RESUMEN
As the SIRTi analogue series (HL1-HL6) show potent antitumor activity in vitro, we synthesized their corresponding zinc(II) complexes (ZnL1-ZnL6) and investigated their potential as anticancer agents. The Zn(II) complexes showed substantially greater cytotoxicity than HL1-HL6 alone in several cancer cell-types. Notably, distinct structure-activity relationships confirmed the significance of tert-butyl (ZnL2) pharmacophore inclusion in their activity. ZnL2 complexes were found to transmetalate with copper ions inside cells, causing the formation of redox-active copper complexes that induced reactive oxygen species (ROS) production, mitochondrial membrane depolarization, ATP decay, and cell death. This is the first study to exhibit Zn(II) complexes that mediate their activity via transmetalation with copper ions to undergo paraptosis cell death pathway. To further confirm if the SIRT1/2 inhibitory property of SIRTi analogues is conserved, a docking simulation study is performed. The binding affinity and specific interactions of the Cu(II) complex obtained after transmetalation with ZnL2 were found to be higher for SIRT2 (K i = 0.06 µM) compared to SIRT1 (K i = 0.25 µM). Thus, the concurrent regulation of several biological targets using a single drug has been shown to have synergistic therapeutic effects, which are crucial for the effective treatment of cancer.
RESUMEN
In the pursuit to combat stubborn bacterial infections, particularly those stemming from gram-positive bacteria, this study is an attempt to craft a precision-driven platform characterized by unparalleled selectivity, specificity, and synergistic antimicrobial mechanisms. Leveraging remarkable potential of metalloantibiotics in antimicrobial applications, herein, this work rationally designs, synthesizes, and characterizes a new library of Pyridine-2,6-dicarboxamide ligands and their corresponding transition metal Cu(II)/Zn(II) complexes. The lead compound L11 demonstrates robust antibacterial properties against Staphylococcus aureus (Minimum Inhibitory Concentration (MIC) = 2-16 µg mL-1), methicillin and vancomycin-resistant S. aureus (MIC = 2-4 µg mL-1) and exhibit superior antibacterial activity when compared to FDA-approved vancomycin, the drug of last resort. Additionally, the compound exhibits notable antimicrobial efficacy against resistant enterococcus strains (MIC = 2-8 µg mL-1). To unravel mechanistic profile, advanced imaging techniques including SEM and AFM are harnessed, collectively suggesting a mechanistic pathway involving cell wall disruption. Live/dead fluorescence studies further confirm efficacy of L11 and its complexes against S. aureus membranes. This translational exploration extends to a rat model, indicating promising in vivo therapeutic potential. Thus, this comprehensive research initiative has capabilities to transcends the confines of this laboratory, heralding a pivotal step toward combatting antibiotic-resistant pathogens and advancing the frontiers of metalloantibiotics-based therapy with a profound clinical implication.