RESUMEN
In the present study, 23 derivatives of 1,3,6-trisubstituted ß-carboline were synthesized and evaluated for cytotoxic potential against four human cancer cells, namely A-549, HeLa, Hep G2 and MCF-7 as well as anti-leishmanial activity against Leishmania donovani (MHOM/80/IN/Dd8) promastigotes. Among the studied compounds, compounds 13c and 13q showed potent cytotoxic activity better than the parent compound 10. For instance, compound 13c was found to be the most cytotoxic with IC50 of 4.72, 3.59, 3.65 and 4.17 µM against A-549, HeLa, Hep G2 and MCF-7 respectively, while for compound 13q, IC50 were 15.47, 5.30, 6.15 and 13.39 µM against the same cancer cells respectively. Further, these two compounds were found to be apoptotic in A-549 and MCF-7 cells when observed using Annexin V/propidium iodide staining under confocal microscope. All the compounds were also tested for anti-leishmanial potential. In which, compounds 13u and 13c were found to show moderate inhibition with IC50 of 23.5±9.0 and 68.0±0.0 µM respectively, while compound 10 was the most active with IC50 of 9.0±2.8 µM, suggesting the modification at C-6 detrimental for anti-leishmanial activity. Interestingly, amongst all, compound 13c was found to be the most active for cytotoxic and moderately active for anti-leishmanial activity which can be further developed as a lead for these disease areas.
Asunto(s)
Antiprotozoarios/síntesis química , Carbolinas/química , Diseño de Fármacos , Antiprotozoarios/química , Antiprotozoarios/farmacología , Apoptosis/efectos de los fármacos , Carbolinas/síntesis química , Carbolinas/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Células HeLa , Humanos , Concentración 50 Inhibidora , Leishmania donovani/efectos de los fármacos , Células MCF-7 , Microscopía Confocal , Relación Estructura-ActividadRESUMEN
ß-carbolines from various natural and synthetic sources have been known to show diverse biological activities. As a part of our current ongoing project to search for potent natural product-derived anti-leishmanial compounds, we have synthesized a series of substituted 1-aryl-ß-carboline derivatives. A total of 22 compounds were synthesized and tested in vitro against Leishmania donovani, out of which 6 compounds (4, 5, 10, 11, 19 and 22) showed notably more activity than the standard miltefosine (IC(50) 12.07±0.82 µM), with compound 4 being the most potent (IC(50) 2.16±0.26 µM).
Asunto(s)
Carbolinas/síntesis química , Leishmania donovani/efectos de los fármacos , Tripanocidas/síntesis química , Carbolinas/farmacología , Supervivencia Celular/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Leishmania donovani/crecimiento & desarrollo , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacología , Relación Estructura-Actividad , Tripanocidas/farmacologíaRESUMEN
Discovery of a new drug is time consuming and laborious process. Natural products have long been a thriving source for the discovery of new drugs due to their chemical diversity and ability to act on various biological targets. The phytochemical exploration of indigeneous flora has contributed to some extent in this race for the discovery of new drugs. The traditional Indian systems of medicine has been a part of our lifestyle since ages and the classical texts like Ayurveda and Charak Samhita have served as materia medica for this purpose. This review focuses on the contributions made from India in the drug discovery and development process and provides future directions in the area.
Asunto(s)
Productos Biológicos/química , Productos Biológicos/uso terapéutico , Descubrimiento de Drogas , Animales , Investigación Biomédica/métodos , Investigación Biomédica/tendencias , Evaluación Preclínica de Medicamentos , Humanos , IndiaRESUMEN
Aryl hydrazine and hydrazide analogues were synthesized based on p-tolyl hydrazine, isolated as a breakdown product of a secondary metabolite from the mushroom, Agaricus bisporus, and tested to be highly active molecule than 5-fluorouracil in in vitro anticancer studies. The synthesized analogues were tested for anticancer activity using NCI protocol. Anolgues 12 and 15 emerged as molecules with significant in vitro anticancer activity. Molecular docking study revealed the binding orientations of aryl hydrazines and hydrazides analogues in the active sites of thymidylate synthase.
Asunto(s)
Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Hidrazinas/metabolismo , Hidrazinas/farmacología , Agaricus/química , Antineoplásicos/síntesis química , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Hidrazinas/síntesis química , Enlace de Hidrógeno , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Estructura Terciaria de Proteína , Timidilato Sintasa/química , Timidilato Sintasa/metabolismoRESUMEN
Natural products have been, and continue to be, a major source of pharmacologically active substances from which drugs can be developed. Currently, tumor necrosis factor-alpha (TNF-alpha) inhibitors from natural origins are being advanced for the treatment of inflammatory disorders. Elevated TNF-alpha synthesis has been associated with the development of diabetes, septic shock, tumorigenesis, rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. Currently, only protein-based drugs are available for the clinical inhibition of TNF-alpha activity. Small-molecule drugs that can regulate TNF-alpha levels or activity might provide a cost-effective alternative to protein-based therapeutics. This review briefly highlights the physiological and pathological roles of TNF-alpha, and covers those natural compounds capable of interfering with TNF-alpha activity.