Biological Activities of Ruthenium NHC Complexes: Comparison
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Ruthenium N-heterocyclic carbene (NHC) complexes have unique physico-chemical properties as catalysts and a huge potential in medicinal chemistry and pharmacology, exhibiting a variety of notable biological activities.

  • Ru-NHC complexes
  • N-heterocyclic carbenes
  • antitumor agents
  • antiproliferative activity
  • antibacterials
  • antimicrobials
  • antifungals

1. N-Heterocyclic Carbenes (NHCs)

N-heterocyclic carbenes (NHCs) are a category of electron donor ligands able to form dative metal–ligand bonds, leading to a universal class of compounds in organometallic and coordination chemistry. NHCs typically mimic the chemical properties of phosphines [39][1]. They belong to five different families: imidazolinylidenes, imidazolylidenes, triazolinylidenes, thiazolilylidenes and pyrazolinylidenes (Figure 1) [40][2].
Antibiotics 12 00365 g001 550
Figure 1.
Structures of NHCs.
NHCs are suitable for efficient design because they can be synthesized within a few steps, offering the possibility of the N and C functionalization for structure modification. They act as excellent σ-donors, generating a structural variety ranging from linear, square pyramidal, trigonal bipyramidal, tetrahedral and octahedral geometries of metal-NHC complexes. The essential role of NHCs is related to their ability to form complexes with metals. Metal-NHCs are widely used for organic processes, such as the formation of amide linkage, hydrogenation, isomerization, cycloisomerization, cyclopropanation, hydrosilylation, allylation and deallylation, enol-ester synthesis, heterocycle synthesis and C-C alkyne coupling [40][2]. Most importantly, different organometallic-NHC complexes, such as silver, gold, platinum, copper, palladium and selenium demonstrated interesting biological properties [41,42,43[3][4][5][6],44], including antimicrobial [45[7][8][9],46,47], anticancer [48[10][11][12][13][14][15][16],49,50,51,52,53,54], antiparasitic [55][17], hemolytic and thrombolytic activities [56,57][18][19]. Recent studies for gold and silver-NHC compounds are addressed to breast [58[20][21],59], ovarian [60][22] and cervical human cancer [61][23]. Research has been carried out in order to understand the mechanism of action of gold and silver-NHC complexes as anticancer agents, finding activity against human topoisomerases I and II [62[24][25],63], actin [64][26] and tubulin [65][27], or triggering the reactive oxygen species-dependent intrinsic apoptotic pathway [66][28]. Recently, gold and silver compounds with NHC have been indicated as promising compounds for the treatment of COVID-19 [67][29], as they demonstrated a strong inhibition of the S/ACE2 interaction and particularly of the PLpro enzymatic activity [68][30]. Moreover, an Ag-N-heterocyclic carbene complex bearing the hydroxyethyl ligand determined the inhibition of human carbonic anhydrase I (hCA I) and hCA II isoenzymes, α-glycosidase and AChE and BChE enzymes, thus suggesting the selection of NHC complexes for further studies in glaucoma, epilepsy and other diseases related to metabolic enzymes [69][31].

2. Ruthenium-NHC Complexes

Besides the importance of ruthenium-NHC complexes in organometallic catalysis [70,71][32][33] and bioinorganic chemistry, they have been described as effective anticancer and antimicrobial agents [40,43,47][2][5][9]. Patil et al., 2020, published the advances in the design, synthesis, characterization and biomedical applications, particularly the antimicrobial and anticancer activities, of ruthenium NHC–metal complexes and other metals (silver, gold, palladium, rhodium, iridium, and platinum), covering works published from 2015 to 2020 [39][1]. Several studies regard only the activity of Ru-NHC complexes as antiproliferative agents, whereas the antimicrobial activity is almost always studied along with other activities, including antiproliferative and antioxidant. The two paragraphs below summarized these studies.

2.1. Ru(II)-NHC Complexes with Antiproliferative Activity

Recent studies regarding the antiproliferative activity of Ru(II)-NHC complexes are summarized and the half-maximal (50%) inhibitory concentration (IC50) values are given, when reported in the literature.
Lam et al., 2018, [72][34] investigated several halide-substituted benzimidazolium-derived NHC of RuII/OsII complexes, using NHCs that were symmetrically and non-symmetrically methyl- and benzyl-substituted, and reported their inhibition of the selenoenzyme thioredoxin reductase (TrxR) and antiproliferative activities. The anticancer activity was studied against human colon (HCT-116), human cervical (SiHa) and human breast cancer (NCI-H460) cells. The diiodido(1,3-dibenzylbenzimidazol-2-ylidene)(η6-p-cymene)ruthenium(II) complex 1 is a potent TrxR inhibitor and an antiproliferative agent. The authors found out that there was no clear correlation between the two activities, thus, it was suggested that TrxR inhibition was unlikely to be the main mode of action.
Tabrizi et al., 2019, [73][35] studied the in vitro antiproliferative potential and cyclooxygenase-2 (COX-2) inhibitory activity of a cyclometalated Ru(II) complex (2) containing ibuprofen (Ibu), 1,3,5-triaza-7-phosphaadamantane (PTA) and a CCC-pincer containing naproxen moiety (CCC-Nap). Antiproliferative studies were carried out on breast cancer (MCF-7 and MDA-MB-231), colon cancer (HT-29) cell lines, healthy breast cell lines (MCF-10A), and human embryonic kidney normal cells (HEK293) by means of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, after 72 h exposure. The complex 2 was quite potent, about twice as active as cisplatin against breast cancer cells, and around 14 times less active against HT-29 cell lines than cisplatin. Interestingly, the complex 2 inhibition studies against COX-2 revealed that it displayed approximately about 16- and 5-times stronger interactions than the free Ibu and CCC-Nap ligands, respectively. Moreover, it improved the production of reactive oxygen species (ROS) by 10.7-fold compared to H2O2, when used as a positive control in MCF-7 cells.
Rana et al., 2021, [74][36] described the synthesis and study of two pyridine and pyrimidine Ru(II)-NHC complexes, functionalized annulated NHC 3 and 4 with a half-sandwich geometry, and their in vitro cytotoxicity studies against lung (A549), colon (HCT-116) and breast (MCF-7) cancer cell lines and non-cancerous 3T3 cells (embryonic fibroblast isolated from a mouse), using cisplatin as the reference (IC50 were 64; 23.2; 14 and 64 µM, respectively) via the MTT assay. Both compounds were more active than the reference, with the exception of 3 against HCT-116 cancer cells, and, overall, compound 4 was more active than compound 3. Moreover, in silico studies, predicting the binding-sites and atomic interactions of lead molecules with B cell CLL/lymphoma (BCL-2) (PDB entry: 4lvt) and DNA dodecamer (PDB entry: 1bna), suggested that the order of reactivity of the molecules is 4 > 3. Subsequently, the same group [75][37] investigated a pyrimidine functionalized non-annulated half-sandwich Ru(II)-NHC complex, namely chloro(p-cymene)-1-methyl-3-pyrimidylimidazolideneruthenium(II)-hexafluorophosphate 5, derived from the non-annulated NHC precursor 1-methyl-3-pyrimidylimidazolium-hexafluorophosphate. The half-sandwich geometry of the molecule was established with single crystal X-ray diffraction. As well, this compound was more active than cisplatin against the cell lines used [74][36]. Particularly, 5 and 4 were 3- to 4-fold more active than 3 and cisplatin. Predicting binding affinities for 5 and 4 were −7.1 and −7.0 kcal/mol–1, respectively, for BCL-2 and −7.3 and −8.2 kcal/mol–1, respectively, for DNA. DNA cleavage activity of complex 5 confirmed the ability of ruthenium to perform a direct double-strand breaking. Moreover, molecular docking analysis suggested that complex 5 binds, with the highest binding affinity, a hydrophobic pocket in BLC-2, different from that of complexes 3 and 4. The opposite was found in the contact simulation of the complexes with a DNA strand: complexes 4 and 5 are superimposed, while complex 3 binds the other side of the DNA strand. However, the binding affinity predicted for 4 was higher than 5.
Rodriguez-Prieto et al., 2021, [76][38] reported the synthesis of three spherical carbosilane metallodendrimers of different generations holding Ru-NHC complexes. Compounds 6 and 7, which belong to the first- and second-generation dendrimers, respectively, are shown in Table 1, while the third-generation dendrimer is not shown. These compounds showed cytotoxic activity similar, or even better, than cisplatin against four cancer cell lines, namely advanced prostate (PC3), breast (HCC1806), cervix (HeLa), human liver (HEPG2) and the non-tumoral fibroblast (HFF-1) cell line, as determined by MTT assay. IC50 for cisplatin was referred to data of the literature: IC50 = 30.18 ± 2.58 µM (MCF-7), 11.75 ± 1.23 µM (HeLa), 17.29 ± 1.05 µM (HFF-1) [77][39]. The complexes have been proposed as possible candidates for cancer treatment, due to their combined double action, i.e., antitumoral and carrier for anticancer siRNA. These compounds were capable of forming dendriplexes by promoting the entrance of Mcl-1-FITC (myeloid cell leukemia-1 fluorescein labelled) small interfering RNA (siRNA) to HEPG2 cancer cells, protecting the siRNA from RNAse. Moreover, the cellular uptake of the three complexes was studied by confocal microscopy with Mcl-1-FITC siRNA. Particularly, the second-generation dendrimer 7 was more active than first-generation dendrimer 6. Compound 7 displayed promising antitumoral properties, being selective, even more than cisplatin, against cancer cell lines, with respect to the normal ones. The different activity was related to the inability of first-generation dendrimer 6 to interact with the siRNA. The compounds were internalized into the cells by endocytosis and internalization increased by generation of the dendritic system.
Table 1.
Antiproliferative activity of Ru(II)-NHC complexes.
Structure Compd. Biological Activities Ref
Antibiotics 12 00365 i001 1 = 18.46 ± 2.3 µM (Hep2)Trx inhibition (%): 71 ± 8

IC50 = 6.2 ± 0.4 µM (HCT-116)

IC50 = 8.4 ± 0.2 µM (SiHa)

IC50 = 7.8 ± 1.0 µM (NCI-H460)		 MICRoymahapatra = 8 µMet al., 2015 (S. epidermidis NCIM 2493)

MIC = 8 µM (P. aeruginosa ATCC 27853)

MIC = 16 µM (C. albicans SJ11, unicellular fungus)

IC50 = 22.70 ± 1.3 µM (HCT15)

50 = 18.46 ± 2.3 µM (Hep2)[47]Lam et al., 2018 [72][34]
Roymahapatra et al., 2015 [85] Antibiotics 12 00365 i002 2
Antibiotics 12 00365 i017 17MIC = 64 µM (S. epidermidis NCIM 2493)

MIC = 64 µM (P. aeruginosa ATCC 27853)

MIC = 256 µM (C. albicans SJ11, unicellular fungus)

IC50 = 82.2 ± 4.6 µM (HCT15)

IC50 = 61.8 ± 3.3 µM (Hep2)		IC50 = 0.91 ± 0.02 µM (MCF-7)

IC50 = 1.32 ± 0.05 µM (MDA-MB-231)

IC50 = 35.82 ± 0.52

µM (HT-29)

IC50 = 4.71 ± 0.05

µM (MCF-10A)

IC50 = 108.20 ± 0.03 µM (HEK-293)		 MICRoymahapatra = 64 µMet al., 2015 (S. epidermidis NCIM 2493)

MIC = 64 µM (P. aeruginosa ATCC 27853)

MIC = 256 µM (C. albicans SJ11, unicellular fungus)

IC50 = 82.2 ± 4.6 µM (HCT15)

Tabrizi et al., 2019 [73][35]
IC50 = 61.8 ± 3.3 µM (Hep2)[47] Roymahapatra et al., 2015 [85] Antibiotics 12 00365 i003 3 IC
Antibiotics 12 00365 i018 18MIC = 16 µg/mL; 22.9 µM (B. subtilis 168 DSM402)

MIC = 16 µg/mL; 22.9 µM (S. aureus DSM 20231)

MIC = 16 µg/mL; 22.9 µM (S. aureus ATCC 43300)

IC50 = 11.6 ± 1.0 µM (MCF-7)

IC50 = 26.4 ± 1.1 µM (HT-29)		50 = 28.7 ± 2.3 µM (A549)

IC50 = > 100 µM (HCT-116)

IC50 = 14.8 ± 2.3 µM (MCF-7)

IC50 = 44.64 ± 2.6 µM (3T3)		 MICStreciwilk = 16 µg/mL; 22.9et al., 2018 µM (B. subtilis 168 DSM402)

MIC = 16 µg/mL; 22.9 µM (S. aureus DSM 20231)

MIC = 16 µg/mL; 22.9 µM (S. aureus ATCC 43300)

IC50 = 11.6 ± 1.0 µM (MCF-7)

IC50 = 26.4 ± 1.1 µM (HT-29)[48]Rana et al., 2021 [74][36]
Streciwilk et al., 2018 [86] Antibiotics 12 00365 i004
Antibiotics 12 00365 i0194 19MIC = 8 µg/mL; 10.5 µM (B. subtilis 168 DSM402)

MIC = 8 µg/mL; 10.5 µM (S. aureus DSM 20231)

MIC = 8 µg/mL; 10.5 µM (S. aureus ATCC 43300)

IC50 = 4.8 ± 0.1 µM (MCF-7)

IC50 = 4.9 ± 0.02 µM (HT-29)IC50 = 2.1 ± 0.7 µM (A549)

IC50 = 8.6 ± 1.8 µM (HCT-116)

IC50 = 3.3 ± 0.4 µM (MCF-7)

IC50 = 9.36 ± 1.16 µM (3T3)		 MICStreciwilk = 8 µg/mL; 10.5et al., 2018 µM (B. subtilis 168 DSM402)

MIC = 8 µg/mL; 10.5 µM (S. aureus DSM 20231)

MIC = 8 µg/mL; 10.5 µM (S. aureus ATCC 43300)

IC[50 = 4.8 ± 0.1 µM (MCF-7)

IC4850Rana et al., 2021 [74][36]
= 4.9 ± 0.02 µM (HT-29)] Streciwilk et al., 2018 [86] Antibiotics 12 00365 i005 5
Antibiotics 12 00365 i020 20MIC = 16 µg/mL; 18.8 µM (B. subtilis 168 DSM402)

MIC = 16 µg/mL; 18.8 µM (S. aureus DSM 20231)

MIC = 8 µg/mL; 9.4 µM (S. aureus ATCC 43300)

IC50 = 26.0 ± 1.1 µM (MCF-7)

IC50 > 100 µM (HT-29)		IC50 = 2.8 ± 0.4 µM (A549)

IC50 = 2.3 ± 0.3 µM (HCT-116)

IC50 = 4.7 ± 0.7 µM (MCF-7)

IC50 = 8.56 ± 1.6 µM (3T3)		 MICStreciwilk = 16 µg/mL; 18.8et al., 2018 µM (B. subtilis 168 DSM402)

MIC = 16 µg/mL; 18.8 µM (S. aureus DSM 20231)

MIC = 8 µg/mL; 9.4 µM (S. aureus ATCC 43300)

IC50 = 26.0 ± 1.1 µM (MCF-7)

IC50 > 100 µM (HT-29)[49]Rana et al., 2020 [75][37]
Streciwilk et al., 2018 [88] Antibiotics 12 00365 i006 6
Antibiotics 12 00365 i021 21MIC = 0.0195 mg/mL (M. luteus LB14110)

MIC = 15.6 µg/mL (L. monocytogenes ATCC 19117)

MIC = 3.9 µg/mL (S. aureus ATCC 6538)

MIC = 3.9 µg/mL (S. typhimurium ATCC 14028)

MIC = 1.25 µg/mL (C. albicans ATCC 10231)

IC50 = 0.67 ± 0.2 µg/mL (MCF-7)

IC50 = 0.8 ± 0.2 µg/mL (MDA-MB-231)

IC50 = 2.52 µg/mL (AChE)

IC50 = 19.88 µg/mL (TyrE)		IC50 = 37.2 ± 3.6 µM (PC3)

IC50 = 25.3 ± 7.6 µM (HCC1806)

IC50 = 71.6 ± 15.4 µM (HeLa)

IC50 = 10.3 ± 1.7 µM (HEPG2)

IC50 = 21.2 ± 1.8 µM (HFF-1)		 MICBoubakri = 0.0195et al., 2019 mg/mL (M. luteus LB14110)



MIC = 3.9 µg/mL (S. aureus ATCC 6538)

MIC = 3.9 µg/mL (S. typhimurium ATCC 14028)

MIC = 1.25 µg/mL (

IC50 = 2.52 µg/mL (AChE)

IC50 = 19.88 µg/mL (TyrE)[50C. albicans ATCC 10231)

IC]Rodriguez-Prieto et al., 2021 [76][38]
MIC = 15.6 µg/mL (L. monocytogenes ATCC 19117)50 = 0.67 ± 0.2 µg/mL (MCF-7)

IC[50 = 0.8 ± 0.2 µg/mL (MDA-MB-231)51]		 Boubakri et al., 2019 [89,90] Antibiotics 12 00365 i007 7
Antibiotics 12 00365 i022 22MIC = 0.0195 mg/mL (M. luteus LB14110)

MIC = 0.0781 mg/mL (L. monocytogenes ATCC 19117)

MIC = 1.25 mg/mL (S. typhimurium ATCC 14028)

Inhibition zone = 15 ± 0.2 mm (E. coli)

IC50 = 0.68 ± 3.2 µg/mL (MCF-7)

IC50 = 1.93 ± 2.6 µg/mL (MDA-MB-231)		IC50 = 21.4 ± 0.9 µM (PC3)

IC50 = 20.6 ± 1.9 µM (HCC1806)

IC50 = 8.3 ± 1.1 µM (HeLa)

IC50 = 6.6 ± 0.5 µM (HEPG2)

IC		 MICBoubakri = 0.0195et al., 2019 mg/mL (M. luteus LB14110)

MIC = 0.0781 mg/mL (L. monocytogenes ATCC 19117)

MIC = 1.25 mg/mL (S. typhimurium50 = 69.3 ± 1.2 µM (HFF-1)		 ATCC 14028)

Inhibition zone = 15 ± 0.2 mm (E. coli)

IC50 = 0.68 ± 3.2 µg/mL (MCF-7)

IC50 = 1.93 ± 2.6 µg/mL (MDA-MB-231)[50]Rodriguez-Prieto et al., 2021 [76][38]
Boubakri et al., 2019 [89] Antibiotics 12 00365 i008 8 IC50 = 14.2 ± 0.5 mM (C6)

IC50 = 11.1 ± 0.5 mM (HeLa)		 Paşahan et al., 2022 [78][40]
Antibiotics 12 00365 i023 23MIC = 3.9 µg/mL (L. monocytogenes ATCC 19117)

MIC = 1.95 µg/mL (S. aureus ATCC 6538)

MIC = 1.95 µg/mL (S. typhimurium ATCC 14028)

MIC = 1.25 µg/mL (C. albicans ATCC 10231)

IC50 = 0.68 ± 0.2 µg/mL (MCF-7)

IC50 = 0.8 ± 0.1 µg/mL (MDA-MB-231)

IC50 = 5.06 µg/mL (AChE)

IC50 = 24.95 µg/mL (TyrE)

EC50 = 32.18 µg/mL (DPPH)

EC50 = 18.17 µg/mL (ABTS)

EC50 = 92.25 µg/mL (β-carotene)		 MICBoubakri = 3.9 µg/mLet al., 2022 (L. monocytogenes ATCC 19117)

MIC = 1.95 µg/mL (S. aureus ATCC 6538)

MIC = 1.95 µg/mL (S. typhimurium ATCC 14028)

MIC = 1.25 µg/mL (C. albicans ATCC 10231)

IC50 = 0.68 ± 0.2 µg/mL (MCF-7)

IC50 = 0.8 ± 0.1 µg/mL (MDA-MB-231)

IC50 = 5.06 µg/mL (AChE)

IC50 = 24.95 µg/mL (TyrE)

EC50 = 32.18 µg/mL (DPPH)

EC50 = 18.17 µg/mL (ABTS)

EC50 = 92.25 µg/mL (β-carotene)[51]		 Boubakri et al., 2022 [90]Antibiotics 12 00365 i009 9 IC
Antibiotics 12 00365 i024 24MIC = 200 µg/mL (B. subtilis ATCC 21332)

MIC = 100 µg/mL (E. coli ATCC 25922)

MIC = 200 µg/mL (C. albicans ATCC 60193)

IC50 = 100 ± 7 µM (Caco-2)

IC50 = 137 ± 2 µM (MCF-7)		50 = 16.2 ± 0.4 mM (C6)

IC50 = 13.7 ± 0.3 mM (HeLa)		 MICOnar et = 200al., 2019 µg/mL (B. subtilis ATCC 21332)

MIC = 100 µg/mL (E. coli ATCC 25922)

Paşahan et al., 2022 [78][40]
MIC = 200 µg/mL (C. albicans ATCC 60193)

IC50 = 100 ± 7 µM (Caco-2)

IC50 = 137 ± 2 µM (MCF-7)[52]		 Onar et al., 2019 [91] Antibiotics 12 00365 i010 10 IC
Antibiotics 12 00365 i025 25MIC = 100 µg/mL (B. subtilis ATCC 21332)

MIC = 200 µg/mL (E. coli ATCC 25922)

MIC = 200 µg/mL (C. albicans ATCC 60193)

IC50 = 90 ± 1 µM (Caco-2)

IC50 = 270 ± 12 µM (MCF-7)		50 = 24.2 ± 0.7 mM (C6)

IC50 = 22.8 ± 0.8 mM (HeLa)		 Paşahan et al., 2022 [78][40]
Antibiotics 12 00365 i011 11 IC50 = 37.3 ± 0.9 mM (C6)

IC50 = 17.3 ± 0.8 mM (HeLa)		 Paşahan et al., 2022 [78][40]
Antibiotics 12 00365 i012 12 IC50 = 2.74 ± 0.15 mM (A2780) Chen et al., 2020 [79][41]
Antibiotics 12 00365 i013 13 IC50 = 1.98 ± 0.10 mM (A2780) Chen et al., 2020 [79][41]
Antibiotics 12 00365 i014 14 IC50 of 3.61 µM (MCF-7) Sari et al., 2020 [80][42]
Antibiotics 12 00365 i015 15 (HB324) G1 Arrest * = ≥1 µM

AC50 ** = ~4 µM		 Wilke et al., 2023 [81][43]
* G1 arrest, which means a proliferation inhibition equal to 100% or above, indicating occurring cell death; ** AC50 is the concentration necessary to induce apoptosis in half of the cell population.
Paşahan et al., 2022, [78][40] recently reported a study on Ru-NHC complexes as potential anticancer agents, examining their antiproliferative activity against rat glioblastoma (C6) and human cervix adenocarcinoma (HeLa) cell lines by ELISA assay. Four complexes, namely 8–11, were more active than cisplatin, used as the standard (IC50 = 136 ± 0.7 mM (C6) and 126 ± 0.6 mM (HeLa)).
Chen et al., 2020, [79][41] reported the synthesis and in vitro antiproliferative activity evaluation of a small panel of NHC-coordinated ruthenium(II) arene complexes. The compounds showed cytotoxic activities against the human ovarian A2780 cancer cells. The highest cytotoxic activities were found for 12 and 13, which were about 2-fold more potent than cisplatin. Furthermore, these compounds induced apoptosis in a caspase-dependent manner, primarily through intracellular ROS overproduction and cell cycle arrest at the G1 phase. Moreover, in a preclinical metastatic model of A2780 tumor xenograft, administration of 12 and 13 resulted in a marked inhibition of tumor progression and metastasis. A significant alleviated systemic toxicity was observed in animals for both complexes in comparison with cisplatin.
Sari et al., [80][42] designed four (NHC)Ru(II)(η6-p-cymene) complexes, bearing 2-morpholinoethyl and 4-vinylbenzyl substituents to the benzimidazole core and different alkyl/aryl groups to the second nitrogen atom, and studied their cytotoxic activity against MCF-7 breast cancer cells and their DNA-binding properties. The authors individuated the compound 14 as lead, showing an IC50 of 3.61 µM, and that it can bind the plasmidic DNA without exerting genotoxic effects.
A recent interesting article by Wilke et al., [81][43] described the study of the ruthenium complex HB324 (15), which showed promising potential as a novel anticancer agent in vitro. This complex showed good effects, even in low micromolar concentrations, especially regarding proliferation inhibition and apoptosis induction via the mitochondrial pathway on human B-cell precursor leukemia Nalm-6 cells. Moreover, of particular interest is the upregulation of the Harakiri resistance protein, which inhibits the anti-apoptotic and death repressor proteins BCL-2 and BCL-xL. Finally, compound 15 showed synergistic activity with various established anticancer drugs, including vincristine, and overcame the resistance in several cell lines, such as neuroblastoma cells.

2.2. Antimicrobial Ru(II)-NHC Complexes Possessing Other Additional Abilities (Antiproliferative, Antioxidant and Anticholinesterase)

Antimicrobic resistance is a cause of great concern worldwide and significantly affects humanity’s capacity to prevent and treat a growing number of bacterial and fungal infections [82][44]. In the past decade, the antimicrobial activity of ruthenium complexes has been reviewed [83][45] and studied as antimicrobial agents and alternatives or adjuvants to the more traditional antibiotics [84][46]. The recent antimicrobial studies regarding complexes of NHC-ruthenium are summarized in Table 2, and the minimal inhibitory concentrations (MICs) are reported.
Table 2.
Antimicrobial and other activities (antiproliferative, antioxidant and anticholinesterase) of Ru(II)-NHC complexes.
Structure Compd.Biological Activities Biological ActivitiesRef Ref
Antibiotics 12 00365 i016 16MIC = 8 µM (S. epidermidis NCIM 2493)

MIC = 8 µM (P. aeruginosa ATCC 27853)

MIC = 16 µM (C. albicans SJ11, unicellular fungus)

IC50 = 22.70 ± 1.3 µM (HCT15)

50
MIC
Onar et
= 100
al., 2019
µg/mL (
B. subtilis ATCC 21332)

MIC = 200 µg/mL (E. coli ATCC 25922)

MIC = 200 µg/mL (C. albicans ATCC 60193)

IC50 = 90 ± 1 µM (Caco-2)

IC = 270 ± 12 µM (MCF-7)[52]50		 Onar et al., 2019 [91]
Antibiotics 12 00365 i026 26MIC = 0.0195 mg/mL (M. luteus LB 14110)

MIC = 0.1562 mg/mL (L. monocytogenes ATCC 19117)

MIC = 0.0781 mg/mL (S. typhimurium ATCC 14028)

IC50 = 0.6 ± 1.1 µg/mL (MCF-7)

IC50 = 1.1 ± 0.3 µg/mL (MDA-MB-231)		 MICSlimani et = 0.0195al., 2020 mg/mL (M. luteus LB 14110)

MIC = 0.1562 mg/mL (L. monocytogenes ATCC 19117)

MIC = 0.0781 mg/mL (S. typhimurium ATCC 14028)

IC50 = 0.6 ± 1.1 µg/mL (MCF-7)

IC50 = 1.1 ± 0.3 µg/mL (MDA-MB-231)[53]		 Slimani et al., 2020 [92]
Antibiotics 12 00365 i027 27MIC = 0.0195 mg/mL (M. luteus LB 14110)

MIC = 0.0781 mg/mL (L. monocytogenes ATCC 19117)

MIC = 1.25 mg/mL (S. typhimurium ATCC 14028)

IC50 = 0.68 ± 1.2 µg/mL (MCF-7)

IC50 = 1.7 ± 0.6 µg/mL (MDA-MB-231)		 MICSlimani et = 0.0195al., 2020 mg/mL (M. luteus LB 14110)

MIC = 0.0781 mg/mL (L. monocytogenes ATCC 19117)

MIC = 1.25 mg/mL (S. typhimurium ATCC 14028)

IC50 = 0.68 ± 1.2 µg/mL (MCF-7)

IC50 = 1.7 ± 0.6 µg/mL (MDA-MB-231)[53]		 Slimani et al., 2020 [92]
Antibiotics 12 00365 i028 28MIC = 11.7 µM (B. subtilis)

MIC = 23.4 µM (S. aureus DSM 20231)

MIC = 11.7 µM (S. aureus ATCC 43300)		 MICBurmeister = 11.7 µMet al., 2021 (B. subtilis)

MIC = 23.4 µM (S. aureus DSM 20231)

MIC = 11.7 µM (S. aureus ATCC 43300)[54]		 Burmeister et al., 2021 [93]

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