Synthesis and evaluation of new salicylaldehyde-2-picolinylhydrazone Schiff base compounds of Ru(II), Rh(III) and Ir(III) as in vitro antitumor, antibacterial and fluorescence imaging agents

Abstract

Reaction of salicylaldehyde-2-picolinylhydrazone (HL) Schiff base ligand with precursor compounds [{(p-cymene)RuCl2}2] 1, [{(C6H6)RuCl2}2] 2, [{Cp*RhCl2}2] 3 and [{Cp*IrCl2}2] 4 yielded the corresponding neutral mononuclear compounds 5-8, respectively. The in vitro antitumor evaluation of the compounds 1-8 against Dalton's ascites lymphoma (DL) cells by fluorescence-based apoptosis study and by their half-maximal inhibitory concentration (IC50) values revealed the high antitumor activity of compounds 3, 4, 5 and 6. Compounds 1-8 render comparatively lower apoptotic effect than that of cisplatin on model non-tumor cells, i.e., peripheral blood mononuclear cells (PBMC). The antibacterial evaluation of compounds 5-8 by agar well-diffusion method revealed that compound 6 is significantly effective against all the eight bacterial species considered with zone of inhibition up to 35 mm. Fluorescence imaging study of compounds 5-8 with plasmid circular DNA (pcDNA) and HeLa RNA demonstrated their fluorescence imaging property upon binding with nucleic acids. The docking study with some key enzymes associated with the propagation of cancer such as ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II revealed strong interactions between proteins and compounds 5-8. Conformational analysis by density functional theory (DFT) study has corroborated our experimental observation of the N, N binding mode of ligand. Compounds 5-8 exhibited a HOMO (highest occupied molecular orbital)-LUMO (lowest unoccupied molecular orbital) energy gap 2.99-3.04 eV. Half-sandwich ruthenium, rhodium and iridium compounds were obtained by treatment of metal precursors with salicylaldehyde-2-picolinylhydrazone (HL) by in situ metal-mediated deprotonation of the ligand. Compounds under investigation have shown potential antitumor, antibacterial and fluorescence imaging properties. Arene ruthenium compounds exhibited higher activity compared to that of Cp*Rh/Cp*Ir in inhibiting the cancer cells growth and pathogenic bacteria. At a concentration 100 µg/mL, the apoptosis activity of arene ruthenium compounds, 5 and 6 (~30 %) is double to that of Cp*Rh/Cp*Ir compounds, 7 and 8 (~12 %). Among the four new compounds 5-8, the benzene ruthenium compound, i.e., compound 6 is significantly effective against the pathogenic bacteria under investigation.

p-Cymene metallo-derivatives: An overview on anticancer activity

“…In this study, an anti-proliferative effect along with antioxidant capacity of the complexes was observed. (31). Moreover, [Ru2(p-cym) 2 (L) 2 ]X 2 -mediated anticancer effect was also seen against HL-60, A2780, MCF7 and PC3 cell lines at 40 mg/mL or ~600 µM (32).…”

“…Scientific reports have suggested that [Ru2(p-cym)2(L)2]X2 complex is the strong cytotoxic agent to cancer cells (32). On the other hand, [{(p-cymene) RuCl2} 2 ] complex was found to act against pathogenic bacteria along with a number of tumor cells (31). By the half-maximal inhibitory concentration (IC 50 ) values and by using fluorescencebased apoptosis study, the in vitro antitumor assessment against Dalton's ascites lymphoma (DL) cells revealed a high antitumor activity.…”

Targeting Methyltransferases in Human Pathogenic Bacteria: Insights into Thymidylate Synthase (TS) and Flavin-Dependent TS (FDTS)

“…In vitro analysis on pyrimidine-5-carbonitrile derivatives [53] and on the ruthenium-based complex [(C 6 H 6 )RuL( N , N )Cl] [54] reported antimicrobial activity on S. aureus and other human pathogenic bacteria. In silico studies have identified them as potential Sa TS inhibitors [53,54]; however no experimental evidences have proven their activity towards Sa TS.…”

Synthesis, Structural and Biological Studies of Some Half‐Sandwich d6‐Metal Complexes with Pyrimidine‐Based Ligands

“…Another ruthenium(II) complex with picolinylhydrazone was reported with antibacterial activity with a zone of inhibition around 35 mm on eight bacterial species as well as with high antitumor activity on Dalton's lymphoma (DL) cells versus normal PBMC cells . We have been working for last few years on synthesis of Cp*Rh(III)/ Cp*Ir(III) complexes with various nitrogen donor ligands and their structural and biological studies . According to our knowledge, there is no report available in literature with these metal complexes of pyrimidine ligands (Figure ).…”