Coordination Chemistry Reviews 414 (2020) 213285

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Coordination Chemistry Reviews

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Review

Platinum(II) and Ruthenium(II) complexes in medicine:

Antimycobacterial and Anti-HIV activities
Divine Mbom Yufanyi a, Hanna S. Abbo b,c, Salam J.J. Titinchi b,c,⇑, Tambua Neville a
a
Department of Chemistry, Faculty of Science, The University of Bamenda, P.O. Box 39, Bambili, Cameroon
b
Department of Chemistry, University of the Western Cape, Robert Sobukwe Rd, Bellville, 7535 Cape Town, South Africa
c
Department of Chemistry, College of Science, University of Basrah, Basrah, Iraq

a r t i c l e i n f o a b s t r a c t

Article history: Approximately 100 million people worldwide are affected by M. Tuberculosis (Mtb), a contagious disease
Received 24 November 2019 which causes death in humans and is considered to be quite deadly throughout the world (about 1.5 mil-
Accepted 5 March 2020 lion deaths annually). Approximately 20% of these deaths are attributed to strains that are resistant to
Available online 16 March 2020
drugs for combating TB. This situation is further exacerbated by the spread of HIV/AIDS worldwide.
Consequently, it is important to identify and fully develop new therapeutic targets in the fight against
Keywords: Mtb. Treatment, over the past decades, has essentially shown limited efficacy and/or undesirable side
Pt(II) and Ru(II) complexes
effects. Due to the high mortality rate of TB and the increase in strains that are resistant to drugs, the
Antimycobacterial
Anti-HIV
exploration and synthesis of novel and more effective treatment regimens with less undesirable side
M. Tuberculosis effects is imperative.
Two approaches are being considered a) chemical modification of currently used drugs with the inten-
tion of reducing the time for treatment and b) the exploration and synthesis of new and novel compounds
which are more effective. In this regard, several transition metal complexes have been identified as
potential chemotherapeutic agents against TB and HIV. Recently, the focus has been on the use of plat-
inum and ruthenium complexes as alternative metal-based antimycobacterial and anti-HIV therapeutic
agents.
This minireview focuses on recent developments in the use of Pt and Ru complexes as novel therapeu-
tic agents for TB and HIV.
Ó 2020 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Metal complexes in medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Oxidation states of Pt and Ru ions and their reactivity in physiological solution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
4. Metal complexes against TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
4.1. Platinum complexes used against TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
4.2. Ruthenium complexes against TB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
5. Metal complexes against HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Abbreviations: 2-OHnicH, 2-hydroxynicotinic acid; 3-OHpicH, 3-hydroxypicolinic acid; 5,50 -mebipy, 5,50 -dimethyl-2,20 -dipyridyl; 6-OHnicH, 6-hydroxynicotinic acid;
BCG, Bacillus Calmette–Guérin; bipy, 2,20 -bipyridine; Caco-2, human epithelial colorectal adenocarcinoma; cART, combinatorial antiretroviral therapy; Cl-bipy, 4,40 -dichloro-
2,20 -bipyridine; cpl, ciprofloxacin; CTZ, clotrimazole; dppb, 1,4-bis(diphenylphosphino)butane; dppe, 1,2-bis(diphenylphosphino)ethane; dppf, 1,10 -bis(diphenylphosphino)
ferrocene; dppm, bis(diphenylphosphino)methane; ddI, didanosine; HepG2, human hepatocellular carcinoma); HTPB, 4,4-trifluoro-1-phenyl-1,3-butanedione; HTTA, 4,4,4-
trifluoro-1-(2-thienyl)-1,3-butanedione; INH, Isoniazid; InhA, NADH-dependent enoyl acyl carrier protein (ACP) reductase; MCF7, human breast adenocarcinoma; MDR,
multidrug-resistant; Me-bipy, 4,40 -dimethyl-2,20 -bipyridine; MIC values, minimal inhibitory concentration; MBC, minimum bactericidal concentration; Mtb, M. Tuberculosis;
MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide; NCp7, Zinc finger protein nucleocapsid protein 7; ofl, ofloxacin; phen, 1,10-phenanthroline; pic, 2-
pyridinecarboxylate; PPh3, triphenylphosphine; REMA, Resazurin Microtiter Assay; spf, sparfloxacin; Spym, pyrimidine-2-thiolate; TAR, Trans Activation Response; TAT,
Transactivator protein; XDR, Extensively drug-resistant.
⇑ Corresponding author.

https://doi.org/10.1016/j.ccr.2020.213285
0010-8545/Ó 2020 Elsevier B.V. All rights reserved.
2 D.M. Yufanyi et al. / Coordination Chemistry Reviews 414 (2020) 213285

5.1. Platinum complexes against HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

5.2. Ruthenium complexes against HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
5.3. Binding mechanism or mechanism of interaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
5.3.1. Mechanisms of action of anti-TB drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
5.3.2. Mechanisms of resistance to anti-TB and anti-HIV agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
5.3.3. Mechanisms of action of Metal-based anti-TB and anti-HIV agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
6. Other biological applications of these complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

1. Introduction [9,10]. The alternative drug formulations are expected to i) lead

Tuberculosis (TB) is an infectious and well-known disease with
an alarming annual infection rate. It is caused by the bacillus
Mycobacterium tuberculosis (Mtb) which is ranked in the top 10%
of deathly infectious agents, ranking above HIV/AIDS [1]. It is esti-
mated to cause about 1.3 million deaths among people who are
HIV-negative. Co-infection with HIV has further increased the
number of deaths by approximately 300 000 from TB infection
among HIV-positive patients [1]. It is more likely for HIV-positive
patients to develop TB (9% of new cases) which also applies to peo-
ple suffering from under-nutrition, diabetes, smoking and alco-
holism [2]. Estimates in 2016 show that nearly 37 million people
are living with HIV [3]. HIV-infection predisposes the patient to
developing active TB and this combination accounts for one in five
HIV-related deaths globally [4,5]. Thus, the duality of TB and HIV is
considered a co-epidemic and is a major health concern world-
wide. It is prevalent in sub-Saharan Africa (80% of the burden of
co-infection) where diagnosis, treatment and follow-up of infected
cases is a major function of health authorities. [2,6]. Despite its
high mortality rate, TB is curable if an early or timely diagnosis
is made and the correct treatment is administered immediately.
However, the drug combination, cost and length of treatment in
addition to the side effects of the drugs are factors that determine
the effective treatment of TB. An inappropriate treatment regime
can lead to the emergence of resistant pathogens. The diagnosis
and treatment of TB is further complicated by the use of anti-
retroviral drugs (ARV’s) in HIV-positive persons [7].
The molecules shown in Fig. 1 are first-line drugs used in the
treatment of TB, while the second-line drugs include p-
aminosalicylic acid, ethionamide, cycloserine, aminoglycosides,
azithromycin, clarithromycin, and fluoroquinolones. However, the
appearance of strains resistant to currently used drugs, has further
complicated the fight against TB. In spite of the alarming emer-
gence of TB cases worldwide and the severe rise of multidrug-
resistant (MDR) strains [8], the search for a new vaccine is taking
much longer than expected. Consequently, it is imperative to seek
alternative and more potent agents against TB. Two approaches are
being pursued to address the scourge of the TB epidemic: a) devel-
oping the existing anti-TB agents and b) pursuing new therapeutic
approaches or new drug therapies with more effective mechanisms
of action against resistant strains of Mycobacterium tuberculosis
to an improvement in the treatment of TB; ii) be void any adverse
interactions with ARV drugs; iii) reduce the period of treatment,
frequency and dosage; iv) target resistant strains; v) be bioavail-
able through the oral route, with suitable pharmacokinetic and
pharmacodynamic profiles and vi) be safer [7].
The fast increase in HIV strains that are resistant to currently
used drugs, poor bioavailability coupled with the aspect of toxicity,
has compromised the effectiveness of treatment regimens of HIV
infection using combinatorial antiretroviral therapy (cART). Conse-
quently, the search for novel anti-HIV drug candidates with
improved properties is imperative [11].
Knowledge of the inorganic chemistry of drugs used currently
with biologically active molecules can potentially provide new
clues in the search for novel drugs to overcome complications
associated with anti-tubercular therapy. One method, being
actively explored, is the introduction of metal centres in the design
of new drugs which can lead to alternative mechanisms of action.
The development of improved analogues of compounds or drugs,
with some proven, but of limited value for TB, coupled with the
development of novel molecules or compounds with new modes
of action or targets against TB is a stimulating and active field of
research [12].
A variety of molecules [8,13–16] and metal complexes have
been investigated for their anti-mycobacterial [14,17–31] and
anti-HIV activities [21,26,32–35]. While some studies focus on
the metal complexes of drugs in use, others base their attention
on known biologically active molecules. In addition, some seek to
explore the activity of modifications of these molecules while
others pursue the synthesis of new compounds such as their tran-
sition metal complexes with improved activities. Amongst the
metal complexes studied, platinum and ruthenium complexes
have received more attention owing to the diversity of their appli-
cations in cancer therapy [34,36–54], antimicrobial agents [55–59],
antiviral agents [21,34,60,61], DNA interaction [62–65], and anti-
inflammatory activity [66].
This mini review focuses on recent studies (2009 – 2019)
involving platinum and ruthenium complexes exhibiting promis-
ing activity as antimycobacterial and anti-HIV agents.
2. Metal complexes in medicine

Recent developments in medicinal chemistry have experienced

an increase in the exploration of metal and metalloid-based drugs
[67,68]. The increased importance of metal-based therapeutic
agents is evidenced by several reviews [12,34,69–77] and drug for-
mulations already in use (e.g. organoarsenic compounds for the
treatment of syphilis, gold preparations for the treatment of arthri-
tis, cisplatin, carboplatin and oxaliplatin for the cancer treatment
of, gold drugs, myocrisin and auranofin for the treatment of
rheumatoid arthritis) [55,78]. Several factors such as the oxidation
Fig. 1. Structures of some of the TB drugs in use. state of the metal, the type and number of coordinated ligands,
 D.M. Yufanyi et al. / Coordination Chemistry Reviews 414 (2020) 213285 3

nuclearity of the metal centre, the nature of the counter ion, as well 4. Metal complexes against TB
as the coordination geometry are critical for recognition by specific
uptake, transport, and delivery proteins [79]. The coordination of Metal complexes have been found to exert a significant impact
metal ions to organic ligands can lead to changes in their biological on various types of treatment regimes. The remarkable impact of
properties, such as solubility, lipophilicity, stability and charge. platinum and ruthenium complexes as therapeutic and diagnostic
These in turn could result in changes in their biodistribution, agents, has thus proven its potential and influence in directing the
in vivo conversion and pharmacokinetics [80]. Desirable changes current focus to design and develop new drug derivatives that may
to the biological behaviour of organic ligands (bioavailability and have improved pharmacological properties. The efficacy of these
bioactivity) could be achieved through coordination to metal ions. metal-based drugs as therapeutic agents depends to a large extent
For example, the coordination of antitubercular drugs or other bio- on their kinetic and thermodynamic properties, which in turn
logically active molecules to metals is an alternative route to the depend on the metal’s oxidation state and the numbers and types
development of more potent compounds against the resistant of ligands attached in addition to their coordination geometry.
pathogens [81]. Several transition metal (silver, gold, copper, iron,
iridium, platinum, rhodium, ruthenium and titanium) complexes
4.1. Platinum complexes used against TB
have been reported to show anticancer activity as well as bind to
DNA and RNA [34,44,55,69,82]. In addition, some transition metal
The potential of platinum complexes [PtCl(L)DMSO] derived
complexes displayed desirable antimicrobial properties [34,83].
from the ligands L = 4,4,4-trifluoro-1-phenyl-1,3-butanedione
Amongst several metals explored, platinum and ruthenium dis-
(HTPB) or 4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedione (HTTA)
played suitable properties for biological applications, although
(Fig. 2), to inhibit Mtb H37Rv ATCC 27,294 were evaluated by the
ruthenium complexes are increasingly being explored due to the
REMA (Resazurin Microtiter Assay) method. The complexes
rate at which they undergo ligand exchange, the number of avail-
showed low cytotoxicity and were also found to be less active
able oxidation states and the facility with which ruthenium binds
(MIC = 24 lg/mL) compared to their ligands (MIC = 11 lg/mL)
to some biological molecules [55,84].
towards Mtb [85].
Advancements in the identification of biological targets or the
Three platinum complexes [Pt(DMSO)(L)Cl]Cl derived from L =
mechanism of action of many metal drugs are being used to
fluoroquinolone, namely, ciprofloxacin (cpl), ofloxacin (ofl), or
develop alternative and more potent drug molecules with reduced
sparfloxacin (spf) (Fig. 3), were evaluated for their activity against
side effects [84].
Mtb (ATCC 27294) by the REMA method. It was observed that all
three complexes were very active against Mtb at concentrations
lower than 2 lM. These activities were however lower compared
to those of the currently used TB drugs. While the platinum com-
3. Oxidation states of Pt and Ru ions and their reactivity in
plexes with L = Spf (MIC = 0.338 lg/mL) or Cpl (MIC = 0.644 lg/
physiological solution
mL) showed activity similar to that of isoniazid and streptomycin
against TB, the complex with sparfloxacin, [Pt(DMSO)(spf)Cl]Cl
Platinum compounds commonly exist in the +2 and +4 oxida-
was the most active against resistant strains of Mtb. Interestingly,
tion states, while those of ruthenium are +2, +3 and +4. The oxida-
the ligand sparfloxacin was also found to be the most active against
tion states Pt(II) and Pt(IV) as well as Ru(Il), Ru(III) and Ru(IV) are
M. tuberculosis [86]. The antitubercular activities of the tested
most common under physiological conditions. Ru(II) and Ru(III) are
compounds were found to be similar to those of platinum com-
stable oxidation states in physiological solutions [41]. In these oxi-
plexes of the type [Pt(fluoroquinolone)Cl2] with MIC values in
dation states the Pt(II) mainly forms tetracoordinate complexes
the range 0.31–1.25 lg/mL. The similarity in activity of these com-
with a principally square planar geometry while the complexes
plexes was attributed to their ability to produce the same active
of Pt(IV) and ruthenium are predominantly hexacoordinate with
species, [Pt(fluoroquinolone)]2+ in solution [86].
essentially an octahedral geometry. Pt(IV) complexes with an octa-
An evaluation of the biological activities of the ligands and com-
hedral coordination environment in the low d6 spin state are kinet-
plexes bis(diphenylphosphino)-2-pyridylplatinum(II) chloride and
ically more stable compared to their Pt(II) counterparts, and thus
bis(diphenylphosphino)-2-ethylpyridylplatinum(II) (Fig. 4) against
the uncoordinated ligand sites on the octahedral metal centre are
Mtb H37Rv by determining the minimal inhibitory concentration
available for bonding a fact leading to the modification of some
(MIC), indicated that both the ligands and complexes had MIC val-
pharmacokinetic parameters. The stability and expanded coordina-
ues>20 lM [21]. Hence, these compounds were considered to be
tion sphere serves as an advantage for overcoming the challenges
less active.
inherent in Pt(II) compounds.
Recently, some newly synthesised platinum(II) complexes with
Ruthenium complexes undergo ligand exchange at a rate simi-
dppf/N,N-disubstituted-N0 -acyl thiourea having the general for-
lar to that of platinum (102 to 103 s1) and thus the complexes of
mula [Pt(dppf)(L)]PF6, [dppf = 1,10 -bis(diphenylphosphino)ferro
Ru(III) are biologically more inert than the related complexes of Ru
cene; L = N,N-disubstituted-N0 -acyl thioureas] have been reported.
(II) and Ru(IV) [12,84]. While Ru(II) and Pt(II) complexes are labile
A single crystal X-ray crystallographic analyses of the complexes
in aqueous media, those of Ru(III) and Pt(IV) are kinetically more
showed that the ligands of N,N-diphenyl-N0 -benzoylthiourea, N,
inert. Square planar Pt(II) bioactive complexes are labile to substi-
tution by ligands present in biological fluids, thus rendering Pt(II)
drugs toxic. This situation can be avoided by converting the Pt(II)
complex to its Pt(IV) oxidation state which is kinetically stable to
substitution. The complexes of Pt(IV) which are less toxic, can be
activated by reduction to square-planar Pt(II) active species [71].
Similarly, kinetically stable Ru(IIl) and Ru(IV) complexes could be
reduced by certain molecules in biological systems to the active
Ru(II) complex, while this complex can also be oxidised to Ru(III)
using many different biological molecules [44,84]. The bioactivity
of the platinum and ruthenium complexes can be improved by
varying the redox potential of these complexes. Fig. 2. Structures of HTTA and HTPB as well as the Pt complex of HTTA.
4 D.M. Yufanyi et al. / Coordination Chemistry Reviews 414 (2020) 213285
Fig. 3. Structures of Ciprofloxacin, Sparfloxacin, Ofloxacin and Pt complex of Cpl.
Fig. 4. Structures of the phosphino platinum complexes.
N-diethyl-N0 -furoylthiourea and N,N-diphenyl-N0 -(thiophene-2-
carbonyl)thiourea are bonded to the metal through sulphur and
oxygen atoms, resulting in a distorted square-planar structure.
An in vitro assay of the ligands and complexes (Fig. 5) for their
activity against Mtb H37Rv strains, by the REMA method indicated
that the activity of the complexes (4.74 ─ 6.63 lmolL1) is greater
than those of the free ligands (>73 lmolL1), highlighting the
importance, in this case, of coordination to the metal ion for
anti-M. tuberculosis activity. Based on the MIC values, the com-
plexes that showed greater activity were those in which the sub-
stituent groups R2 are small e.g. methyl or ethyl groups [87].
Most recently, Sen et al. synthesised and tested the anti-
mycobacterial activities of 1-alkyl-2-(arylazo)imidazoles (Haai-
C4H9, Haai-C10H21) and their Pt(II) complexes, [Pt(Haai-C4H9)Cl2]
and [Pt(Haai-C10H21)Cl2] (Fig. 6), against Mtb H37Ra (ATCC
25177), H37Rv (ATCC 25618) strains and two clinical strains [88].
The platinum complexes were found to be active (MIC 16–
64 lg/ml; MBC 64–256 lg/ml) against all the tested Mtb strains
and demonstrated better potency than standard drugs [88].
An earlier study, demonstrated the potent inhibition of the
splicing activity of the intein present in protein RecA recombinase
Fig. 5. Structures of N,N-disubstituted-N0 -acyl thioureas (left) and 1,10 -bis
(diphenylphosphino)ferrocene (right).
Fig. 6. Structure of Haai ligand and synthesis scheme of Pt-Haai complexes.
of M. tuberculosis by cisplatin, using an in vitro intein splicing assay
and a genetic reporter for intein splicing in Escherichia coli. The
evaluation of similar platinum(II) complexes (Fig. 7) for their inhi-
bition activity indicated that it was highly structure-dependent.
While transplatin was found to be inactive, the inhibitory activity
of the others decreased in the order cisplatin (IC50 = 2.5 lM), oxali-
platin and carboplatin. Cisplatin was found to be toxic towards M.
tuberculosis (MIC ~ 40 lM) similar to that of the antimycobacterial
agent ethambutol [89].
4.2. Ruthenium complexes against TB
The toxicity observed with platinum anticancer complexes was
the driving force for the exploration of alternatives which are less
toxic. Numerous biological studies on ruthenium complexes indi-
cated their lower toxicity and varied action modes compared to
those of platinum. The well-known redox chemistry of ruthenium
was found to be suitable with biological media [55,90–93].
Research interest has recently received more attention for ruthe-
nium complexes due to their ability to undergo ligand exchange,
their decreased toxicity and their ability to mimic iron in binding
with proteins in the plasma [55,84].
A family of substituted polypyridyl ligands (2,20 -bipyridines or
2,20 -60 ,20 -terpyridines) containing Ru(II)-X moieties where X = Cl,
CO, CH3CN or H2O (Fig. 8) were investigated for their antitubercu-
lar activities [9]. Results showed that the polypyridine ligands and
their ruthenium complexes had lower in vitro antimycobacterial
activities compared to isoniazid. One complex [Ru(D)2(OH2)2]2+
(MIC < 6.25 mg/mL) however showed remarkable (100%) activity
compared to the rest of the library of free ligands tested against
 D.M. Yufanyi et al. / Coordination Chemistry Reviews 414 (2020) 213285 5

Fig. 7. Structures of platinum complexes tested for splicing activity.

Mtb. The potent activity of these complexes was attributed to the

Fig. 8. Structures of tested polypyiridine ligands and some complexes.
presence of the aquo ligand and the influence of the redox proper-
ties of the ruthenium [9].
The activity of three promising anti-Mtb ruthenium(II)
complexes viz. [Ru(L)(dppb)(bipy)]PF6, L = 2-hydroxynicotinic acid
(2-OHnicH), 6-hydroxynicotinic acid (6-OHnicH) and 3-
hydroxypicolinic acid (3-OHpicH) (Fig. 9) were explored. Results
obtained demonstrate that the ruthenium(II) complexes exhibited
good antimycobacterial activity (MIC 0.4–6.4 lM) compared to
that of some standard drugs. Furthermore, these complexes
showed no cytotoxic activity against Mtb H37Rv compared to nor-
mal cells, indicating a good selectivity index [94].

Fig. 9. Structures of substituted nicotinic and picolinic acids and coordination modes in some complexes.
6 D.M. Yufanyi et al. / Coordination Chemistry Reviews 414 (2020) 213285

Fig. 10. Synthetic scheme of the ruthenium complexes cis-[Ru(pic)(dppm)2]PF6 and cis-[Ru(pic)(dppe)2]PF6.

Fig. 11. Synthesis of the ruthenium(II) complexes containing the pic ligand.

Fig. 12. Structures of 1,4-bis(diphenylphosphino) ligands (left) and the diimines

(right).

The in vitro activities of the complexes [Ru(2-OHnic)(dppb)

(bipy)]+ (MIC = 0.4 lM) and [Ru(3-OHpic)(dppb)(bipy)]+ (MIC = 3.
2 lM) were found to be greater than that of ethambutol (MIC = 5
.62 lM), while the activity of the complex [Ru(2-OHnic)(dppb)
(bipy)]+ (MIC = 0.4 lM) was greater than that of gatifloxacin
(MIC = 0.99 lM) but similar to that of isoniazid (MIC = 0.36 lM).
The improved activity of the complexes was attributed to the for-
mation of coordinate bonds between the ligands (2-OHnic, 6-
OHnic and 3-OHpic) and the metal ruthenium [94].
Pavan et al. evaluated a series of ruthenium complexes for their
antimycobacterial activity. Initially, the authors synthesised and
tested the anti-Mycobacterium tuberculosis activities of the ruthe-
nium complexes, with formulae cis-[Ru(pic)(dppm)2]PF6, cis-[Ru
(pic)(dppe)2]PF6 and [Ru(pic)2(PPh3)2] [pic = 2-pyridinecarboxy
late; dppm = bis(diphenylphosphino)methane; dppe = 1,2-bis(dip
henylphosphino)ethane; PPh3 = triphenylphosphine] (Fig. 10).
The complexes cis-[Ru(pic)(dppm)2]PF6 (MIC = 0.78 mg/mL) and
cis-[Ru(pic)(dppe)2]PF6 (MIC = 0.26 mg/mL) exhibited the best
activities. These activities were similar to or greater than that of
TB drugs in current use. The free phosphine ligands dppm
(MIC = 25 mg/mL) and dppe (MIC = 6.5 mg/mL) when complexed
within a scaffold with ruthenium resulted in a 32-fold and 70-
fold increase activity, respectively. This increase in activity was
attributed to the replacement of methylene by ethylene which
Fig. 13. Structure of [RuCl2(P)2(N–N)].
leads to a change in the molecule’s conformation and conse-
quently, the separation between certain functional groups, that
are pertinent for interaction with a receptor of the bacterium. In
addition, the cationic nature of the complexes compared to the
neutral ligands probably favours the uptake of these active com-
plexes by the bacteria, enhancing their activity [95].
Later, the same authors reported the synthesis of four new
ruthenium complexes with formulae [Ru(pic)(dppb)(bipy)]PF6,
[Ru(pic)(dppb) (Me-bipy)]PF6, [Ru(pic)(dppb)(Cl-bipy)]PF6 and
[Ru(pic)(dppb)(phen)]PF6 [dppb = 1,4-bis(diphenylphosphino)but
ane, pic = 2-pyridinecarboxylic acid anion bipy = (2,20 -bipyridine,
Me-bipy = 4,40 -dimethyl-2,20 -bipyridine, Cl-bipy = 4,40 -dichloro-2,
20 -bipyridine and phen = 1,10-phenanthroline] (Figs. 11 and 12).
Assessment of the in vitro anti-Mtb activity of the complexes and
the free ligands indicated that all the tested compounds showed
excellent activity MIC (0.49 – 0.91 lg/mL), lower cytotoxicities
and a higher selectivity index (>10) [90]. The complex [Ru(pic)
(dppb)(bipy)]PF6 was found to be 5.5 times more active than cis-
[RuCl2(dppb)(bipy)], possibly as a result of the non-coordination
 D.M. Yufanyi et al. / Coordination Chemistry Reviews 414 (2020) 213285
of Hpic in the latter. The ligands dppe (MIC = 15.70 mM) and phen
(MIC = 11.80 mM) had good MICs which were greater than (71 and
16 times) those of their respective complexes [90].
A third publication by these authors presents the in vitro and
in vivo activities of ruthenium(II) phosphine/diimine/picolinate
complexes, [Ru(pic)(dppb)(bipy)]PF6, [Ru(pic)(dppb)(Me-bipy)]
PF6, [Ru(pic)(dppb)(phen)]PF6, cis-[Ru(pic)(dppe)2]PF6, cis-
[RuCl2(dppb)(bipy)] and [Ru(pic)(dppe)(phen)]PF6, against Mtb.
These complexes showed very good activities (MIC 0.8 – 1.6 lM)
which were close to 150 times greater than that of the free ligand.
The cytotoxicity of these complexes was low and demonstrated
high selectivity. These in vitro assay results were extremely
encouraging and were similar to or even better than those of
first-line drugs in development [96]. Assessment of the activity
of these complexes against twenty-five (25) clinically isolated
drug-resistant strains, demonstrated promising activity (MIC 0.39
– 7.3 lM) on all the isolates [96].
An evaluation of the in vitro anti-mycobacterial activity
against Mtb H37Rv ATCC 27,294 of the ruthenium complexes,
[RuCl2(P)2(N–N)] where [(P)2 = (PPh3)2; dppb = 1,4-bis(diphenyl-
phosphino)butano; dppp = 1,3-bis(diphenylphosphino)propane;
and N–N = 5,50 -dimethyl-2,20 -dipyridyl (5,50 -mebipy) or 4,40 -dime
thyl-2,20 -dipyridyl (4,40 -mebipy)] (Fig. 13) indicated that the MICs
for these complexes cis-[RuCl2(dppb)(5,50 -mebipy)], cis-
[RuCl2(dppp)(5,5 -mebipy)] and cis-[RuCl2(dppp)(4,40 -mebipy)]
0
(12.5 – 25.0 lg/mL) was comparable to that of cycloserine
(12.5 – 50.0 lg/mL) [91]. The MICs of the complexes were far less
than those of the ligands dppp, dppb, 4,40 -mebipy and 5,50 -mebipy
(MIC > 200 lM), indicating that coordination to the ruthenium
centres resulted in increased activity [91].
Additionally, the activities against M. tuberculosis H37Rv ATCC
27294, of six new cationic ruthenium complexes of general
formula [Ru(AA-H)(dppb)(phen)]PF6 (AA = Glycine, L-Alanine,
L-Valine, L-Tyrosine, L-Methionine or L-Tryptophan) (Fig. 14), were
assessed. The activity of the complexes (MIC 0.78 – 3.10 lg mL1)
were similar to those of ethambutol (MIC = 5.61 lg mL1) and
cycloserine (MIC 12.5 – 50.0 lg mL1). [Ru(L-Trp-H)(dppb)
(phen)]PF6 proved to be the most active while [Ru(L-Met-H)
(dppb)(phen)]PF6 was the least active [97]. Coordination of amino
acids and the slightly active dppb (MIC > 50 lg mL1) ligands to the
neutral precursor complex cis-[RuCl2(-dppb)(phen)], enhanced the
activity of the complexes formed.
In a leading preliminary study to evaluate the anti-Mycobac-
terium tuberculosis activities of some ruthenium-cymene com-
plexes of general formula [RuCl(g6-p-cymene)(P─NR─P)]X
(R = CH2Py (Py = pyridine), CH2Ph (Ph = phenyl) , Ph and p-tol
(p-tol = p-tolyl); X = PF 
6 or BF4 ), da Silva and co-workers noted
that the complexes were potential anti-Mtb agents with MIC90 val-
Fig. 14. Structure of the complex [Ru(L-AA-H)(dppb)(phen)]PF6.
7
ues comparable with that of Ethambutol. Variation of the P─N─P
ligand tended to increase the activity. The complex [RuCl(g6-p-
cymene)(P─NR─P)]BF4 (R = CH2Py (Py = pyridine) showed the
highest selectivity index [98].
The reactivity of isoniazid metal complexes as models for new
self-activating metallodrugs against TB aimed at overcoming resis-
tance, has been reported [99]. Results of electron transfer reactions
performed with either free isoniazid or the isoniazid-pentacyano
ferrate(II) complex showed that similar oxidized isoniazid prod-
ucts were detected when the KatG enzyme was used. It was further
noted that coordination to a metal significantly improved the for-
mation of isonicotinic acid compared to that of isonicotinamide.
This suggested that, upon coordination to the Fe(II), there is a
change in pathway which involves a carbonyl-centred radical,
due to the p-back-bonding effect promoted by Fe(II). Conse-
quently, the metal complex containing isoniazid could possibly
serve as a metallodrug. While the cyanoferrate moiety was not
essential for this inhibition, as demonstrated by enzyme inhibition
assays conducted with InhA, that of isoniazid was crucial. The
inability of the metal complexes, [Ru(CN)5(INH)]3 and [Ru
(NH3)5(INH)]2+ (INH = isoniazid), to inhibit InhA, provides addi-
tional evidence to the proposed self-activating mechanism of
action [99].
A series of ruthenium complexes of formulae (g5-p-cymene)
(AA)chlororuthenium (AA = L-gly, L-phe, L-ala, L-ser, en, L-methyl
en, Ethambutol (EMB)) (Fig. 15) have been shown to have antibi-
otic activity against Mycobacterium bovis BCG, Mycobacterium
abscessus and Mycobacterium chelonae [100].
The studied compounds were soluble in aqueous solution with
the lowest concentration > 3 mg/ml, and did not degrade nor form
precipitates. Analysis of the MIC values indicates that hydrophobic
a-amino acids were more active than hydrophilic a-amino acids.
D-amino acids were found to coordinate with transition metals
Fig. 15. Structure of ruthenium-aminoacidato complexes.
Fig. 16. Structures of Ru(II) arene complexes.
8 D.M. Yufanyi et al. / Coordination Chemistry Reviews 414 (2020) 213285
and be inactive under these conditions. The complex of Ethambutol
(EMB) with ruthenium showed weak antimycobacterial activity for
all three rapidly growing mycobacterial strains [100].
Gichumbi et al. synthesised the complexes [(g6-C6H6)RuCl
(C5H4N-2-CH = N-Ar)]PF6 (Ar = phenylmethylene, (4-
methoxyphenyl)methylene, and phenylhydrazone) (Fig. 16)
through reaction of [(g6-C6H6)Ru(l-Cl)Cl]2 with N,N0 -bidentate
ligands in a 1 : 2 M ratio. The complexes were found to show inter-
esting anti-mycobacterial activities against M. smegmatis, when
their antimicrobial susceptibilities were evaluated using the disc
diffusion assay [101].
Colina-Vegas et al. investigated the in vitro antimycobacterial
activity of the ruthenium complexes [RuCl(CTZ)(bipy)(P-P)]PF6
[P-P = 1,2-bis(diphenylphosphino)ethane (dppe), 1,4-bis(diphenyl
phosphino)butane (dppb) and 1,10 -bis(diphenylphosphino)ferro
cene (dppf), bipy = 2,20 -bipiridine and clotrimazole (CTZ) 1-[(2-ch
lorophenyl)diphenylmethyl]-1H-imidazole] (Fig. 17).
The activities of these complexes were found to be similar to or
greater than those of cycloserine (MIC = 12.50–50 lM), gentamicin
(MIC = 4.20–8.40 lM), tobramycin (MIC = 8.56–17.10 lM) and
clarithromycin (MIC = 10.70–21.40 lM), all of which are in com-
mon use as anti-Mtb agents. Thus, these complexes should be fur-
ther explored as promising agents against mycobacterial infections
[102]. In a series of publications, these researchers showed that Ru
(II) complexes containing biphosphines and bipyridines as ligands
were very active, with MIC values comparable to or better than
that of currently used drugs for the treatment of Mtb. Generally,
replacement of the chloride atoms in the precursor complexes of
Ru(II) with bidentate ligands (N–O, N–S or O–O) and two diphos-
phines or diphosphines/bipyridine ligands led to greater activity
[90,91,94,95].
In another study, Lima et al. synthesised and screened in vitro
anti-mycobacterial activities of the complexes [Ru(Spym)(bipy)
(P–P)]PF6, [Spym = pyrimidine-2-thiolate anion; P–P = 1,2-bis(dip
Fig. 17. Structure of Ru(II)/clotrimazole/diphenylphosphine/bipyridine complexes.
Fig. 18. Syntheses Reaction of [Ru(Spym)(bipy)(P–P)]PF6 complexes (P–P = dppe, dppp or dppf).
henylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)pro
pane (dppp) and 1,10 -bis(diphenylphosphino)ferrocene (dppf)]
(Fig. 18). While the free ligands had much higher MIC values
(dppe = 6.25 mg mL1, dppp and dppf > 50 mg mL1, 2,2-bipy =
25 mg mL1), the complexes displayed potential activities (MIC
1.56–4.12 mg mL1), with the complex [Ru(Spym)(bipy)(dppp)]
PF6 having the lowest value. These values are lower than those of
the standard cycloserine (MIC 12.5–50.0 mg mL1) [103].
Smith et al. synthesised a ruthenium(II) complex that incorpo-
rates the anti-tuberculosis drug, isoniazid viz. cis-[Ru
(bpy)2(INH)2][PF6]2 (INH = isoniazid) (Fig. 19) which had photoac-
tive properties. The complex ionises rapidly in aqueous solution,
releasing two equivalents of isoniazid, in a stepwise manner, to
form the photoproduct cis-[Ru(bpy)2(H2O)2]2+, upon irradiation
with blue light (465 nm) [104].
The high photoactivity (after 1 min of photoirradiation with
blue light) of the complex against M. Smegmatis, was obvious from
its high activity (MIC = 4 lM). This activity is 5.5 times greater than
that of isoniazid. >80% of the bacteria incubated with the complex
in the dark, at the MIC value, survived, indicating that the active
ligand (isoniazid) was released only upon photoirradiation. They
also found that the complexes in the cells were best activated
when they were irradiated with blue (465 nm) and green
(520 nm) lights. This was not possible with yellow or red lights
[104].
Cardo et al. explored the activity of diverse metallo-
supramolecular triple stranded helicates, di-nuclear triple stranded
helicate (cylinder) [M2L3]4+ obtained when the bis-pyridylimine
ligand L (Fig. 20) is reacted with the metal ions Fe2+, Ni2+ and
Ru2+, to target the Trans Activation Response (TAR) bulge motif
and inhibit the formation of TAR-TAT (TAT = Transactivator pro-
tein) complexes and HIV infection [33].
The ability of the cylinders to prevent HIV-1 infection was addi-
tionally evaluated. Both Ru and Ni cylinders inhibit HIV replication
in a TAT-dependent manner, with the Ru cylinder proving to be the
more potent (>95% efficiency at 5 lM incubation concentration)
anti-viral agent in both cell lines. These compounds and their ana-
logues could be explored for the development of a new class of
anti-viral agents [33].
In order to improve the activity of isoniazid against both sensi-
tive and resistant strains of Mtb, Aguiar et al. evaluated the anti-M.
tuberculosis activity of [Ru(NH3)5(INH)](BF4)2 and trans-[Ru
(NH3)4(L)(INH)]2+ (L = SO2 or NH3) complexes (Fig. 21) by the REMA
method [105].
Results indicate that the complexes [Ru(NH3)5(INH)]2+ (MIC = 0.
6 mg/mL, IC50 = 250 mg/mL) and trans-[Ru(NH3)4(SO2)(INH)]2+
(MIC = 0.88 mg/mL, IC50 = 500 mg/mL) were the most active, with
activities comparable to or greater than that of first- and second-
line treatment drugs [105]. These same complexes demonstrated
promising activity against resistant strains of Mtb. The coordina-
tion of INH to the Ru centre followed by oxidation to the acy
 D.M. Yufanyi et al. / Coordination Chemistry Reviews 414 (2020) 213285
Fig. 19. Structure of the complex cis-[Ru(bpy)2(INH)2][PF6]2 and its photoactivation to the antibacterial prodrug cis-[Ru(bpy)2(INH)2]2+.
Fig. 20. Structure of the bis-pyridylimine ligand (L).
Fig. 21. Structures of [Ru(NH3)4(L)(INH)]2+ (L = SO2 or NH3) complexes.
radical, was shown, to be central to the activity of the complexes.
In this study, it was discovered that the radical is stabilised by
coordination of INH to the metal centre [99,105].
Stringer et al. evaluated the anti-mycobacterial activity of a ser-
ies of ferrocenyl complexes of isoniazid and pyrazinoic acid hydra-
zide precursors and the half-sandwich complexes (Ir, Rh and Ru) of
the ferrocenyl-isoniazid conjugate (Fig. 22), against Mtb H37Rv in a
glycerol-based GAST-Fe and a glucose-based Middlebrook 7H9-
ADC growth media [106].
While the former evaluated the effect of ferrocene, the latter
highlighted the effect of incorporating a second metal on antimy-
cobacterial activity. While most of the tested compounds demon-
strated strong activity (MIC90 and MIC99 < 1 mM) in a GAST-Fe
medium, the half-sandwich complexes tended to illustrate activi-
Fig. 22. Structures of (a) ferrocenyl complex and (b) half-sandwich complexes of Ir,
Rh and Ru.
9
ties which were glycerol-dependent. This was evidenced by the
increase in MICs in the glucose-based 7H9 medium [106]. The Ru
half-sandwich complexes demonstrated very potent activities
(MIC90 = 0.514 mM, MIC99 = 0.751 mM) in GAST-Fe media. The activ-
ity profile was found to be similar to that of the glycerol-dependent
control, indicating that a possible pathway for their inhibitory
action is through the disruption of glycerol metabolism, with pos-
sible accumulation of toxic intermediates [106].
5. Metal complexes against HIV
The rapid increase in the incidence of co-infection with M.
tuberculosis has resulted in the treatment regime of HIV becoming
more complicated. The development of drug candidates that per-
mit concurrent treatment of HIV and tuberculosis (TB) would pos-
itively impact the all-inclusive treatment of HIV/AIDS, especially in
sub-Saharan Africa with the highest incidence of co-infection. Con-
sequently, exploration by scientists of the efficacy of metal com-
plexes of the proven active molecules or new ones for their anti-
HIV activity, is ongoing.
5.1. Platinum complexes against HIV
The Pt(II) complexes viz. bis(diphenylphosphino)-2-pyridylplati
num(II) chloride and bis(diphenylphosphino)-2-ethylpyridyl- plat-
inum(II) (Fig. 4) were synthesised and investigated for their inhibi-
tion of HIV-1 through interactions with the viral protease. Single
crystal X-ray analysis shows that these complexes have distorted
square-planar geometries around the metal centre. Unfortunately,
none of these complexes showed inhibition against the HIV-1 pro-
tease enzyme [21].
The Pt(II) complexes of 3-methyl-6,7-diphenyl-2-thiolumazine
and 5,6-diamino-2-thiouracil (Fig. 23) were evaluated for their anti
HIV-1 and HIV-2 activity through the investigation of their ability
to inhibit cytopathogenicity induced by HIV in MT-4 cells. None of
the Pt(II) complexes was found to inhibit HIV-2 replication in cell
culture but the dichloro Pt(II) complex exhibited some activity
(EC50 > 2.23 lg/mL) against HIV-1 and HIV-2. However, it was
not selective (selectivity index (SI) < 1). Based on these results,
new and more potent substituted 2-thiolumazine and 2-
thiouracil derivatives could be designed and synthesised to evalu-
ate their activities against HIV-1 and HIV-2 [32].
A study of drug-DNA interactions is important in understanding
the mechanisms of drug action as well in the design of new drugs
that target DNA which is a major intracellular target for anticancer,
antibiotic and antiviral drugs. In this regard, Shahabadi et al. eval-
uated the ability of a newly synthesised fluorescent platinum (Pt)
complex K[PtCl(OCH3)2(ddI)] (Fig. 24), containing the anti-HIV
drug didanosine (ddI), to bind with calf thymus-DNA (ct-DNA),
using UV absorption and fluorescence spectroscopic techniques
[107].
10 D.M. Yufanyi et al. / Coordination Chemistry Reviews 414 (2020) 213285
Fig. 23. Structures of Pt(II) complexes with 3-methyl-6,7-diphenyl-2-thiolumazine and 5,6-diamino-2-thiouracil.
Results obtained indicate that the water soluble complex pref-
erentially binds to DNA in a groove-binding mode, as evidenced
by hyperchromism of the UV–visible band, a decrease in the
Hoechst-DNA fluorescence on increasing the concentration of the
Pt complex coupled with fluorescence quenching of the complex
[107].
Fig. 24. Structure of the Pt(II) K[PtCl(OCH3)2(ddI)].
Fig. 25. Synthetic scheme of [Ru(PPh3)2(N,S-L1–3)2]2H3O+(Cl)2XH2O.
Fig. 26. Synthetic scheme of ruthenium complexes of ethyl 4-aryl-6-methyl-2-thioxo-pyrimidine-5-carboxylate derivatives.
5.2. Ruthenium complexes against HIV
Only a limited study has been done on ruthenium-based-
complexes that target HIV. However, scientific research-based
knowledge of the chemistry of bioactive ruthenium-based com-
pounds can be an alternative for better understanding and provid-
ing new routes to design and search for novel drugs to solve the
complications associated with anti-HIV therapy. In this regard,
some Ru complexes have indeed been explored for their anti-HIV
activity or as possible inhibitors.
Ruthenium complexes [Ru(Spym)(bipy)(P–P)]PF6, [Spym = pyri
midine-2-thiolate; bipy = 2,20 -bipyridine; P–P = 1,2-bis(diphenyl
phosphino)ethane, 1,3-bis(diphenylphosphino)propane or 1,10 -bis
(diphenylphosphino)ferrocene)], were found to, on the one hand
exhibit a low DNA binding affinity but on the other hand demon-
strate high activity against human breast tumour cells, as evi-
denced by their low IC50 values compared to high values for the
tumour cells. The interaction between the complexes with DNA
or other biomolecules, through an atom that is not coordinated
to a metal (e.g. nitrogen atom of the Spym– ligand), could possibly
explain the increase in cytotoxicity of the complexes [103].
In a separate study, the ruthenium(II) complex cis-[Ru
(bpy)2(INH)2][PF6]2 (INH = isoniazid) was evaluated for its pho-
toactivity against bacteria (E. coli and B. subtilis) and the human
lung cell MRC-5. The cationic complex cis-[Ru(bpy)2(INH)2]2+
showed no activity against E. coli (Gram-negative) but was slightly
active against B. subtilis (Gram-positive) upon photo-irradiation
with blue light for 2 h at concentrations of 100 lM and 200 lM.
The complex showed high selectivity in killing mycobacteria com-
pared to the normal human lung cell line MRC-5 [104].
Recently, Al-Masoudi et al. described a number of mononuclear
ruthenium(II) complexes of formulae [Ru(PPh3)2(N,S-L1–3)2]
2H3O+(Cl)2XH2O, [RuCl(dmso)3(N,S-L1–3)], and [Ru2(Cl)2(N,S-L1–3)2]
XH2O, [L1 = ethyl 4-(3-hydroxyphenyl)-6-methyl-2-thioxo-pyrimi
dine-5-carboxylate (monastrol), L2 = 4-hydroxyphenyl analogue
while L3 = 4-bromophenyl analogue of monastrol (Figs. 25 and
26) [108].
 D.M. Yufanyi et al. / Coordination Chemistry Reviews 414 (2020) 213285
Fig. 27. Structures of the ligands (HL1 and HL2) and [RuCl (g6-p-arene)L].
Fig. 28. Structures of mononuclear and dinuclear Ru(II) complexes.
An assay of the ability of these complexes to inhibit HIV-1
(strain IIIB) and HIV-2 (strain ROD), by examining their ability to
inhibit cytopathic effects induced by the virus on MT-4 cells, indi-
cated that all the tested complexes were not active against HIV-1
and HIV-2. Complex d showed IC50 > 0.21 while that of complex
e (Fig. 26) was greater than 2.14 lM. However, neither was selec-
tive [108].
Carcelli et al. designed and synthesised a small library of
quinolone-based ligands (HL1 and HL2) (Fig. 27), that retained the
pharmacophoric motif of the parent enzyme HIV-1 Integrase inhi-
bitors Elvitegravir, as well as their ruthenium p-arene complexes
[RuCl(g6-p-cymene)L1] (a), [RuCl (g6-p-cymene)L2] (b) and [RuCl
(g6-hexamethylbenzene)L1] (c) [109].
Evaluation of the anti-HIV-1 IN enzymatic activities indicate
that, complexes a and b possess the greatest potency (in the sub/
low-micromolar concentration range) towards inhibition of HIV-
1 Integrase. It is interesting to note that the Ru-arene moiety did
not play a notable role towards improving the activity of the
ligands. While complex a partially hydrolysed in aqueous solution,
with a consequent change in its activity, b did not hydrolyse and
the activity remained the same. [109].
In another study, Sheng et al., exploited the reactivity of three
mononuclear (A-C) and two dinuclear (D and E) Ru(II) complexes
(Fig. 28) with a small zinc finger protein nucleocapsid protein 7
(NCp7) known to be significant in the HIV life cycle, to elucidate
11
what effect the ligands have on reactivity as well as their recogni-
tion to nucleic acid [110].
The Ru complexes demonstrated diverse reactivity with NCp7.
Compound D was the most reactive. Reactivity of the Ru complexes
with NCp7 decreased in the order D > E > A > B ~ C as evidenced by
the results obtained from fluorescence spectroscopy and fluores-
cence titration. Furthermore, the results of an Ellman’s assay
demonstrate that as the concentration of D increased, its absor-
bance decreased indicating the binding of Ru to the thiol group
of NCp7. The other complexes were reactive to a lesser extent com-
pared to D. A zinc assay release for NCp7 on reaction with different
concentrations of D indicate that, the release of Zn from NCp7
when reacted with D was dependent on the concentration of D.
Thus, zinc is ejected from the protein NCp7 when Ru binds to its
cysteine residue and thereby disrupting the protein folding [110].
EMSA assay on the effect of ruthenium binding on the interaction
of NCp7 with SL2 DNA (an analogue of RNA SL2) indicates that the
interaction of D or A with NCp7 inhibited protein recognition for
SL2 DNA and in addition, disruption of formation of the NCp7/
SL2 complex by D or A was found to be concentration dependent,
with D being the most potent inhibitor [110].
5.3. Binding mechanism or mechanism of interaction
While several drugs and ARVs are currently being used in the
treatment of TB and HIV, respectively, increased drug resistance
has necessitated the search for more active compounds with alter-
native modes of action, to overcome the resistance. Knowledge of
the mechanisms of action and resistance of currently used drugs
could pave the way for the development of new and more active
compounds with alternative mechanisms of action.
5.3.1. Mechanisms of action of anti-TB drugs
Currently, anti-TB drugs that are employed are known to show
the following mechanisms of action:
a) Host cell penetration and diffusion across the Mtb mem-
brane followed by oxidative activation e.g. INH
b) Diffusion across the Mtb cell membrane followed by binding
to bacterial DNA-dependent RNA polymerase e.g. rifamycins
c) Inhibition of cell wall polymerization e.g. Ethambutol
d) Binding to the 30S ribosomal subunit leading to the inhibi-
tion of translation e.g. aminoglycosides
e) Gyrase and topoisomerase IV trapping as ternary complexes
resulting in blockage of the movement of replication forks
and transcription complexes and hence disruption of Mtb
DNA replication and transcription e.g. floroquinolones
f) Inhibition of RNA-dependent protein synthesis e.g.
macrolides (Clarithromycin)
g) Inhibition of mycolic acid synthesis e.g. Ethionamide
h) Inhibition of peptidoglycan synthesis e.g. cycloserine
i) Inhibition of folic acid biosynthesis and uptake of iron
e.g. Paraaminosalicylic acid
5.3.2. Mechanisms of resistance to anti-TB and anti-HIV agents
It is imperative for one to understand the drug-resistance
mechanisms developed by microorganisms given the rapid and
severe rise in multidrug-resistant (MDR) strains. This resistance
is usually exhibited through many biochemical processes, promi-
nent among which is gene mutation, which renders the bacteria
resistant to the drug [111,112]. These mechanisms of resistance
to currently used anti-TB [111,112] and anti-HIV [113] drugs have
been reviewed.
12 D.M. Yufanyi et al. / Coordination Chemistry Reviews 414 (2020) 213285
5.3.3. Mechanisms of action of Metal-based anti-TB and anti-HIV
agents
Exploration of new effective metal-based anti-TB and anti-HIV
strategies including a number of Pt and Ru complexes has demon-
strated them to indeed have anti-TB and anti-HIV activities in addi-
tion to their ability to interact with diverse cellular targets.
Coordination geometries, variable stereochemistry, chirality, coor-
dinated ligands and high positive charge are all important factors
for the recognition and interaction with biological molecules (e.g.
DNA, RNA, phospholipids, proteins and enzymes).
Isoniazid action involves activation by the enzyme KatG and
inhibition of the mycolic acid biosynthesis, while gene mutations
in InhA are responsible for INH resistance. Oxidation potential
changes of coordinated INH to metal centres could be explored
more extensively in the development of new anti-TB drugs. In this
regard, exploration of the anti-Mtb activities of the complexes [Ru
(NH3)5(INH)]2+ and trans-[Ru(NH3)4(SO2)(INH)]2+ (Fig. 21) indi-
cated that their increased activity was thought to be enhanced
by the rapid and efficient oxidation of coordinated INH coupled
with the change in electrochemical potential for Ru(III/II). A possi-
ble intermediate in the drug action mechanism of the complex [Ru
(NH3)5(INH)]2+ is the acyl radical formed after the INH is oxidised
[105].
Another mechanism of action that has been explored for com-
batting antibiotic resistance is the photoactivation of the prodrug
cis-[Ru(bpy)2(INH)2]2+ to release INH. Its high selectivity towards
mycobacteria makes it a good candidate for use in surface infec-
tions with shallow application and not deep penetration of light
[104].
Targeted HIV-1 enzyme inhibition, especially inhibition of the
enzyme HIV-1 Integrase (IN), which acts as a catalyst for the inte-
gration of proviral cDNA into the host cell genome, has been
exploited as a target in the design of ARV drugs [109].
IN-promoted integration comprises two separate reactions: a)
30 -processing (30 -P) and b) strand transfer (ST). Consequently,
evaluation of the anti-HIV-1 IN enzymatic activities of some
ruthenium p-arene complexes [RuCl(g6-p-cymene)L1] (a), [RuCl
(g6-p-cymene)L2] (b) and [RuCl(g6-hexamethylbenzene)L1] (c)
(Fig. 27) indicate that they probably inhibit the activity of HIV-1
integrase by transportation of the ligand inside the enzyme active
site, leading to interactions with the magnesium metal cofactors.
The inhibition was more selective towards the strand transfer
(ST) catalytic process [109].
Another important drug target of the HIV virus is the class of
nucleocapsid proteins of which a case in point is NCp7, a nucle-
oside chaperone relevant in the process of HIV viral replication
by binding to RNA through zinc fingers. Evaluation of the reactivity
of three mononuclear (A-C) and two dinuclear (D and E) Ru(II)
complexes (Fig. 28) with NCp7 indicated that reactivity of the Ru
complexes decreased in the order D > E > A > B ~ C. I Interaction
of D or A with NCp7 inhibited protein recognition of SL2 DNA
and the disruption in the formation of NCp7/SL2 complex by D or
A was concentration dependent [110]. Appropriate modification
of the ligands in the Ru complexes could lead to improved reactiv-
ity and thus better targeting of NCp7 by Ru complexes and could
thus be further explored as a mechanism for anti-HIV activity for
these complexes.
DNA is also a primary target for many antiviral drugs, implying
that knowledge of the mechanism of its interaction is imperative in
the design of new and more effective drugs. In this regard, analysis
of the interaction of DNA containing the fluorescent platinum (Pt)
complex with the anti-human immunodeficiency virus drug dida-
nosine (ddI) K[PtCl(OCH3)2(ddI)] indicated a tendency towards
groove-binding [107].
6. Other biological applications of these complexes
Some of the platinum and ruthenium complexes included in
this review have additionally been evaluated for their antitumoral
activity [85,86,88,90,97,101] as well as their antimicrobial activity
[101,104] against both Gram-negative and Gram-positive bacteria.
7. Conclusion
While the biological application of transition metal complexes
to treat Mtb and HIV is still an active field of study, those of plat-
inum and ruthenium, with the examples exemplified in the review,
based on publications from 2009  2019, have enjoyed increasing
interest. New, more effective and active antimycobacterial and
anti-HIV drugs are imperative to address the problem of increasing
drug resistance. A growing area of research interest has emerged
which may be described as metallo-drugs. Platinum and ruthe-
nium complexes have recently been explored for their application
as antimycobacterials and anti-HIV drugs, with varying degrees of
activity and success. Given the relative toxicity related to platinum
complexes, the focus has been shifted lately to involve ruthenium
complexes since these have demonstrated very good activity
against M. tuberculosis and HIV. The enhanced activity of the ruthe-
nium complexes depends on the charge, ease of ligand exchange
and lipohilicity. However, for the active complexes to be consid-
ered for drug development, they must be relatively non-toxic to
the host. Thus, it is necessary to redesign the ruthenium complexes
and develop new complexes, with higher activities and selectivities
driving their toxicity towards microorganisms.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
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