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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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    Hexahydroquinoline Featuring Amide Functionality: A Promising Scaffold With Calcium Channel Blocking Activity
    (Wiley, 2026) Kocak Aslan, Ebru; Lam, Kevin; Huang, Sun; Coskun, Goknil Pelin; Karaguzel, Ayse; Denzinger, Katrin; Birgul, Kaan
    Hexahydroquinoline (HHQ) is a widely recognized scaffold that has garnered considerable attention owing to its diverse pharmacological properties. The structure of HHQ includes a 1,4-dihydropyridine (DHP) ring, which serves as the pharmacophore for the predominant class of drugs known as calcium channel blockers. DHPs are frequently utilized in the management of cardiovascular diseases and also show potential for pain management. Since all DHPs on the market possess ester functionality, we aimed to employ bioisosteric replacement to observe if their amide-containing counterparts would still block calcium channels. Therefore, we synthesized new HHQs with ester or amide functionality (EM1-EM15) and investigated their effects on L-(Cav1.2) and T-(Cav3.2)-type calcium channels using the whole-cell patch clamp technique. Although the amide derivatives were somewhat less effective than their ester counterparts, they still blocked calcium channels to a significant degree. Retesting EM4 enantiomers on two types of calcium channels demonstrated that the (R)-isomer was more responsible for the blocking activity in both cases. Molecular docking and molecular dynamics simulations demonstrated that ( R )-EM4 and ( R )-EM6 adopt binding modes in Cav1.2 similar to amlodipine, while showing favorable stability. Docking studies in Cav3.2 suggested that EM compounds bind within the III-IV fenestration, a reported non-selective DHP binding site. Furthermore, amide derivatives were found to be more metabolically stable based on the in vitro experiments conducted on rat microsomes. Overall, our study reveals HHQ with an amide group as a promising new scaffold for developing future calcium channel blockers for treating cardiovascular and pain conditions.