RESUMEN
Synthesis, characterization and theoretical studies of a novel coumarin-triazole-thiophene hybrid 4-(((4-ethyl-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-6,7-dimethyl-2H-chromen-2-one (1), which was fabricated from 4-ethyl-5-(thiophen-2-yl)-4H-1,2,4-triazole-3-thiol and 4-(chloromethyl)-6,7-dimethyl-2H-chromen-2-one, are reported. The resulting compound was characterized by microanalysis, IR, 1H, and 13C APT NMR spectroscopy. The DFT calculations examined the structure and electronic properties of 1 in gas phase. Its reactivity descriptors and molecular electrostatic potential revealed the reactivity and the reactive centers of 1. ADMET properties of 1 were evaluated using the respective online tools. It was established that 1 exhibit positive gastrointestinal absorption properties and negative human blood-brain barrier penetration. The Toxicity Model Report revealed that 1 belongs to toxicity class 4. Molecular docking was additionally applied to study the interaction of 1 with some SARS-CoV-2 proteins. It was established that the title compound is active against all the applied proteins with the most efficient interaction with Papain-like protease (PLpro). The interaction of 1 with the applied proteins was also studied using molecular dynamics simulations. Graphical abstract: A novel coumarin-triazole-thiophene hybrid 4-(((4-ethyl-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-6,7-dimethyl-2H-chromen-2-one (1) is reported. The structure and electronic properties of 1 were examined by the DFT calculations. ADMET properties of 1 were also evaluated. Molecular docking and molecular dynamics simulations were applied to study interactions of 1 with a series of the SARS-CoV-2 proteins. Supplementary Information: The online version contains supplementary material available at 10.1007/s12039-022-02127-0.
RESUMEN
The 1,2,4-triazole and its derivatives were reported to exhibit various pharmacological activities such as antimicrobial, analgesic, anti-inflammatory, antitumoural, cytotoxic, and antioxidant properties. In this study, a series of triazole compounds (M1-M10) were evaluated for some biological activities. In vitro qualifications of these compounds on acetylcholinesterase (AChE) and human carbonic anhydrase enzyme activities were performed. Also, their antitumoral activities in human colon cancer (HT29) cell line cultures were examined. In addition, colon cancer experimentation was induced in rats by an in vivo method, and the in vivo anticancer effects of triazole derivatives were investigated. Also, the effects of these derivatives in levels of antioxidant vitamin A, vitamin E, and MDA were studied in rat liver and blood samples. Most of the compounds were found to exhibit significant antioxidant and antitumoral activities. All the compounds had cytotoxic activities on HT29 cell lines with their IC50 values lower than 10 µM concentrations. The low IC 50 values of the compounds are M1 (3.88 µM), M2 (2.18 µM), M3 (4.2 µM), M4 (2.58 µM), M5 (2.88 µM), M6 (2.37 µM), M7 (3.49 µM), M8 (4.01 µM), M9 (8.90 µM), and M10 (3.12 µM).
RESUMEN
Thiadiazole derivatives and its metal compounds have antibacterial, antifungal, antitumoral, antiproliferative and antioxidant properties. In the study, the effects caused by thiadiazole ligand and its metal complexes upon the fatty acids and lipophilic vitamins in livers of rats were examined. The fatty acids in liver were specified by GC while the lipophilic vitamins were specified by HPLC. It was observed that the amounts of oleic acids (18:1, n-9) and monounsaturated fatty acids (MUFA) notably increased in the Mn complex group while the amounts of arachidonic acid (20:4, n-6) notably increased in the ligand group, compared to control group. The amounts of vitamin K2, vitamin D3 and α-tocopherol considerably increased in all groups compared to control group. It was noted that the amounts of α-tocopherol were elevated in both the Mn and Cr complex groups compared to control group. However, this elevation was matching with the amount in the same groups. Nevertheless, the amount of retinol was determined to be lower in the Mn complex group compared to other groups. Accordingly, it can be considered that thanks to the utilization of toxic metals such as manganese, cadmium and chrome, unsaturated fatty acids influenced the activities of the enzymes in liver tissue, which are in charge of fatty acid chain elongation.
Asunto(s)
Ácidos Grasos/metabolismo , Hígado/efectos de los fármacos , Esteroles/metabolismo , Tiadiazoles/química , Tiadiazoles/farmacología , Vitaminas/metabolismo , Animales , Hígado/metabolismo , Masculino , Ratas , Ratas WistarRESUMEN
In this study, it was aimed to examine the antioxidant and antihepatotoxic effects of hydroxyurea derivative Schiff bases on serum biochemical parameters (AST, ALT, LDH, urea, creatinine and total bilirubin) and antioxidant parameters (SOD, CAT, GPx, MDA). In this study, a total of 49 adult male Wistar rats was examined and they were divided into 7 equal groups. DMSO, which is diluted only with corn oil, was administered to control group. 25 mg / kg ligand, 25 mg / kg Schiff base - manganese, 25 mg / kg Schiff base-copper, 25 mg / kg Schiff base - zinc, 25 mg / kg Schiff base - nickel, 25 mg / kg Schiff base - cobalt complexes were administered to rats of experimental group subcutaneously for 15 days with three-day intervals throughout the test process. All specimens were killed by decapitation and their livers were extracted. According to the results obtained, ALT level was observed to be higher (P<0.05) in the Cu-L group compared to other groups. LDH level was observed to be higher (P<0.05) in the Cu-L and Co-L groups compared to other groups. SOD level was observed to be higher (P<0.05) in the Cu-L, Mn-L and Zn-L groups compared to other groups. MDA level was observed to be higher (P<0.05) in the Ni-L, Cu-L, Zn-L groups compared to other groups. In conclusion, it can be suggested that the determination of the pharmacological characteristics of them can be beneficial in numerous fields of application thanks to the antioxidant and hepatotoxic activities demonstrated by hydroxyurea derivative Schiff bases.
Asunto(s)
Hidroxiurea/metabolismo , Hígado/metabolismo , Bases de Schiff/metabolismo , Animales , Catalasa/metabolismo , Glutatión Peroxidasa/metabolismo , Peroxidación de Lípido/fisiología , Masculino , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismoRESUMEN
The aim of this study was to evaluate biologically active novel molecules having potentials to be drugs by their antitumor properties and by activities of apoptotic caspase and topoisomerase. Following syntheses of novel eight bis(α-aminoalkyl)phosphinic acid derivatives (4a-h) as a result of array of reactions, compounds were evaluated by cytotoxic effects in vitro on human breast cancer (MCF-7) and normal endothelial (HUVEC) cell lines. All phosphinic acid derivatives were effective for cytotoxicity on both MCF-7 and HUVEC lines, while 4c, 4e, and 4f compounds were found significantly more effective. For the evaluation of antitumor properties of compounds in a highly sensitive method, their effects on inhibiting topoisomerases I and II were investigated. Also, some of the bis(α-aminoalkyl)phosphinic acid derivatives (4a, 4e-h) showed nice inhibitory action against acetylcholinesterase and human carbonic anhydrase isoforms I and II.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de la Colinesterasa/farmacología , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa II/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores de la Colinesterasa/química , ADN-Topoisomerasas de Tipo I/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Células MCF-7 , Ácidos Fosfínicos/química , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa II/químicaRESUMEN
Aminophosphinic acids which are organophosphorus compounds widely investigated for potential production of antibacterial, antitumor and antiviral materials. In vitro antioxidant, cytotoxic and antimicrobial activities of synthesized novel compounds of 8 different bis(ß-amino alkyl)phosphinic acids (4a-h) were investigated on MCF-7 breast adenocarcinoma cell and human umbilical vein endothelial cell (HUVEC) cultures. Malondialdehyde (MDA) levels were evaluated as an indication of lipid peroxidation in cell cultures for antioxidant capacities. In vitro antioxidant activities in cell cultures were determined by evaluating totals of antioxidant, oxidant, thiol levels and activities of paraoxanase, aryl esterase. It was found that 4c compound reduced MDA level significantly while 4a and 4g compounds increased MDA levels significantly compared to control. 4c compound was found most effective in reducing MDA levels by neutralizing reactive oxygen species to prevent cell damage while compounds 4c, 4f and 4h were found presenting adequate activity with other antioxidants. In vitro anti-proliferation was evaluated on MCF-7 and HUVEC cells using XTT to investigate anti-cancer potentials as therapeutics. Compounds 4c, 4e and 4f were exhibited better compared to others. Most compounds were found cytotoxic to both MCF-7 and HUVECs. Antimicrobial and antifungal activities were investigated by disc diffusion and compared to MICs of Gentamycin and Nystatin.
Asunto(s)
Antioxidantes/farmacología , Proliferación Celular/efectos de los fármacos , Ácidos Fosfínicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Células Endoteliales de la Vena Umbilical Humana , Humanos , Células MCF-7 , Malondialdehído/metabolismo , Ácidos Fosfínicos/químicaRESUMEN
A novel series of compounds were synthesized by cyclic condensation reaction of substituted isothiocyanate (2a-c) with 2-thiophenecarboxylic acid hydrazide (1) in the presence of ethyl alcohol, to obtain intermediate thiosemicarbazides (3a-c), which were further treated with sodium hydroxide in the presence of ethanol to obtain triazole derivatives (4a-c). The latter were refluxed with substituted secondary amines and formaldehyde for 6-10 h to afford Mannich bases (5a-k). The synthesized compounds were characterized on the basis of their spectral (IR, (13)C and (1)H NMR) data and evaluated for biological activities. Some of the compounds were found to exhibit significant antimicrobial and antioxidant activity.
Asunto(s)
Antibacterianos/síntesis química , Antifúngicos/síntesis química , Tionas/síntesis química , Triazoles/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Antifúngicos/química , Antifúngicos/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Antioxidantes/farmacología , Aspergillus flavus/efectos de los fármacos , Aspergillus fumigatus/efectos de los fármacos , Compuestos de Bifenilo/metabolismo , Relación Dosis-Respuesta a Droga , Escherichia coli/efectos de los fármacos , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Pruebas de Sensibilidad Microbiana , Modelos Químicos , Estructura Molecular , Oxidación-Reducción/efectos de los fármacos , Penicillium/efectos de los fármacos , Picratos/metabolismo , Staphylococcus aureus/efectos de los fármacos , Tionas/química , Tionas/farmacología , Triazoles/química , Triazoles/farmacología , Trichophyton/efectos de los fármacosRESUMEN
This work presents the characterization of 4-ethyl-5-(2-hydroxyphenyl)-2H-1,2,4-triazole-3(4H)-thione (III) by quantum chemical calculations and spectral techniques. The molecular geometry, vibrational frequencies and gauge including atomic orbital (GIAO) (1)H and (13)C NMR chemical shift values of III in the ground state have been calculated using the density functional method (B3LYP) with the 6-31G(d) basis set. The calculated results show that the optimized geometry can well reproduce the crystal structure, and the theoretical vibrational frequencies and chemical shift values show good agreement with experimental values. To determine conformational flexibility, the molecular energy profile of the title compound was obtained by DFT calculations with respect to the selected torsion angle, which was varied from -180° to +180° in steps of 10°. The energetic behavior of III in solvent media was examined using the B3LYP method with the 6-31G(d) basis set by applying the Onsager and the polarizable continuum model (PCM). The predicted nonlinear optical properties of III are greater than ones of urea. In addition, DFT calculations of molecular electrostatic potentials and frontier molecular orbitals of III were carried out at the B3LYP/6-31G(d) level of theory. The title compound was screened for antibacterial, antifungal and antioxidant activities.
Asunto(s)
Antiinfecciosos/química , Antiinfecciosos/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Tionas/química , Tionas/farmacología , Antiinfecciosos/síntesis química , Antioxidantes/síntesis química , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Cristalografía por Rayos X , Hongos/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Micosis/tratamiento farmacológico , Espectroscopía Infrarroja por Transformada de Fourier , Tionas/síntesis química , Triazoles/síntesis química , Triazoles/química , Triazoles/farmacologíaRESUMEN
The triazol compound N-cyclohexyl-2-[5-(4-pyridyl)-4-(p-tolyl)-4H-1,2,4-triazol-3-ylsulfanyl]-acetamide dihydrate has been synthesized and characterized by (1)H NMR, (13)C NMR, IR, and X-ray single-crystal determination. The molecular geometry, vibrational frequencies and gauge including atomic orbital (GIAO) (1)H and (13)C NMR chemical shift values of III in the ground state have been calculated using the density functional method (B3LYP) with the 6-31G(d) basis set. The calculated results show that the optimized geometry can well reproduce the crystal structure, and the theoretical vibrational frequencies and chemical shift values show good agreement with experimental values. The energetic behavior of III in solvent media was examined using the B3LYP method with the 6-31G(d) basis set by applying the Onsager and the polarizable continuum model (PCM). The predicted nonlinear optical properties of III are greater than ones of urea. In addition, DFT calculations of molecular electrostatic potentials, frontier molecular orbitals and thermodynamic properties of III were carried out at the B3LYP/6-31G(d) level of theory. The title compound was screened for antibacterial, antifungal and antioxidant activities.
Asunto(s)
Acetamidas/síntesis química , Acetamidas/farmacología , Triazoles/síntesis química , Triazoles/farmacología , Acetamidas/química , Antibacterianos/farmacología , Antifúngicos/farmacología , Antioxidantes/farmacología , Bacterias/efectos de los fármacos , Cristalografía por Rayos X , Depuradores de Radicales Libres/farmacología , Hongos/efectos de los fármacos , Enlace de Hidrógeno , Cinética , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Dinámicas no Lineales , Fenómenos Ópticos , Soluciones , Solventes/química , Espectroscopía Infrarroja por Transformada de Fourier , Electricidad Estática , Termodinámica , Triazoles/química , VibraciónRESUMEN
The title molecule, 4-allyl-5-pyridin-4-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione (C(10)H(10)N(4)S), was synthesized and characterized by IR-NMR spectroscopy and single-crystal X-ray diffraction. The compound crystallizes in the monoclinic space group is P2(1)/c, a=8.006(5)Å, b=15.363(5)Å, c=8.936(5)Å, ß=104.441(5)° and V=1064.4(10)Å(3), F(000)=456, D(x)=1.362 g/cm(3). In addition to the molecular geometry from X-ray experiment, the molecular geometry, vibrational frequencies, gauge including atomic orbital (GIAO) (1)H and (13)C chemical shift values of the title compound in the ground state have been calculated using the Hartree-Fock (HF) and density functional method (DFT/B3LYP) with 6-31G(d) basis set. To determine conformational flexibility, molecular energy profile of the title compound was obtained by HF/6-31G(d) and (DFT/B3LYP) calculations with respect to selected degree of torsional freedom, which was varied from -180° to +180° in steps of 10°. Besides, molecular electrostatic potential (MEP), frontier molecular orbitals (FMO), and several thermodynamic properties were performed by the HF and DFT methods.