RESUMEN
A novel series of antitumor hybrids was synthesized using 1,4-benzohydroquinone and chalcone, furane, or pyrazoline scaffolds. This were achieved through isosteric substitution of the aryl group of the chalcone ß-carbon with the furanyl moiety and structural modification of the α,ß-unsaturated carbonyl system. The potential antitumor activity of these hybrids was evaluated in vivo on MCF-7 breast adenocarcinoma and HT-29 colorectal carcinoma cells, demonstrating cytotoxic activity with IC50 values ranging from 28.8 to 124.6 µM. The incorporation of furan and pyrazoline groups significantly enhanced antiproliferative properties compared to their analogues and precursors (VII-X), which were inactive against both neoplastic cell lines. Compounds 4, 5, and 6 exhibited enhanced cytotoxicity against both cell lines, whereas compound 8 showed higher cytotoxic activity against HT-29 cells. Molecular docking studies revealed superior free-energy values (ΔGbin) for carcinogenic pathway-involved kinase proteins, with our in silico data suggesting that these derivatives could be promising chemotherapeutic agents targeting kinase pathways. Among all the synthesized PIBHQ compounds, derivatives 7 and 8 exhibited the best drug-likeness properties, with values of 0.53 and 0.83, respectively. ADME results collectively suggest that most of these compounds hold promise as potential candidates for preclinical assays.
Asunto(s)
Antineoplásicos , Hidroquinonas , Simulación del Acoplamiento Molecular , Pirazoles , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Hidroquinonas/química , Hidroquinonas/farmacología , Hidroquinonas/síntesis química , Células MCF-7 , Proliferación Celular/efectos de los fármacos , Chalcona/química , Chalcona/farmacología , Células HT29 , Chalconas/química , Chalconas/farmacología , Chalconas/síntesis química , Relación Estructura-Actividad , Línea Celular Tumoral , AnimalesRESUMEN
New pyridine-based chalcones 4a-h and pyrazolines 5a-h (N-acetyl), 6a-h (N-phenyl), and 7a-h (N-4-chlorophenyl) were synthesized and evaluated by the National Cancer Institute (NCI) against 60 different human cancer cell lines. Pyrazolines 6a, 6c-h, and 7a-h satisfied the pre-determined threshold inhibition criteria, obtaining that compounds 6c and 6f exhibited high antiproliferative activity, reaching submicromolar GI50 values from 0.38 to 0.45 µM, respectively. Moreover, compound 7g (4-CH3) exhibited the highest cytostatic activity of these series against different cancer cell lines from leukemia, nonsmall cell lung, colon, ovarian, renal, and prostate cancer, with LC50 values ranging from 5.41 to 8.35 µM, showing better cytotoxic activity than doxorubicin. Furthermore, the compounds were tested for antibacterial and antiplasmodial activities. Chalcone 4c was the most active with minimal inhibitory concentration (MIC) = 2 µg/mL against methicillin-resistant Staphylococcus aureus (MRSA), while the pyrazoline 6h showed a MIC = 8 µg/mL against Neisseria gonorrhoeae. For anti-Plasmodium falciparum activity, the chalcones display higher activity with EC50 values ranging from 10.26 to 10.94 µg/mL. Docking studies were conducted against relevant proteins from P. falciparum, exhibiting the minimum binding energy with plasmepsin II. In vivo toxicity assay in Galleria mellonella suggests that most compounds are low or nontoxic.
Asunto(s)
Antibacterianos , Antimaláricos , Antineoplásicos , Chalconas , Pruebas de Sensibilidad Microbiana , Plasmodium falciparum , Pirazoles , Piridinas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Chalconas/farmacología , Chalconas/síntesis química , Chalconas/química , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Línea Celular Tumoral , Relación Estructura-Actividad , Plasmodium falciparum/efectos de los fármacos , Pirazoles/farmacología , Pirazoles/química , Pirazoles/síntesis química , Piridinas/farmacología , Piridinas/química , Piridinas/síntesis química , Antimaláricos/farmacología , Antimaláricos/síntesis química , Antimaláricos/química , Simulación del Acoplamiento Molecular , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Animales , Relación Dosis-Respuesta a Droga , Neisseria gonorrhoeae/efectos de los fármacosRESUMEN
Breast cancer (BC) is the most frequently diagnosed cancer and is the second-most common cause of death in women worldwide. Because of this, the search for new drugs and targeted therapy to treat BC is an urgent and global need. Histone deacetylase 6 (HDAC6) is a promising anti-BC drug target associated with its development and progression. In the present work, the design and synthesis of a new family of dihydropyrazole-carbohydrazide derivatives (DPCH) derivatives focused on HDAC6 inhibitory activity is presented. Computational chemistry approaches were employed to rationalize the design and evaluate their physicochemical and toxic-biological properties. The new family of nine DPCH was synthesized and characterized. Compounds exhibited optimal physicochemical and toxicobiological properties for potential application as drugs to be used in humans. The in silico studies showed that compounds with -Br, -Cl, and -OH substituents had good affinity with the catalytic domain 2 of HDAC6 like the reference compounds. Nine DPCH derivatives were assayed on MCF-7 and MDA-MB-231 BC cell lines, showing antiproliferative activity with IC50 at µM range. Compound 2b showed, in vitro, an IC50 value of 12 ± 3 µM on human HDAC6. The antioxidant activity of DPCH derivatives showed that all the compounds exhibit antioxidant activity similar to that of ascorbic acid. In conclusion, the DPCH derivatives are promising drugs with therapeutic potential for the epigenetic treatment of BC, with low cytotoxicity towards healthy cells and important antioxidant activity.
RESUMEN
A new series of N-substituted pyrazoline derivatives 6a-g, 7a-g, 8a-g, and 9a-g was synthetized by reaction of hydrazine derivatives and chalcone-thiazole hybrids bearing nitrogen mustard 5a-g. The chalcones 5a-g were obtained by Claisen-Schmidt condensation of thiazole-2-nitrogen mustard 3 and selected acetophenones 4a-g. These new compounds 6/7/8/9a-g were screened for their antifungal activity against Cryptococcus neoformans, with IC50 values of 3.9-7.8 µg/ml for the N-3,5-dichlorophenyl pyrazolines 9e-g. Interestingly, those compounds show low cytotoxic effects toward erythrocytes (RBC). In addition, N-acetyl (6a,b) and N-formyl pyrazolines (7a, 7b, 7c, and 7g) showed inhibitory activity against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, and vancomycin-intermediate S. aureus, with the most important minimum inhibitory concentration values ranging from 31.25 to 125 µg/ml. Regarding the antiprotozoal activity, thiazolyl-pyrazolines 9g, 8f, and 7c display high activity against Plasmodium falciparum, Leishmania (V) panamensis, and Trypanosoma cruzi, with EC50 values of 11.80, 6.46, and 4.98 µM, respectively, and with 7c being approximately 2.6-fold more potent than benznidazole with a selectivity index of 1.61 on U-937 human cells, showing promising potential as a novel antitrypanosomal agent.
Asunto(s)
Antibacterianos/farmacología , Antiprotozoarios/farmacología , Mecloretamina/farmacología , Pirazoles/farmacología , Tiazoles/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Relación Dosis-Respuesta a Droga , Leishmania/efectos de los fármacos , Mecloretamina/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/efectos de los fármacos , Pirazoles/química , Relación Estructura-Actividad , Tiazoles/química , Trypanosoma cruzi/efectos de los fármacos , Staphylococcus aureus Resistente a Vancomicina/efectos de los fármacosRESUMEN
Pyrazoline is an important 5-membered nitrogen heterocycle that has been extensively researched. Ten derivatives were synthesized and tested for antileukemic effects on 2 human acute leukemia cell lines, K562 and Jurkat. The most cytotoxic of these derivatives, compound 21, was chosen for investigation of cytotoxicity mechanisms. The results obtained with selectivity calculations revealed that compound 21 is more selective for acute leukemia (K562 and Jurkat cell lines) than for other tumor cell lines. Moreover, compound 21 was not cytotoxic to normal cell lines, indicating a potential use in clinical tests. Compound 21 caused a significant cell cycle arrest in the S-phase in Jurkat cells and increased the proportion of cells in the sub G0/G1 phase in both cell lines. Cells treated with compound 21 demonstrated morphological changes characteristic of apoptosis in the EB/AO assay, confirmed by externalization of phosphatidylserine by the annexin V - fluorescein isothiocyanate method and by DNA fragmentation. An investigation of cytotoxicity mechanisms suggests the involvement of an intrinsic apoptosis pathway due to mitochondrial damage and an increase in the ratio of mitochondrial Bax/Bcl2. Pyrazoline 21 obeyed Lipinski's "rule of five" for drug-likeness. Based on these preliminary results, the antileukemic activity of compound 21 makes it a potential anticancer agent.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Leucemia/patología , Pirazoles/química , Pirazoles/farmacología , Antineoplásicos/farmacocinética , Coagulación Sanguínea/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Fragmentación del ADN/efectos de los fármacos , Humanos , Células Jurkat , Células K562 , Pirazoles/farmacocinética , Transducción de Señal/efectos de los fármacosRESUMEN
An efficient and facile synthesis of fused, substituted and spiro pyrazoline steroid derivatives through a cycloaddition reaction of different α,ß-unsaturated ketones with hydrazine acetate in acetic acid is reported. Depending on the starting material, the ring closure reaction provided a mixture of two steroidal pyrazoline epimers that were separated and studied by NMR techniques. In one case it was possible to isolate and characterize the hydrazone derivative as the reaction intermediate, which confirms the mechanism proposed in the literature [11,25,26].