RESUMEN
Monoamine oxidase inhibitors (MAOIs) have been crucial in the search for anti-neurodegenerative medications and continued to be a vital source of molecular and mechanistic diversity. Therefore, the search for selective MAOIs is one of the main areas of current drug development. To increase the effectiveness and safety of treating Parkinson's disease, new scaffolds for reversible MAO-B inhibitors are being developed. A total of 24 pyridazinobenzylpiperidine derivatives were synthesized and evaluated for MAO. Most of the compounds showed a higher inhibition of MAO-B than of MAO-A. Compound S5 most potently inhibited MAO-B with an IC50 value of 0.203 µM, followed by S16 (IC50 = 0.979 µM). In contrast, all compounds showed weak MAO-A inhibition. Among them, S15 most potently inhibited MAO-A with an IC50 value of 3.691 µM, followed by S5 (IC50 = 3.857 µM). Compound S5 had the highest selectivity index (SI) value of 19.04 for MAO-B compared with MAO-A. Compound S5 (3-Cl) showed greater MAO-B inhibition than the other derivatives with substituents of -Cl > -OCH3 > -F > -CN > -CH3 > -Br at the 3-position. However, the 2- and 4-position showed low MAO-B inhibition, except S16 (2-CN). In addition, compounds containing two or more substituents exhibited low MAO-B inhibition. In the kinetic study, the Ki values of S5 and S16 for MAO-B were 0.155 ± 0.050 and 0.721 ± 0.074 µM, respectively, with competitive reversible-type inhibition. Additionally, in the PAMPA, both lead compounds demonstrated blood-brain barrier penetration. Furthermore, stability was demonstrated by the 2V5Z-S5 complex by pi-pi stacking with Tyr398 and Tyr326. These results suggest that S5 and S16 are potent, reversible, selective MAO-B inhibitors that can be used as potential agents for the treatment of neurological disorders.
Asunto(s)
Inhibidores de la Monoaminooxidasa , Monoaminooxidasa , Piperidinas , Inhibidores de la Monoaminooxidasa/farmacología , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/síntesis química , Monoaminooxidasa/metabolismo , Piperidinas/farmacología , Piperidinas/química , Humanos , Relación Estructura-Actividad , Piridazinas/química , Piridazinas/farmacología , Piridazinas/síntesis química , Simulación del Acoplamiento Molecular , Estructura MolecularRESUMEN
Novel 3(2H)-pyridazinone derivatives were designed, synthesised in satisfactory yields and evaluated in different experimental assays to assess their preliminary toxicity in vivo and anti-proliferative effects against HCT116 cell lines in vitro. Artemia salina lethality test provided LC50 values >100 µg/mL for all compounds. Successive assays revealed that some compounds were endowed with a promising anti-proliferative effect against HCT116 cells, alone or stimulated by serotonin as a pro-inflammatory factor in order to mimick an inflamed model in vivo of cancer cell microenvironment. Moreover, the kinurenic acid level after treatment with these newly synthesised compounds was monitored as a marker of anti-proliferation in colon carcinoma models. The IC50 values obtained for the best-in-class compounds were comparable to that of daunorubicin as a reference drug. Conversely, these compounds were not able to counteract the spontaneous migration of human cancer HCT116 cell line in the wound healing paradigm.
Asunto(s)
Antineoplásicos/farmacología , Piridazinas/farmacología , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Estructura Molecular , Piridazinas/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
BACKGROUND: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are known to be serine hydrolase enzymes responsible for the hydrolysis of acetylcholine (ACh), which is a significant neurotransmitter for regulation of cognition in animals. Inhibition of cholinesterases is an effective method to curb Alzheimer's disease, a progressive and fatal neurological disorder. OBJECTIVE: In this study, 30 new hydrazone derivatives were synthesized. Then we evaluated their anticholinesterase activity of compounds. We also tried to get insights into binding interactions of the synthesized compounds in the active site of both enzymes by using molecular docking approach. METHODS: The compounds were synthesized by the reaction of various substituted/nonsubstituted benzaldehydes with 6-(substitute/nonsubstituephenyl)-3(2H)-pyridazinone-2-yl propiyohydrazide. Anticholinesterase activity of the compounds was determined using Ellman's method. Molecular docking studies were done by using the ADT package version 1.5.6rc3 and showed by Maestro. RMSD values were obtained using Lamarckian Genetic Algorithm and scoring function of AutoDock 4.2 release 4.2.5.1 software. RESULTS: The activities of the compounds were compared with galantamine as cholinesterase enzyme inhibitor, where some of the compounds showed higher BChE inhibitory activity than galantamine. Compound F111 was shown to be the best BChE inhibitor effective in 50 µM dose, providing 89.43% inhibition of BChE (IC50=4.27±0.36 µM). CONCLUSION: This study supports that novel hydrazone derivates may be used for the development of new BChE inhibitory agents.
Asunto(s)
Acetilcolinesterasa/metabolismo , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Hidrazonas/farmacología , Simulación del Acoplamiento Molecular , Animales , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Electrophorus , Caballos , Humanos , Hidrazonas/síntesis química , Hidrazonas/química , Estructura Molecular , Programas Informáticos , Relación Estructura-ActividadRESUMEN
BACKGROUND: The pyridazinone nucleus has been incorporated into a wide variety of therapeutically interesting molecules to transform them into better drugs. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are known to be serine hydrolase enzymes responsible for the hydrolysis of acetylcholine (ACh). Inhibition of cholinesterases is an effective method to curb Alzheimer's disease. Here, we prepared 12 new 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(nonsubstituted/4-substituted benzenesulfonohydrazide) derivatives and evaluated their inhibitory effects on AChE/BChE in pursuit of potent dual inhibitors for Alzheirmer's Disease. We also tried to get insights into binding interactions of the synthesized compounds in the active site of both enzymes by using molecular docking approach. METHOD: We obtained our compounds by the reaction of various substituted/nonsubstituted benzenesulfonic acid derivatives with 6-substitutedphenyl-3(2H)-pyridazinone-2-yl acetohydrazide and determined their anticholinesterase activities according to the Ellman's method. Molecular docking studies were done using Glide and the results were evaluated on Maestro (Schrödinger, LLC, New York, NY, 2019). RESULTS: The title compounds showed moderate inhibition at 100⯵g/ml against both enzymes, yet with better activity against BChE. Compound VI2a emerged as a dual inhibitor with 25.02% and 51.70% inhibition against AChE and BChE, respectively. CONCLUSION: This study supports that novel pyridazinone derivates may be used for the development of new BChE inhibitory agents. It was less potent than the reference drugs, yet promising for further modifications as a lead. The ability of the compounds to adopt energetically more favourable conformations and to engage in more key interactions in the ECBChE active gorge explains their better activity profile against ECBChE.
Asunto(s)
Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Butirilcolinesterasa/metabolismo , Humanos , Simulación del Acoplamiento Molecular/métodos , Relación Estructura-ActividadRESUMEN
CONTEXT: Tranexamic acid is commonly used for curing abnormal bleeding in a variety of diseases. In a previous study, 12 different tetrahydro-2H-1,3,5-thiadiazine derivatives were synthesized from the amine group of tranexamic acid. Their antifibrinolytic and antimicrobial activities were compared with tranexamic acid. 3-Methyl-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (3-MTTT) was the most remarkable one, which may be used as a drug. OBJECTIVES: In vitro genotoxicity of 3-MTTT was investigated using chromosome aberrations (CAs), sister chromatid exchanges (SCEs), micronucleus (MN) and comet assays. MATERIALS AND METHODS: Various concentrations 0.78, 1.56, 3.13, 6.25, 12.50 and 25.00 µg/mL of 3-MTTT were applied to lymphocytes obtained from two donors for periods of 24 and 48 h. A negative (distilled water), a solvent (2:1 PBS:10% NaOH for cultured lymphocyte, and PBS for isolated lymphocytes) and a positive control (MMC for cultured lymphocytes and H2O2 for isolated lymphocytes) were also maintained. RESULTS: While this compound did not increase the frequency of abnormal cells and CA/cell ratio compared to negative control (except 48 h, 25 µg/mL), it significantly increased the frequency of SCEs at the four highest concentrations at both treatment periods (except 6.25 µg/mL, 48 h). It significantly decreased the MI in all the concentrations at 24 h (except 0.78 µg/mL) and in the highest three concentrations at 48 h. This compound did not significantly increase the frequency of MN and DNA damage compared to negative control. This compound did not affect the replication and nuclear division index. DISCUSSION AND CONCLUSION: Our results demonstrated that this compound does not represent a significant risk at the genetic level in in vitro human lymphocytes.
Asunto(s)
Daño del ADN/efectos de los fármacos , Daño del ADN/genética , Linfocitos/efectos de los fármacos , Linfocitos/fisiología , Tiazinas/toxicidad , Tionas/toxicidad , Adulto , Células Cultivadas , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Femenino , Humanos , Peróxido de Hidrógeno/toxicidad , Masculino , Pruebas de Mutagenicidad/métodosRESUMEN
OBJECTIVES: The aim of this study was to investigate the in-vitro cytotoxic activity of new platinum(II) complexes on the human HeLa (ER-), MCF-7 (ER+) and MDA-MB 231 (ER-) cell lines. Furthermore, we investigated plasmid DNA interactions and inhibition of BamHI and HindIII restriction enzyme activity of the complex 1-4,7. METHODS: Platinum(II) complexes were synthesised from precursor complexes of [PtL2 Cl2 ] and [PtL2 I2 ]. Their cytotoxic activity was tested by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Their plasmid DNA interactions and restriction enzyme activities were also investigated using the agarose gel electrophoresis method. KEY FINDINGS: The growth inhibitory effect results showed that the cytotoxicity of complex 2 was found to be the most active complex among the synthesised complexes. CONCLUSIONS: The MTT results showed that complex 2 was found to be cytotoxic equal to cisplatin and higher than carboplatin against the MCF-7 and MDA-MB-231 cell lines. Furthermore, the estrogen or progesterone co-treatment slightly increased the cytotoxicity of complex 2, the cisplatin and carboplatin compared with the complex 2 tested alone in 50 µm concentration. According to plasmid DNA interaction and the restriction studies, complexes 1-4,7 modified the tertiary structure of pBR322 plasmid DNA, and complexes 2-4 prevented enzyme digestion at high concentrations.
Asunto(s)
Antineoplásicos/uso terapéutico , Bencimidazoles/química , ADN/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Plásmidos/efectos de los fármacos , Platino (Metal)/uso terapéutico , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Carboplatino/farmacología , Carboplatino/uso terapéutico , Cisplatino/farmacología , Cisplatino/uso terapéutico , ADN/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Estrógenos/farmacología , Estrógenos/uso terapéutico , Células HeLa , Humanos , Técnicas In Vitro , Ligandos , Células MCF-7 , Plásmidos/genética , Platino (Metal)/farmacología , Progesterona/farmacología , Progesterona/uso terapéutico , Progestinas/farmacología , Progestinas/uso terapéutico , Mapeo RestrictivoRESUMEN
In the present study, four Pt(II) complexes with 2-ethyl (1)/or benzyl (2)/or p-chlorobenzyl (3)/or 2-phenoxymethyl (4) benzimidazole carrier ligands were evaluated for their in vitro cytotoxic activities against the human HeLa cervix, oestrogen receptor-positive MCF-7 breast, and oestrogen receptor-negative MDA-MB 231 breast cancer cell lines. The plasmid DNA interactions and inhibition of the BamHI restriction enzyme activities of the complexes were also studied. Complex 3 was found to be more active than carboplatin for all examined cell lines and comparable with cisplatin, except for the HeLa cell line.
Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/química , ADN/efectos de los fármacos , Compuestos Organoplatinos/toxicidad , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Desoxirribonucleasa BamHI/antagonistas & inhibidores , Desoxirribonucleasa BamHI/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Ligandos , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Plásmidos , Relación Estructura-ActividadRESUMEN
In the current study, some novel ethyl 6- [(substituted-phenylpiperazine]-3(2H)-pyridazinone-2-yl propionate III and 6-[(substituted-phenylpiperazine]-3(2H)-pyridazinone-2-yl propionohydrazide IV derivatives were synthesized as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The structures of these new pyridazinone derivatives were confirmed by their IR, 1H-NMR spectra and elementary analysis. 6-Substituted-3(2H)-pyridazinone-2-yl propionate IIIa-e derivatives showed significant inhibitory activity against AChE and BChE. 6-[4-(3-Trifluoromethylphenyl)piperazine]-3(2H)-pyridazinone-2-yl propionate IIIe has been found to be the most active compound in terms of inhibition of either AChE or BChE. Compound IIIe exhibited inhibitory activity close to that of galantamine (CAS 357-70-0) and did not show any selectivity between the two enzymes. Also the antimicrobial activities of III and IV derivatives have been evaluated. All III and IV derivatives exhibited poor antibacterial activities but moderate antifungal activities.
Asunto(s)
Acetilcolinesterasa/metabolismo , Antibacterianos/farmacología , Antifúngicos/farmacología , Azidas/farmacología , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Candida/efectos de los fármacos , Enterococcus faecalis/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Piperazinas/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A series of 3-substituted-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1,3,5thiadiazine-2-thione derivatives was prepared and examined for antifibrinolytic and antimicrobial activities. Their structures were elucidated by spectral methods. Antifibrinolytic activities of these compounds, were investigated in vitro and compared to tranexamic acid (CAS 1197-18-8). Among the synthesized compounds, 3-methyl-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (Ia) was the most prominent one (104%) when compared to tranexamic acid. Besides, 3-ethyl-5-(4-carboxycyclohexyl-methyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (Ib), 3-iso-propyl-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (Id) and 3-isobutyl-5-(4-carboxycyclohexyl-methyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (Ig) showed antifibrinolytic activity similar to tranexamic acid. Antibacterial activities of these compounds against Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis), Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and yeast-like fungi (Candida albicans, Candida tropicalis) were investigated by the micro-dilution method and compared with the activity of tranexamic acid, ofloxacin and fluconazole. By this way their minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC) and minimal fungicidal concentration (MFC) values were determined. Compound Ia exhibited almost equally potent activity against B. subtilis (MIC and MBC: 6.25 microg/mL). Compounds Ib-Id, If-Ig and In exhibited similar bactericidal activity against B. subtilis (MBC: 12.5 microg/mL). Compounds Ik and Im showed bacteriostatic activity against S. aureus. None of the compounds exhibited activity against Gram-negative bacteria. On the other hand, all compounds had potent antifungal activities against the yeast utilized. Among the synthesized compounds, 3-methyl-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (Ia) seems to be the most effective compound with antifibrinolytic and antimicrobial activity.