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    Copper(II) and zinc(II) complexes of N2O2-thiosemicarbazones as inhibitors of Mycobacterium tuberculosis and bacterial quorum sensing
    (Elsevier, 2026) Kaya, Busra; Vagolu, Siva Krishna; Karaguzel, Ayse; Bogojevic, Sanja Skaro; Sahin, Onur; Tonjum, Tone; Nikodinovic-Runic, Jasmina
    The rise of resistance to existing antimicrobial drugs has become a significant global health concern, underscoring the urgent need for new and effective antimicrobial agents. In this context, we prepared six copper(II) (Cu1-Cu6) and six zinc(II) (Zn1-Zn6) complexes bearing N2O2-thiosemicarbazones and confirmed their structures by spectral techniques, including X-ray diffraction analysis. The antimicrobial potential of the target compounds was initially tested against drug-sensitive and isoniazid-resistant Mycobacterium tuberculosis strains. Cu(II)-based complexes were identified as more effective antitubercular agents with negligible cytotoxicity compared to Zn(II)-including counterparts. Furthermore, Cu1-Cu6 and Zn1-Zn6 were tested for their antibacterial and antifungal properties. Although the compounds failed to inhibit the growth of bacterial and fungal strains at low concentrations, Zn1 and Zn2 were determined as effective blockers of the bacterial cell-to-cell communication system known as quorum sensing. Finally, molecular docking studies indicated that inhibiting the enoyl acyl carrier protein reductase (InhA) enzyme could be the mechanism behind the significant antitubercular activity of Cu2. Overall, our study shows that copper(II) and zinc(II) complexes of thiosemicarbazones are promising agents against bacterial infections due to their antitubercular and anti-quorum sensing activities.
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    Öğe
    Linking azoles to isoniazid via hydrazone bridge: Synthesis, crystal structure determination, antitubercular evaluation and computational studies
    (Elsevier, 2022) Aslan, Ebru Kocak; Krishna, Vagolu Siva; Armakovic, Sanja J.; Armakovic, Stevan; Sahin, Onur; Tonjum, Tone; Gunduz, Miyase Gozde
    The current emergence of drug-resistant and multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains has complicated and hampered attempts to eliminate or considerably reduce the global prevalence of the often life-threatening disease tuberculosis (TB). Hence, the development of novel antitubercular agents is crucial to combat this challenge. Here, we applied the molecular hybridization approach to link isoniazid (INH), the frontline antitubercular drug, to various azole rings (pyrazole, imidazole, and triazole) through hydrazone functionality. The designed compounds were synthesized and characterized by using spectral techniques including IR, H-1 NMR, C-13 NMR and HRMS. Additionally, single crystal X-ray analysis was employed to resolve the proposed chemical structure of INH-T. All compounds were then extensively screened for their antitubercular activities against Mtb H37Rv, drug-resistant and MDR Mtb strains, as well as against a clinical Mtb isolate with no mutation. Notably, INH-azole hybrids presented outstanding antimycobacterial activity with negligible cytotoxicity. Computational methods based on density functional theory calculations and molecular dynamics simulations were applied to identify the characteristic reactive centers of the title compounds, predict stability towards autoxidation, understand their interactions with water molecules and predict the temperature dependence of density. Finally, molecular docking studies revealed that new INH-azole hybrids are likely to exert their antimycobacterial activity via direct inhibition of the Mtb InhA enzyme. (C) 2022 Elsevier B.V. All rights reserved.