RESUMEN
The current study demonstrates the synthesis of coumarin-triazole hybrids 8 (a-e) in four steps starting from substituted salicylaldehyde 1 (a-e), and diethyl malonate 2. The spectroscopic studies provide the structure proofs of the new compounds, and the molecular structure of an intermediate 3a by crystallographic studies. The crystal structure analysis revealed the C-H...O, C-H... π, C-O...π and π...π molecular interactions. Further, the intermolecular interactions were quantified using Hirshfeld surface analysis and the DFT method B3LYP functional with 6-311++ G (d,p) basis set was employed to optimize the molecular geometry. The synthesized new coumarin-triazole hybrids, 8 (a-e) were screened for their α-amylase inhibitory potentials, and the results suggest that amongst the series, compounds 8c, and 8e show the promising inhibition of the enzyme, and might act as lead molecules for anti-diabetic activities. To understand the mode of action in silico molecular docking and ADME screening were performed.
RESUMEN
Oxidative-stress induces inflammatory diseases. Further, infections caused by drug-resistant microbial strains are on the rise. This necessitates the discovery of novel small-molecules for intervention therapy. A series of 3-(2,3-dichlorophenyl)-1-(aryl)prop-2-en-1-ones are synthesized as intermediates via Claisen-Schmidt reaction approach. Subsequently, these intermediates were transformed into 2-pyrazolines by their reaction with phenylhydrazine hydrochlorides in methanol and few drops of acetic acid under reflux conditions. Synthesized compounds were characterized by spectroscopic, crystallographic and elemental analyses studies and then, were evaluated for their in vitro antimicrobial and anti-inflammatory activities. Amongst the series, 3-(4-chlorophenyl)-5-(2,3-dichlorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (5e), 5-(2,3-dichlorophenyl)-3-(4-fluorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (5c) and 5-(2,3-dichlorophenyl)-3-(4-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (5h) showed significant inhibition of phospholipase A2 with IC50 values of 10.2, 11.1 and 11.9µM, respectively. Protein structure modelling and docking studies indicated that the compounds showed binding to a highly conserved calcium-binding pocket on the enzyme. Further, compounds (5e), 1-(3-chlorophenyl)-5-(2,3-dichlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazole (5b), and 1-(3-chlorophenyl)-3-(4-chlorophenyl)-5-(2,3-dichlorophenyl)-4,5-dihydro-1H-pyrazole (5f) showed excellent antimicrobial activities against various bacterial and fungal strains. In conclusion, this study is a successful attempt at the synthesis and characterization of chalcone derivatives that can target phospholipase A2, an enzyme that is a prominent player in the physiological inflammatory cascade. Thus, these compounds show promise for development as next-generation nonsteroidal anti-inflammatory drugs.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores de Fosfolipasa A2/farmacología , Fosfolipasas A2/metabolismo , Pirazoles/farmacología , Relación Estructura-Actividad Cuantitativa , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Fosfolipasa A2/síntesis química , Inhibidores de Fosfolipasa A2/química , Pirazoles/síntesis química , Pirazoles/químicaRESUMEN
A series of new of furan derivatised [1,4] benzothiazepine analogues were synthesized starting from 1-(furan-2-yl)ethanone. 1-(Furan-2-yl)ethanone was converted into chalcones by its reaction with various aromatic aldehydes, then were reacted with 2-aminobenzenethiol in acidic conditions to obtain the title compounds in good yields. The synthesized new compounds were characterized by 1H NMR, 13C NMR, Mass spectral studies and elemental analyses. All the new compounds were evaluated for their in vitro VRV-PL-8a and H+/K+ ATPase inhibitor properties. Preliminary studies revealed that, some molecules amongst the designed series showed promising VRV-PL-8a and H+/K+ ATPase inhibitor properties. Further, rigid body docking studies were performed to understand possible docking sites of the molecules on the target proteins and the mode of binding. This finding presents a promising series of lead molecules that can serve as prototypes for the treatment of inflammatory related disorder that can mitigate the ulcer inducing side effect shown by other NSAIDs.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Fosfolipasas A2 Grupo II/antagonistas & inhibidores , ATPasa Intercambiadora de Hidrógeno-Potásio/química , Tiazepinas/síntesis química , Tiazepinas/farmacología , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/metabolismo , Antiinflamatorios no Esteroideos/farmacología , Sitios de Unión , Chalconas/química , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Furanos/química , Fosfolipasas A2 Grupo II/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Conformación Molecular , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Inhibidores de la Bomba de Protones/síntesis química , Inhibidores de la Bomba de Protones/química , Inhibidores de la Bomba de Protones/metabolismo , Inhibidores de la Bomba de Protones/farmacología , Tiazepinas/química , Tiazepinas/metabolismoRESUMEN
A series of novel coumarin pyrazole hybrids of biological interest were synthesized from the hydrazones, carbazones and thiocarbazones via Vilsmeier Haack formylation reaction. These intermediates and formyl pyrazoles were evaluated for antimicrobial and antioxidant activities. Among the series, compounds 6g and 6h showed excellent antimicrobial activity against different bacterial and fungal strains and compounds 7g, 7h were found to be potent antioxidant agents in both DPPH and hydroxyl radical scavenging assays. Further, detailed quantitative structure-activity relationship (QSAR) analysis indicated the molecular parameters that contribute to increased potency of inhibition. The above findings would further encourage our understanding in employing coumarin pyrazole hybrids as potential antibiotic agents for treating infections caused by pathogenic microbes and fungi. Further, it also paves the way for exploration of these compounds as potential therapeutic agents to treat conditions arising because of excessive oxidative damage.
Asunto(s)
Antiinfecciosos/química , Antiinfecciosos/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Cumarinas/química , Cumarinas/farmacología , Antiinfecciosos/síntesis química , Antioxidantes/síntesis química , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Cumarinas/síntesis química , Hongos/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Micosis/tratamiento farmacológico , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Relación Estructura-Actividad CuantitativaRESUMEN
A series of coumarin appended formyl-pyrazoles 14-18 were synthesized by a simple and accessible approach. The reaction of 8-acetyl-4-methyl-7-hydroxy coumarin 3 and phenyl hydrazine hydrochlorides 4-8 produces the intermediate compounds 8-acetyl-4-methyl-7-hydroxy coumarin hydrazones 9-13. The reaction of compounds 9-13 and DMF in the presence of POCl3 yielded formyl-pyrazoles bearing coumarin moiety 14-18 in good yield. The synthesized new compounds 14-18 and the intermediates 8-acetyl-4-methyl-7-hydroxy coumarin hydrazones 9-13 prepared were screened in vitro for their antibacterial, antifungal antioxidant activities. The compounds 12 and 17 having chloro substitution exhibited promising antifungal and antibacterial activity against the different organisms tested. The compound 17 showed remarkable DPPH radical scavenging ability.