The toxicity profile of fac -Re(CO) 3 (N-N)L + complexes against microbial and tumoral cells has been extensively studied, primarily focusing on modifications to the bidentate diimine (N-N) ligand. However, less attention has been paid to modifications of the axial ligand L, which is perpendicular to the Re-N-N plane. This study reveals that the high toxicity of the fac -Re(CO) 3 (bpy)(Ctz) + complex may be attributed to the structural effect of the trityl (CPh 3 ) group present in clotrimazole, as removal of phenyl rings causes a significant decrease in the activity against Staphylococcus aureus ( S. aureus ). Moreover, substitution of the 1-tritylimidazole ligand by the structurally related ligands PPh 3 and PCy 3 maintains similarly high activity levels. These findings contribute to understanding the interactions of toxic complexes with bacterial membranes, suggesting that the ligand structures play a crucial role in inhibiting cell wall synthesis processes, potentially including Lipid II synthesis. Compounds with Ph 3 E (E = C-imidazole; P) groups also showed to be 10 times more toxic than cisplatin against three mammalian cell lines (IC 50 : 2-4 μM). In contrast, the analogue 1-benzylimidazole and 1- tert -butylimidazole derivatives were as toxic as cisplatin. We observed that the decomposition of the Re (I) (CO) 3 fragment inside mammalian cell lines liberates CO, which is expected to exert biological effects. Therefore, compounds of this family possessing the structural motif Ph 3 E seem to combine high antimicrobial and antitumoral activities, the latter being much higher than that of cisplatin. The bulky pyramidal structures of CPh 3 and PPh 3 impart high antimicrobial and anti-tumoral activities to the Re(CO) 3 bpy + moiety.