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1.
Bioorg Chem ; 146: 107247, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38493635

RESUMEN

The current investigation encompasses the structural planning, synthesis, and evaluation of the urease inhibitory activity of a series of molecular hybrids of hydroxamic acids and Michael acceptors, delineated from the structure of cinnamic acids. The synthesized compounds exhibited potent urease inhibitory effects, with IC50 values ranging from 3.8 to 12.8 µM. Kinetic experiments unveiled that the majority of the synthesized hybrids display characteristics of mixed inhibitors. Generally, derivatives containing electron-withdrawing groups on the aromatic ring demonstrate heightened activity, indicating that the increased electrophilicity of the beta carbon in the Michael Acceptor moiety positively influences the antiureolytic properties of this compounds class. Biophysical and theoretical investigations further corroborated the findings obtained from kinetic assays. These studies suggest that the hydroxamic acid core interacts with the urease active site, while the Michael acceptor moiety binds to one or more allosteric sites adjacent to the active site.


Asunto(s)
Ácidos Hidroxámicos , Ureasa , Sitio Alostérico , Dominio Catalítico , Inhibidores Enzimáticos/química , Ácidos Hidroxámicos/química , Cinética , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Cinamatos/química
2.
Arch Pharm (Weinheim) ; 356(6): e2200653, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36922908

RESUMEN

Vanillin is the main component of natural vanilla extract and is responsible for its flavoring properties. Besides its well-known applications as an additive in food and cosmetics, it has also been reported that vanillin can inhibit fungi of clinical interest, such as Candida spp., Cryptococcus spp., Aspergillus spp., as well as dermatophytes. Thus, the present work approaches the synthesis of a series of vanillin derivatives with 1,2,3-triazole fragments and the evaluation of their antifungal activities against Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Cryptococcus gattii, Trichophyton rubrum, and Trichophyton interdigitale strains. Twenty-two vanillin derivatives were obtained, with yields in the range of 60%-91%, from copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click reaction between two terminal alkynes prepared from vanillin and different benzyl azides. In general, the evaluated compounds showed moderate activity against the microorganisms tested, with minimum inhibitory concentration (MIC) values ranging from 32 to >512 µg mL-1 . Except for compound 3b against the C. gattii R265 strain, all vanillin derivatives showed fungicidal activity for the yeasts tested. The predicted physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties for the compounds indicated favorable profiles for drug development. In addition, a four-dimensional structure-activity relationship (4D-SAR) analysis was carried out and provided useful insights concerning the structures of the compounds and their biological profile. Finally, molecular docking calculations showed that all compounds bind favorably at the lanosterol 14α-demethylase enzyme active site with binding energies ranging from -9.1 to -12.2 kcal/mol.


Asunto(s)
Fungicidas Industriales , Fungicidas Industriales/farmacología , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Antifúngicos/química , Triazoles/farmacología , Pruebas de Sensibilidad Microbiana
3.
J Adv Res ; 9: 51-61, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30046486

RESUMEN

Twenty-five piperidines were studied as potential radical scavengers and antitumor agents. Quantitative interaction of compounds with ctDNA using spectroscopic techniques was also evaluated. Our results demonstrate that the evaluated piperidines possesses different abilities to scavenge the radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) and the anion radical superoxide (•O2-). The piperidine 19 was the most potent radical DPPH scavenger, while the most effective to •O2- scavenger was piperidine 10. In general, U251, MCF7, NCI/ADR-RES, NCI-H460 and HT29 cells were least sensitive to the tested compounds and all compounds were considerably more toxic to the studied cancer cell lines than to the normal cell line HaCaT. The binding mode of the compounds and ctDNA was preferably via intercalation. In addition, these results were confirmed based on theoretical studies. Finally, a linear and exponential correlation between interaction constant (Kb) and GI50 for several human cancer cell was observed.

4.
J Photochem Photobiol B ; 172: 129-138, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28549321

RESUMEN

Thirty-nine Schiff bases were synthesized by performing microwave-assisted condensation of the corresponding aldehydes and aromatic amines. Their reactive nitrogen species (RNS) scavenging activity and inhibitory effects against cancer cell growth were then subsequently investigated. Additionally, the interaction between the calf thymus DNA (ctDNA) and selected Schiff bases was evaluated using fluorescence spectroscopy, and their binding parameters were determined. The yields of the various compounds ranged from moderate to excellent (43-99%) after only a 2-min reaction. The hydroxylated Schiff bases 2, 8, 15, 16, 18, 20, 29, 32, 34, and 37 were found to be potent scavengers of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals with half-maximal scavenging concentration (SC50) values lower than that of the positive control, resveratrol. The presence of hydroxyl substituents on the aromatic rings also proved essential to the cytotoxicity of the compounds. The binding constants (Kb) obtained using fluorescence spectroscopy ranged from 0.37 to 3.07×105Lmol-1, and were strongly influenced by the structure and hydroxylation degree. Schiff bases 3 and 8 showed promising cytotoxic activity, with half-maximal growth inhibitory (GI50) values in the same order of magnitude as those exhibited by the reference drug, doxorubicin against various cell lines. Interestingly, these compounds also showed the highest Kb, suggesting that the cytotoxic activity could be related to their interaction with the DNA of the tumor cells. The results of this study highlighted some Schiff bases as potential lead compounds for the design of new free radical scavengers and anticancer agents.


Asunto(s)
Antineoplásicos/química , ADN/química , Depuradores de Radicales Libres/química , Bases de Schiff/química , Animales , Antineoplásicos/toxicidad , Bovinos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Cinética , Especies de Nitrógeno Reactivo/química , Bases de Schiff/metabolismo , Bases de Schiff/toxicidad , Termodinámica
5.
Chem Biol Drug Des ; 78(5): 810-5, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21756287

RESUMEN

Aldimines are aldehyde-derived compounds that contain a C=N group. Besides its broad industrial applications, this class of non-naturally occurring compounds are found to possess antibacterial, antifungal, antimalarial, antiproliferative, anti-inflammatory, antiviral, and antipyretic properties. Based on this, six aryl aldimines were synthesized from the condensation of aromatic amines with benzaldehydes. The antifungal activities of synthesized compounds were evaluated against nineteen fungal strains that included Candida and Aspergillus species, Cryptococcus neoformans. The aryl aldimines 2-(benzylideneamino)phenol (3) and 4-(benzylideneamino)phenol (8) were the most active compounds against the fungi studied. Compounds 3 and 8 efficiently inhibited the metabolism of C. neoformans mature biofilm.


Asunto(s)
Antifúngicos/síntesis química , Antifúngicos/farmacología , Compuestos de Bencilideno/química , Candida/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Fenoles/farmacología , Antifúngicos/química , Biopelículas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Fenoles/síntesis química , Fenoles/química
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