RESUMEN
BACKGROUND: Indole and pyrazole constitute a major class of biologically active scaffolds. The amalgamation of two or more pharmacophores would generate novel molecular templates that are likely to unveil remarkable biological properties. OBJECTIVE: An efficient and high yielding synthesis of indole-pyrazole integrated α-cyano substituted chalcones and their in vitro anti-breast cancer and antioxidant evaluation. METHODS: The synthesis of a series of indole-pyrazole amalgamated α-cyano substituted chalcones (6a-o) was achieved by reacting substituted 3-cyanoacetyl indole 2 with substituted pyrazole aldehyde 5 in the presence of piperidine. All the newly synthesized compounds have been characterized by IR, 1H NMR and HRMS spectroscopy. RESULTS: Anti-breast cancer evaluation of the synthesized compounds in vitro against MCF-7 cell line revealed high anti-breast cancer activities. Amongst the compounds screened 6f, 6g, 6h, 6c, 6d, 6e, 6i and 6k unveiled excellent activity against breast carcinoma (GI50 <0.1µM) as good as adriamycin (GI50 <0.1µM). The compounds were also screened against the normal Vero monkey cell line and the results demonstrated more selectivity against MCF-7. On the other hand, compounds 6b, 6c, 6d, 6h and 6i have shown moderate DPPH and NO radical scavenging activity. CONCLUSION: Most of the synthesized compounds exhibited significant antitumor activities. These results further support its safety margin by studying the activity on normal Vero monkey cell line. These results acclaim the possible use of these compounds for the design and development of potent anti-breast cancer agents.
Asunto(s)
Antineoplásicos/farmacología , Antioxidantes/farmacología , Chalconas/farmacología , Indoles/farmacología , Pirazoles/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antioxidantes/síntesis química , Antioxidantes/química , Proliferación Celular/efectos de los fármacos , Chalconas/síntesis química , Chalconas/química , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Radicales Libres/antagonistas & inhibidores , Humanos , Indoles/química , Células MCF-7 , Estructura Molecular , Pirazoles/química , Células VeroRESUMEN
BACKGROUND: The blending of two pharmacophores would generate novel molecular templates that are likely to exhibit interesting biological properties. OBJECTIVE: A facile, efficient and high yielding synthesis of (E)-3-(benzo[d]thiazol-2-ylamino)-2-(1-methyl-1Hindole- 3-carbonyl)-3-(methylthio) acrylonitrile derivatives and evaluation of therapeutic potential. METHOD: The synthesis of target molecules has been achieved by reacting 2-aminobenzothiazole and substituted 2-(1-methyl-1H-indole-3-carbonyl)-3,3-bis(methylthio)acrylonitrile in the presence of a catalytic amount of sodium hydride in THF. Structural investigations were carried using 1H NMR, 13C NMR, FT-IR, and HRMS data. RESULTS: In vitro anti-tumor evaluation of the synthesized compounds against MCF-7 (breast carcinoma) cell line revealed that they possess good anti-tumor activities. Compounds, 4j and 4i demonstrated significant activities against breast carcinoma (GI50 14.3 and 19.5 µM respectively). Most of the synthesized compounds were also found to be excellent NO, H2O2, DPPH, and superoxide radical scavengers. Anti-diabetic and antiinflammatory evaluation also displayed moderate activity. CONCLUSION: Among the compounds synthesized some of the compounds possess significant anticancer, antioxidant and anti-inflammatory properties.
Asunto(s)
Acrilonitrilo/farmacología , Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Etilenos/farmacología , Cetonas/farmacología , Acrilonitrilo/síntesis química , Acrilonitrilo/química , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Compuestos de Bifenilo/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Etilenos/química , Humanos , Cetonas/química , Células MCF-7 , Estructura Molecular , Óxido Nítrico/antagonistas & inhibidores , Ovalbúmina/antagonistas & inhibidores , Ovalbúmina/metabolismo , Picratos/antagonistas & inhibidores , Desnaturalización Proteica/efectos de los fármacos , Relación Estructura-Actividad , alfa-Amilasas/antagonistas & inhibidores , alfa-Amilasas/metabolismoRESUMEN
In the present investigation, synthesis of a series of extended conjugated δ-chloro-α-cyano substituted indolyl chalcones (5a-p) was accomplished by reacting 3-cyanoacetylindole 2 with 3-chloro-3-phenyl-propenal 4 in the presence of piperidine. The structural interpretations of newly synthesized compounds were based on chemical and spectroscopic evidences. Anti-tumor evaluation of the synthesized compounds in vitro against MCF-7 (breast carcinoma) cell line revealed that they possess high anti-tumor activities. Among them, compound 5e and 5a demonstrated excellent activity against breast carcinoma (GI50 <0.1 and 4µM respectively) as good as adriamycin (GI50 <0.1µM). The compounds were also screened against the normal Vero monkey cell line, which showed moderate selectivity against inhibition of cancer cells. The effect of extended conjugation on activity authenticated by comparing activity profile of compound 5a, 5i and 5m with their simple analogues. Among the synthesized compounds, 5i and 5l were found to be active anti-inflammatory agents in addition to having noteworthy antioxidant potential. These results suggest the possible use of these compounds for the design and development of novel anti-breast cancer agents.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Chalconas/farmacología , Depuradores de Radicales Libres/farmacología , Indoles/farmacología , Albúminas/metabolismo , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antineoplásicos/síntesis química , Chalconas/síntesis química , Chlorocebus aethiops , Diclofenaco/farmacología , Doxorrubicina/farmacología , Proteínas del Huevo/metabolismo , Femenino , Depuradores de Radicales Libres/síntesis química , Humanos , Indoles/síntesis química , Células MCF-7 , Óxido Nítrico/metabolismo , Desnaturalización Proteica , Relación Estructura-Actividad , Superóxidos/metabolismo , Células VeroRESUMEN
This study investigates anti-inflammatory activity with improved pharmacokinetic and non-ulcerogenic properties of various novel synthesized prodrugs of ketoprofen in experimental animals. Prodrugs 3a, 3f and 3k were found to possess significant anti-inflammatory activity with almost non-ulcerogenic potential than standard drug ketoprofen (1) in both normal and inflammation-induced rats. The experimental findings elicited higher AUC and plasma concentration at 1 and 2 h indicating improved oral bioavailability as compared to parent drug ketoprofen. These prodrugs are found to have no gastric ulceration with retained anti-inflammatory activity. Therefore, present experimental findings demonstrated significant improvement of various pharmacokinetic properties with non-ulcerogenic potential of ester prodrugs of ketoprofen.
Asunto(s)
Cetoprofeno , Profármacos , Administración Oral , Animales , Evaluación Preclínica de Medicamentos , Cetoprofeno/efectos adversos , Cetoprofeno/síntesis química , Cetoprofeno/química , Cetoprofeno/farmacocinética , Ratones , Profármacos/efectos adversos , Profármacos/síntesis química , Profármacos/química , Profármacos/farmacocinética , Ratas , Sigmodontinae , Úlcera Gástrica/sangre , Úlcera Gástrica/inducido químicamenteRESUMEN
A series of novel pyrazole amalgamated flavones has been designed and synthesized from 1-methyl-5-(2,4,6-trimethoxy-phenyl)-1H-pyrazole 6. The structures of regioisomers 6 and 7 were resolved by 2D (1)H-(1)H COSY, (1)H-(13)C HSQC and (1)H-(13)C HMBC experiments. The newly synthesized compounds were tested for their in vitro COX inhibition and in vivo carrageenan induced hind paw edema in rats and acetic acid induced vascular permeability in mice. Although the compounds have inhibitory profile against both COX-1 and COX-2, some of the compounds are found to be selective against COX-2, supported by inhibition of paw edema and vascular permeability. Docking studies were also carried out to determine the structural features which sway the anti-inflammatory activity of the tested compounds. The keto and phenolic -OH are major factors that are prominently involved in interaction with COX-2 active site.