RESUMEN

To develop novel bacterial biofilm inhibiting agents, a series of 1,3,4-thiadiazole derivatives containing sulfonylpiperazine structures were designed, synthesized, and characterized using 1H nuclear magnetic resonance (1H NMR), 13C nuclear magnetic resonance (13C NMR), and high-resolution mass spectrometry. Meanwhile, their biological activities were evaluated, and the ensuing structure-activity relationships were discussed. The bioassay results showed the substantial antimicrobial efficacy exhibited by most of the compounds. Among them, compound A24 demonstrated a strong efficacy with an EC50 value of 7.8 µg/mL in vitro against the Xanthomonas oryzae pv. oryzicola (Xoc) pathogen, surpassing commercial agents thiodiazole copper (31.8 µg/mL) and bismerthiazol (43.3 µg/mL). Mechanistic investigations into its anti-Xoc properties revealed that compound A24 operates by increasing the permeability of bacterial cell membranes, inhibiting biofilm formation and cell motility, and inducing morphological changes in bacterial cells. Importantly, in vivo tests showed its excellent protective and curative effects on rice bacterial leaf streak. Besides, molecular docking showed that the hydrophobic effect and hydrogen-bond interactions are key factors between the binding of A24 and AvrRxo1-ORF1. Therefore, these results suggest the utilization of 1,3,4-thiadiazole derivatives containing sulfonylpiperazine structures as a bacterial biofilm inhibiting agent, warranting further exploration in the realm of agrochemical development.

Asunto(s)

Antibacterianos , Biopelículas , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Tiadiazoles , Xanthomonas , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/síntesis química , Relación Estructura-Actividad , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Xanthomonas/efectos de los fármacos , Biopelículas/efectos de los fármacos , Piperazinas/farmacología , Piperazinas/química , Piperazinas/síntesis química , Estructura Molecular , Oryza/microbiología

RESUMEN

In the current study, a series of novel quinolinedione-linked sulfonylpiperazine derivatives have been reported as NQO1-directed antitumor agents. A majority of compounds in this study were found to be more effective in resisting the proliferation of cancer cells than that of the positive control 5-Fu and TSA. Among the tested compounds, the derivative 22r exhibited considerable effect (IC50, 3.29-5.19 µM) against the proliferation of three NQO1-rich cancer cells (HepG2, MCF-7, and A549), and was recognized to be an excellent NQO1 substrate as revealed by in vitro enzyme reduction assay and molecular docking study with NQO1. In studies on the mechanisms involved, 22r induced reactive oxygen species (ROS) production, caused DNA damage, and induced apoptosis in HepG2 cells. Remarkably, compound 22r exhibited excellent anticancer activity against HepG2 xenograft models in vivo. The study demonstrated that compound 22r provided a promising strategy for the management of malignant tumors.

Asunto(s)

Antineoplásicos , Humanos , Estructura Molecular , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Antineoplásicos/química , Apoptosis , Línea Celular Tumoral , Diseño de Fármacos , NAD(P)H Deshidrogenasa (Quinona)/metabolismo

RESUMEN

PI3K signal pathway plays a vital role in cellular functions and becomes an attractive approach for cancer therapy. Herein, a new series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivatives bearing sulfonylpiperazine based on the PI3K inhibitors and our previous research. They were screened for their PI3K inhibitory activities and anticancer effects in vitro. Biological studies indicated that compound 7m revealed the remarkable antiproliferative activity (IC50 ranging from 0.03 to 0.09 µM) against four cancer cell lines (A549, Huh7, HL60 and HCT-116). Besides, compound 7m displayed a certain selective for PI3Kα (IC50 = 0.009 µM) over PI3Kß, γ and δ, and meanwhile, it can remarkable decreased the expression level of p-Akt (Ser473) and p-S6K. In addition, compound 7m could not only induce HCT-116 cell arrest at G1 phase in a dose-dependent manner, but also induce cell apoptosis via upregulation of Bax and cleaved-caspase 3/9, and downregulation of Bcl-2. Besides, compound 7m can remarkably inhibit the growth of tumor in vivo. The above results suggested that compound 7m could be considered as a promising PI3Kα inhibitor.

Asunto(s)

Antineoplásicos/farmacología , Cromonas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Piperazina/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Ácidos Sulfínicos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cromonas/síntesis química , Cromonas/química , Relación Dosis-Respuesta a Droga , Desarrollo de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Piperazina/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Ácidos Sulfínicos/química , Células Tumorales Cultivadas

RESUMEN

Chrysin-based sulfonylpiperazines 7a-k were synthesized and investigated for their in vitro free radical scavenging potential as well as cytotoxic efficacies against selected cancer cell lines. Cytotoxicity of the new compounds toward noncancer cells was confirmed using the SRB assay against Madin-Darby Canine Kidney cells. Reaction of piperazine with different substituted benzenesulfonyl chlorides in triethylamine furnished sulfonylpiperazines (3a-k), which were then allowed to react with 7-(4-bromobutoxy)-5-hydroxy-2-phenyl-4H-chromen-4-one (6) prepared reacting chrysin with 1,4-dibromobutane to give the final derivatives 7a-k. The results concluded that chrysin-sulfonylpiperazines exerted better antioxidant and anticancer efficacies than previously studied chrysin-piperazine precursors. For example, compounds 7h, 7j, and 7k with 4-OCF3 , 4-OCH3 , and 2,4-diOCH3 groups exhibited the best antioxidant potential against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radicals. Moreover, halogenated analogues (7b, 7c, 7g, and 7h) demonstrated promising anticancer potential against SK-OV3, HeLa, and HT-29 cell lines, whereas those bearing a methoxy functional group (7j and 7k) had beneficial effects against the cell lines A-549 and HT-29. Thus, it can be confirmed from the bioassay results that the overall structural design as well as proper substitution is crucial to deliver the anticipated biological effects. Spectroscopic techniques such as FT-IR, 1 H NMR, 13 C NMR, mass and elemental analysis (CHN) were carried out to confirm the final structures.

Asunto(s)

Antineoplásicos/síntesis química , Antioxidantes/síntesis química , Flavonoides/química , Células A549 , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Benzotiazoles/química , Compuestos de Bifenilo/química , Supervivencia Celular/efectos de los fármacos , Perros , Radicales Libres/química , Células HT29 , Células HeLa , Humanos , Concentración 50 Inhibidora , Células de Riñón Canino Madin Darby , Estructura Molecular , Picratos/química , Ácidos Sulfónicos/química

RESUMEN

In an effort to discover potent camptothecin-derived antitumor agents, novel camptothecin analogues with sulfonylpiperazinyl motifs at position-7 were designed and synthesized. They were evaluated for in vitro cytotoxicity with the sulforhodamine-B (SRB) method in five types of human tumor cell lines, A-549, MDA-MB-231, KB, KB-VIN and MCF-7. With IC50 values in the low µM to nM level, most of the new analogues showed greater cytotoxicity activity than the reference compounds irinotecan and topotecan. Furthermore, compounds 12l (IC50, 1.2nM) and 12k (IC50, 20.2nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that integration of sulfonylpiperazinyl motifs into position-7 of camptothecin is an effective strategy for discovering new potent cytotoxic camptothecin derivatives.

Asunto(s)

Antineoplásicos/química , Antineoplásicos/farmacología , Camptotecina/análogos & derivados , Camptotecina/farmacología , Piperazinas/química , Piperazinas/farmacología , Antineoplásicos/síntesis química , Camptotecina/síntesis química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Metilación , Neoplasias/tratamiento farmacológico , Piperazina , Piperazinas/síntesis química , Sulfonas/síntesis química , Sulfonas/química , Sulfonas/farmacología