Integrating experimental and theoretical approaches to unveil structure-bioactivity relationships in silver(I)
Gabriela Kuzderová1, Róbert Gyepes2, Alan Liška3
1Department of Inorganic Chemistry, Faculty of Science, P. J. Šafárik University, Moyzesova 11, 041 54 Košice, Slovakia. zuzana.vargova@upjs.sk.
Abstract:
N-methyl and N-glycyl glycine derivatives - namely (trimethylammonium)acetate (N,N,N-trimethylglycine, betaine, Bet), N,N-dimethylglycine (Dmg), N-methylglycine (sarcosine, Sar), and glycylglycylglycine (GlyGlyGly) - as naturally occurring glycine metabolites, were employed as stabilizing ligands for silver(I) ions, leading to the formation of water-soluble polymeric coordination compounds: {[Ag(HSar)(NO3)]}n (AgSar), {[Ag(HDmg)(NO3)]}n (AgDmg), {[Ag3(HBet)2(NO3)3]}n (AgBet), and [Ag(HGlyGlyGly)(NO3)] (AgGlyGlyGly). The composition and structures of the resulting complexes were unambiguously confirmed using attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR), elemental analysis, thermogravimetric analysis (TGA), and single-crystal X-ray diffraction (SC-XRD). Speciation and stability studies in relevant test and growth media were conducted using a novel multi-technique approach combining potentiometric titrations, electrochemical measurements, 1H NMR and UV-Vis spectroscopy and were additionally supported by theoretical calculations. From a biological evaluation standpoint, all complexes demonstrated significantly enhanced antistaphylococcal activity (including S. aureus L12) compared to silver(I) nitrate (AgNO3), with AgBet and AgGlyGlyGly exhibiting approximately 10-fold, and AgSar and AgDmg approximately 5-fold, increased efficacy. Moreover, AgBet and AgGlyGlyGly were nearly twice as active as silver(I) sulfadiazine (AgSD), a clinically used but poorly water-soluble antimicrobial agent. Remarkably, AgBet and AgGlyGlyGly also showed unusual potent antifungal activity, being 10- to 100-fold more effective than both AgNO3 and AgSD against Rhizopus oryzae, the causative agent of mucormycosis. In cytotoxicity assays, AgSar exhibited the greatest selectivity and sensitivity, being over three times higher than cisplatin (cisPt), against the human breast adenocarcinoma cell line MDA-MB-231. New approaches from the perspectives of structure-activity relationships and bioavailability of the novel silver(I) complexes were explored through human serum albumin (HSA) binding studies and molecular docking calculations, as well as experimental and computational evaluations of lipophilicity and additional Lipinski parameters. Furthermore, the silver(I) complexes' action mechanism was assessed via β-galactosidase inhibition and PCR amplification inhibition in E. coli, intracellular reactive oxygen species (ROS) production, their effects on cell cycle progression and binding to ctDNA.
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