with alkyl iodides in the presence of dry acetone and potassium hydroxide. The constitution of the products was supported by IR, PMR and mass spectral study. The compounds synthesized were tested in in vitro against E. coli, S. aureus, P. aeruginosa, B. cereus and B. subtilis and fungal stains, Candida albicans and Aspergillus niger. Standard drugs were also tested under identical conditions for comparing the results.
Asunto(s)
Amidinas/síntesis química , Antibacterianos/síntesis química , Antifúngicos/síntesis química , Alquilación , Amidinas/farmacología , Antibacterianos/farmacología , Antifúngicos/farmacología , Butadienos/química , Candida albicans/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Isotiocianatos/química , Estructura Molecular , Piperidinas/químicaRESUMEN
PURPOSE: The present study was undertaken to examine the effect of monocyclic beta-lactams (compounds 5a-5o) for anti-hyperglycemic activity against alloxan-induced diabetes in rats. As these compounds have been shown to control disturbances in cholesterol metabolism induced by diabetes. METHODS: The test compounds were synthesized via [2+2] cycloaddition (Staudinger) reaction of imines with ketenes. The anti-hyperglycemic effect of test compounds was evaluated in alloxan-induced diabetes in rats by monitoring their effect on blood glucose and liver glycogen contents. RESULTS AND DISCUSSION: In the diabetic rats, high glucose levels and depression in hepatic glycogen contents were observed which could be attributed to the less availability of active form of enzyme glycogen synthetase. Test compounds significantly lowered the serum glucose levels indicating their anti-hyperglycemic activity. This activity of test compounds may be due to increased utilization of glucose as indicated by decreased serum glucose levels and an increase in the activity of glycogen synthetase enzyme as evidenced by rise in liver glycogen contents in test groups. Based on the results structure activity relationship (SAR) has been discussed and favorable substitutions around of monocyclic beta-lactam have been reported. Present study concluded that these compounds could have potential anti-hyperglycemic effect, which might be due to increased utilization of glucose either through increased insulin activity or induction of glycogen synthetase enzyme. CONCLUSION: Present study concluded that these compounds have significant anti-hyperglycemic effect. Further studies are required to reveal the mechanism of action.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Glucógeno Hepático/metabolismo , Monobactamas/uso terapéutico , Aloxano , Animales , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/inducido químicamente , Modelos Animales de Enfermedad , Hipoglucemiantes/química , Monobactamas/química , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
A series of novel-2-phenyl-1-p-tolyl-4-thiomethyl-1,3-diazabuta-1,3-dienes compounds (5a-5e) possessing morpholino, diethyl amino, pyrrolidino, piperidino and 2-aminopyridino groups respectively at C-4 were prepared by reaction of alpha-aryliminobenzyl isothiocyanates with secondary amines and S-alklyation of the resultant thioureas with aqueous potassium hydroxide. The isothiocyanates were obtained from easily available starting materials. These 1,3-diazabuta-1,3-dienes were obtained in pure form after recrystallization and their structures were established by analytical and spectral data. The synthesized compounds were screened for their antibacterial activity and some of them were found to exhibit significant antibacterial activity.