Synthesis, X-ray structure, in vitro HIV and kinesin Eg5 inhibition activities of new arene ruthenium complexes of pyrimidine analogs

Abstract

Three new ruthenium(II)-arene complexes of the general formula [{(η⁶-p-cymene)Ru(L)}₂](Cl)₂), where L are monastrol (L¹), ethyl 4-(3-hydroxyphenyl)-6-methyl-2-thioxo-pyrimidine-5-carboxylate (L²) or its 4-bromophenyl analog (L³), have been synthesized and characterized by elemental analysis, ¹H, ¹³C, and 2-D NMR spectroscopy. The X-ray diffraction study of complex 1 showed the presence of a dicationic diruthenium complex where two thioxopyrimidines act as tridentate μ,κN:κ²S ligand, bridging two Ru ions through the pyrimidine nitrogen and sulfur atoms. All new complexes were evaluated in vitro for their antiviral activity against the replication of HIV-1 and HIV-2 in MT-4 cells using MTT assay. Additionally, complexes 1–3 were screened for their inhibitory activity against the ATPase enzyme and the motor-protein Kinesin Eg5. Complex 1 was found to inhibit microtubule-stimulated ATPase activity of kinesin of IC₅₀ = 30 μM (monastrol, IC₅₀ = 10 μM).

Keywords:

• Anti-HIV activity
• pyrimidines
• kinesin Eg5 inhibitors
• arene ruthenium complexes

Acknowledgement

We thank Prof. C. Pannecouque of Rega Institute for Medical Research, Katholieke Universiteit, Leuven, Belgium, for the anti-HIV screening. W. Al-Masoudi would like to thank Basrah University for the sabbatical leave. Miss A. Friemel and Mr U. Haunz, Chemistry Department, Konstanz University, Germany are acknowledged for the NMR experiments. The authors also thank Prof. Dr Thomas Mayer and Dr Martin Möckel from the Department of Biology at the University of Konstanz for anti-Kinesin Eg5 screening.