In the face of the recent pandemic and emergence of infectious diseases of viral origin, research on parasitic diseases such as malaria continues to remain critical and innovative methods are ...required to target the rising widespread resistance that renders conventional therapies unusable. The prolific use of auxiliary metallo-fragments has augmented the search for novel drug regimens in an attempt to combat rising resistance. The development of organometallic compounds (those containing metal-carbon bonds) as antimalarial drugs has been exemplified by the clinical development of ferroquine in the nascent field of Bioorganometallic Chemistry. With their inherent physicochemical properties, organometallic complexes can modulate the discipline of chemical biology by proffering different modes of action and targeting various enzymes. With the beneficiation of platinum group metals (PGMs) in mind, this review aims to describe recent studies on the antimalarial activity of PGM-based organometallic complexes. This review does not provide an exhaustive coverage of the literature but focusses on recent advances of bioorganometallic antimalarial drug leads, including a brief mention of recent trends comprising interactions with biomolecules such as heme and intracellular catalysis. This resource can be used in parallel with complementary reviews on metal-based complexes tested against malaria.
A tailored series of coumarin-based ferrocenyl 1,3-oxazine hybrid compounds was synthesized and investigated for potential antiparasitic activity, drawing inspiration from the established biological ...efficacy of the constituent chemical motifs. The structural identity of the synthesized compounds was confirmed by common spectroscopic techniques: NMR, HRMS and IR. Biological evaluation studies reveal that the compounds exhibit higher in vitro antiparasitic potency against the chemosensitive malarial strain (3D7
) over the investigated trypanosomiasis causal agent (
427) with mostly single digit micromolar IC
values. When read in tandem with the biological performance of previously reported structurally similar non-coumarin, phenyl derivatives (i.e., ferrocenyl 1,3-benzoxazines and α-aminocresols), structure-activity relationship analyses suggest that the presence of the coumarin nucleus is tolerated for biological activity though this may lead to reduced efficacy. Preliminary mechanistic studies with the most promising compound (
) support hemozoin inhibition and DNA interaction as likely mechanistic modalities by which this class of compounds may act to produce plasmocidal and antitrypanosomal effects.
2-Ferrocenylbenzimidazole metallofragments have been prepared.The complexes were characterized using several spectroscopic and analytical techniques.In silico simulations were predict their affinity ...to proteins.Preliminary cytotoxic studies against two breast cancer cell lines.
The synthesis of 2-ferrocenylbenzimidazole metallofragments, with varying substituents in the 5-position of a benzimidazole scaffold is described. This strategy involves linking bioactive multinuclear compounds with known pharmacophores with the potential to interact with protein targets. To further understand the interactions of multinuclear complexes with proteins, in silico simulations were performed by employing protein models of common cancer therapeutic targets to predict their affinity to bind to these proteins. The trinuclear complexes show higher affinities and superior binding energies over monomeric congeners. The synthesized compounds were screened for their cytotoxic activity against two breast cancer cell lines, and selected compounds showed moderate activity. These results suggest that the conjugation of the ferrocene moiety to the benzimidazole motif presents a valuable strategy in the design of organometallic compounds for anticancer chemotherapy.
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A new ditopic, quinoline-based ligand
L
(7-chloro-4-(pyridin-4-yl)quinoline) was synthesized
via
a Suzuki cross-coupling reaction. The ligand was utilized to synthesize the corresponding ...half-sandwich iridium(
iii
) and ruthenium(
ii
) binuclear complexes (
1c
and
1d
) and the subsequent metallarectangles (
2c
,
2d
,
3c
, and
3d
),
via
2 + 2 coordination-driven self-assembly. Single-crystal X-ray diffraction confirmed the proposed molecular structure of the binuclear complex {IrCl
2
(Cp*)}
2
(μ-
L
) (
1c
) and DFT calculations were used to predict the optimized geometry of the rectangular nature of {Ir(μ-Cl)(Cp*)}
4
(μ-
L
)
2
(CF
3
SO
3
)
4
(
2c
). All of the metallarectangles were isolated as their triflate salts and characterized using various spectroscopic (
1
H,
13
C{
1
H}, DOSY NMR, and IR spectroscopy) and analytical techniques (ESI-MS). The synthesized compounds were screened against the NF54 chloroquine-sensitive (CQS) and K1 chloroquine-resistant (CQR) strains of
Plasmodium falciparum
. Incorporation of the ubiquitous quinoline core and metal complexation significantly enhanced the
in vitro
biological activity, with an increase in the nuclearity correlating with an increase in the resultant antiplasmodial activity. This was observed across both parasitic strains, alluding to the potential of supramolecular metallarectangles to act as antiplasmodial agents. Inhibition of haemozoin formation was considered a potential mechanism of action and selected metallarectangles exhibit β-haematin inhibition activity with near comparable activity to chloroquine.
Quinoline-based PGM metallarectangles were evaluated against chloroquine-sensitive and chloroquine-resistant strains of
Plasmodium falciparum
.
A discrete series of tricarbonyl manganese and rhenium complexes conjugated to a quinoline-triazole hybrid scaffold were synthesised and their inhibitory activities evaluated against Plasmodium ...falciparum. In general, the complexes show moderate activity with improved inhibitory activities for the photoactivatable manganese(I) tricarbonyl complexes in the malaria parasite. All complexes are active in the dark against the NF54 CQS (chloroquine-sensitive) and K1 MDR (multidrug-resistant) strains of Plasmodium falciparum, with IC50 values in the low micromolar range. Of significance, the complexes retain their activity in the MDR strain with resistance indices ranging between 1.1 and 2.1. The Mn(I) analogues display photodissociation of all three CO ligands upon irradiation at 365 nm. More importantly, the complexes show increased antimalarial activity in vitro upon photoactivation, something not observed by the clinically used reference drug, chloroquine. As a purported mechanism of action, the compounds were evaluated as β-haematin inhibitors. To further understand the interactions of the complexes, in silico hemozoin docking simulations were performed, attesting to the fact that CO-release could be vital for blocking the hemozoin formation pathway. These results show that this strategy may be a valuable, novel route to design antimalarial agents with higher efficacy.
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•Quinoline-triazole manganese and rhenium complexes were synthesised.•The complexes show good in vitro activity against Plasmodium falciparum in the dark.•The manganese complex shows enhanced antimalarial activity upon photoactivation.•The compounds show inhibition of β-haematin formation in a cell-free NP-40 assay.•In silico molecular docking simulations attest to the CO-release.
A small library of aminoquinoline and imidazolopiperidine (IMP)-based ligands, containing the 1,2,3-triazole moiety, and their corresponding tricarbonyl rhenium complexes were synthesised and their ...inhibitory activities evaluated against the chloroquine-sensitive (CQS) and multidrug-resistant (MDR) strains (NF54 and K1, respectively) of P. falciparum. The quinoline-based compounds (L1, L2, ReL1, and ReL2) were at least six-fold more potent than their IMP-based counterparts (L3, L4, ReL3, and ReL4) against both strains of P. falciparum, with the most promising compound (L1) displaying activity comparable to chloroquine diphosphate (CQDP) in the MDR strain. Additionally, all of the synthesised compounds have resistance indices less than CQDP. To gain insight into a possible mechanism of action, in silico hemozoin docking simulations were performed. These studies proposed that the tested compounds may act via hemozoin inhibition, as the new aminoquinoline-derivatives, with the exception of complex ReL2 (binding affinity: -12.62 kcal/mol), showed higher binding affinities than the reference drug chloroquine (CQ, -13.56 kcal/mol). Furthermore, the ligands exhibited superior binding affinity relative to their corresponding Re(I) complexes, which is reflected in their antiplasmodial activity.
Amodiaquine (AQ) is a potent antimalarial drug used in combination with artesunate as part of artemisinin-based combination therapies (ACTs) for malarial treatment. Due to the rising emergence of ...resistant malaria parasites, some of which have been reported for ACT, the usefulness of AQ as an efficacious therapeutic drug is threatened. Employing the organometallic hybridisation approach, which has been shown to restore the antimalarial activity of chloroquine in the form of an organometallic hybrid clinical candidate ferroquine (FQ), the present study utilises this strategy to modulate the biological performance of AQ by incorporating ferrocene. Presently, we have conceptualised ferrocenyl AQ derivatives and have developed facile, practical routes for their synthesis. A tailored library of AQ derivatives was assembled and their antimalarial activity evaluated against chemosensitive (NF54) and multidrug-resistant (K1) strains of the malaria parasite, Plasmodium falciparum. The compounds generally showed enhanced or comparable activities to those of the reference clinical drugs chloroquine and AQ, against both strains, with higher selectivity for the sensitive phenotype, mostly in the double-digit nanomolar IC50 range. Moreover, representative compounds from this series show the potential to block malaria transmission by inhibiting the growth of stage II/III and V gametocytes in vitro. Preliminary mechanistic insights also revealed hemozoin inhibition as a potential mode of action.
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•Ferrocenyl derivatives of the clinical antimalarial drug, amodiaquine, have been prepared.•The lead compounds show enhanced/comparable nanomolar activity to both chloroquine and amodiaquine.•The lead compounds inhibit growth of stage II/III gametocytes.•Hemozoin inhibition is revealed as a potential mode of action.
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•A series of thirty-nine quinoline derivatives has been synthesised and characterised by common spectroscopic techniques.•Most compounds displayed significant antiplasmodial activity ...with IC50 values from mid to sub-micromolar.•Compounds 40 and 59 displayed strong binding mode to hemozoin crystal after computational docking.
Several classes of antimalarial drugs are currently available, although issues of toxicity and the emergence of drug resistant malaria parasites have reduced their overall therapeutic efficiency. Quinoline based antiplasmodial drugs have unequivocally been long-established and continue to inspire the design of new antimalarial agents. Herein, a series of mono- and bisquinoline methanamine derivatives were synthesised through sequential steps; Vilsmeier-Haack, reductive amination, and nucleophilic substitution, and obtained in low to excellent yields. The resulting compounds were investigated for in vitro antiplasmodial activity against the 3D7 chloroquine-sensitive strain of Plasmodium falciparum, and compounds 40 and 59 emerged as the most promising with IC50 values of 0.23 and 0.93 µM, respectively. The most promising compounds were also evaluated in silico by molecular docking protocols for binding affinity to the {001} fast-growing face of a hemozoin crystal model.
A focused series of novobiocin derivatives containing a ferrocene unit together with their corresponding organic novobiocin analogues have been synthesized in modest to good yields. These compounds ...were screened for biological activity against a chloroquine-sensitive strain of Plasmodium falciparum (3D7) and human breast cancer cell line (HCC38). With the exception of compounds 5c and 5d, the general trend observed is that incorporation of the ferrocene moiety into novobiocin scaffold resulted in compounds 6a–d/6f showing enhanced activity compared to organic analogues 5a–b and 5e–f.
Herein, the synthesis and characterization of ferrocenyl and organic novobiocin derivatives is presented. In vitro biological evaluation of these compounds revealed that incorporation of ferrocene framework resulted in compounds with enhanced activity compared novobiocin and its organic analogues. Display omitted
•New ferrocenyl novobiocin derivatives were synthesized and characterised.•The compounds give insight into permissible moieties on the right hand side.•The ferrocenyl novobiocin derivatives appeared to display high activity.•Excluding two compounds, organic novobiocin was generally less active.
Cancer and malaria remain relevant pathologies in modern medicinal chemistry endeavours. This is compounded by the threat of development of resistance to existing clinical drugs in use as first-line ...option for treatment of these diseases. To counter this threat, strategies such as drug repurposing and hybridization are constantly adapted in contemporary drug discovery for the expansion of the drug arsenal and generation of novel chemotypes with potential to avert or delay resistance. In the present study, a polymer precursor scaffold, 1,3-benzoxazine, has been repurposed by incorporation of an organometallic ferrocene unit to produce a novel class of compounds showing in vitro biological activity against breast cancer, malaria and trypanosomiasis. The resultant ferrocenyl 1,3-benzoxazine compounds displayed high potency and selectivity against the investigated diseases, with IC50 values in the low and sub-micromolar range against both chloroquine-sensitive (3D7) and resistant (Dd2) strains of the Plasmodium falciparum parasite. On the other hand, antitrypanosomal (Trypanosoma brucei brucei) potencies were observed between 0.15 and 38.6 μM. The majority of the compounds were not active against breast cancer cells (HCC70), however, for the toxic compounds, IC50 values ranged from 11.0 to 30.5 μM. Preliminary structure-activity relationships revealed the basic oxazine sub-ring and lipophilic benzene substituents to be conducive for biological efficacy of the ferrocenyl 1,3-benzoxazines reported in the study. DNA interaction studies performed on the most promising compound 4c suggested that DNA damage may be one possible mode of action of this class of compounds.
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•A polymer precursor, 3,4-dihydro-2H-1,3-benzoxazine, has been repurposed for potential antimicrobial and antitumour applications.•A series of ferrocenyl 1,3-benzoxazine derivatives have been synthesized and characterized by common spectroscopic techniques.•Most compounds displayed significant activity with IC50 values from mid-micromolar to sub-micromolar concentrations.•Preliminary mechanistic studies revealed DNA interaction and damage as possible modes of action of the investigated compounds.
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