RESUMEN
Based on our recent findings that piperine is a potent Staphylococcus aureus NorA efflux pump inhibitor (EPI), 38 piperine analogs were synthesized and bioevaluated for their EPI activity. Twenty-five of them were found active with potentiating activity equivalent or more than known EPIs like reserpine, carsonic acid and verapamil. The inhibitory mechanism of the compounds was confirmed by efflux inhibition assay using ethidium bromide as NorA substrate. The present communication describes the synthesis, bioevaluation and structure related activity of these efflux pump inhibitors.
Asunto(s)
Alcaloides/química , Alcaloides/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Benzodioxoles/química , Benzodioxoles/farmacología , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Piperidinas/química , Piperidinas/farmacología , Alcamidas Poliinsaturadas/química , Alcamidas Poliinsaturadas/farmacología , Staphylococcus aureus/efectos de los fármacos , Alcaloides/síntesis química , Proteínas Bacterianas/metabolismo , Benzodioxoles/síntesis química , Ciprofloxacina/química , Ciprofloxacina/farmacología , Inhibidores Enzimáticos/farmacología , Etidio/metabolismo , Pruebas de Sensibilidad Microbiana , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Inhibidores de la Síntesis del Ácido Nucleico/química , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , Piperidinas/síntesis química , Alcamidas Poliinsaturadas/síntesis química , Staphylococcus aureus/metabolismoRESUMEN
Monoterpene citral and citronellal have been used as starting material for the preparation of 5,9-dimethyl-deca-2,4,8-trienoic acid amides and 9-formyl-5-methyl-deca-2,4,8-trienoic acid amides. The amides on bioevaluation as efflux pump inhibitors (EPIs) against Staphylococcus aureus 1199 and NorA overexpressing S. aureus 1199B bacteria resulted in the identification of several of these as potent EPIs. Many of these amides have been shown to possess potency higher or equivalent to known EPIs such as reserpine, verapamil, carsonic acid, and piperine. In this communication, we report a convenient synthesis of alkenyl amides, their bioevaluation and identification as efflux pump inhibitors against S. aureus.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Amidas/química , Ciprofloxacina/química , Ciprofloxacina/farmacología , Estructura Molecular , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A library of 28 compounds comprising of acyl, amino, halo, nitro, styryl and cyclized derivatives of bakuchiol have been evaluated against a panel of eight human cancer cell lines. Bioevaluation studies have resulted in the identification of potent cytotoxic molecules exhibiting concentration dependent growth inhibition against leukemia cancer cells with best results observed for compounds 17 and 22 exhibiting IC(50) 1.8 and 2.0 µM respectively. As evident from various biological end-points, inhibition of cell proliferation by inducing G2/M cell cycle arrest, mitochondrial membrane disruption followed by DNA fragmentation and apoptosis is demonstrated.
Asunto(s)
Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Fenoles/química , Fenoles/farmacología , Psoralea/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Fragmentación del ADN/efectos de los fármacos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismoRESUMEN
Novel bisstyryl derivatives of bakuchiol using Heck coupling reaction as the key step were synthesized and screened against a panel of six oral cavity pathogens for their antimicrobial activity. Four compounds (9-12) showed two to fourfold and four to eightfold better activity (MIC 0.25-16 microg/ml) than bakuchiol and triclosan respectively. These compounds effectively inhibit the biofilm formation of single and multiple species at 2 - 8 x MICs. 4- and 4'-Hydroxy/methoxy styryl moieties of the bakuchiol derivatives play a pivotal role towards the activity as established in the SAR studies. Mechanism of action studies revealed microbial membrane structure disruption as the probable mode of action of these compounds.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Boca/microbiología , Fenoles/química , Fenoles/farmacología , Estireno/química , Antibacterianos/síntesis química , Bacterias/citología , Biopelículas/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Fenoles/síntesis química , Estereoisomerismo , Relación Estructura-Actividad , Triclosán/farmacologíaRESUMEN
A new series of 3-(substituted-3,4-dihydronaphthyl)-2-propenoic acid amides has been prepared through convergent synthetic strategies and tested in combination with ciprofloxacin against NorA overexpressing Staphylococcus aureus 1199B as test strain for potentiating of the drug activity. Out of 24 compounds evaluated, 12 compounds potentiated the activity of ciprofloxacin and resulted in 2-16 fold reduction in the MIC (4-0.5 microg/mL) of the drug. The failure of these efflux pump inhibitors (EPIs) to potentiate the activity of ciprofloxacin when tested against NorA knock out S. aureus SA-K1758 established their identity as NorA inhibitors. The structure of all these newly synthesised compounds was confirmed by spectral data. The present communication describes the synthesis, bioevaluation, structure activity relationship and mechanism of action of these EPIs.