Water-soluble piano-stool arene ruthenium complexes based on 1-(4-cyanophenyl)imidazole (CPI) and 4-cyanopyridine (CNPy) with the formulas [(η⁶-arene)RuCl₂(L)] (L = CPI, η⁶-arene = benzene (1), p-cymene (2), hexamethylbenzene (3); L = CNPy, η⁶-arene = benzene (4), p-cymene (5), hexamethylbenzene (6)) have been prepared by our earlier methods. The molecular structure of [(η⁶-C₆Me₆)RuCl₂(CNPy)] (6) has been determined crystallographically. Analogous rhodium(III) complex [(η⁵-C₅Me₅)RhCl₂(CPI)] (7) has also been prepared and characterized. DNA interaction with the arene ruthenium complexes and the rhodium complex has been examined by spectroscopic and gel mobility shift assay; condensation of DNA and B→Z transition have also been described. Arene ruthenium(II) and EPh₃ (E = P, As)-containing arene ruthenium(II) complexes exhibited strong binding behavior, however, rhodium(III) complexes were found to be Topo II inhibitors with an inhibition percentage of 70% (7) and 30% (7a). Furthermore, arene ruthenium complexes containing polypyridyl ligands also act as mild Topo II inhibitors (10%, 3c and 40%, 3d) in contrast to their precursor complexes. Complexes 4−6 also show significant inhibition of β-hematin/hemozoin formation activity.