Understanding the Modes of Action of β-Ketoiminato Iridium(III) Complexes in Cancer Cells.

Four new charged iridium(III) 1,2,3,4,5-pentamethylcyclopentadienyl (Cp*) complexes, , of the type [Cp*Ir()(PTA)](PF) (where = functionalized β-ketoiminate ligands and PTA = 1,3,5-triaza-7-phosphaadamantane), have been successfully synthesized and characterized. Single crystal X-ray crystallographic data have been obtained for all compounds and confirm a typical -octahedral half-sandwich geometry. Cytotoxicity values have been determined against a range of cancerous and noncancerous cell lines and highlight high cytotoxicity and selectivity toward breast cancers.

Fluorinated -Heterocyclic Carbene Silver(I) Complexes with High Cancer Cell Selectivity.

This work presents the synthesis of five new functionalized (benz)imidazolium -heterocyclic (NHC) ligands () and four new (benz)imidazole silver(I) NHC (Ag(I)-NHC) complexes of mononuclear or binuclear type. The complexes have been fully characterized, including single crystal X-ray diffraction of three new structures. The complexes and their corresponding free NHC ligands have been screened against breast cancer and noncancerous cell lines, showing the mononuclear benzimidazole complex has the highest activity, while the binuclear benzimidazole complex has the highest cancer cell selectivity.

Ferrocenyl β-Diketonate Compounds: Extended Ring Systems for Improved Anticancer Activity.

A library of ferrocenyl β-diketonate compounds with varying degrees of aromatic functionality have been synthesized and fully characterized. This includes cyclic voltammetry and the analysis of four new structures by single crystal X-ray diffraction. The compounds cytotoxic potential has been determined by MTT screening against pancreatic carcinoma (MIA PaCa-2), ovarian adenocarcinoma (A2780), breast adenocarcinomas (MDA-MB-231 and MCF-7) and normal epithelial retinal (ARPE-19).

Chemistry of glycol nucleic acid (GNA): Synthesis, photophysical characterization and insight into the biological activity of phenanthrenyl GNA constituents.

The knowledge pertaining to the chemistry and biological activity of glycol nucleic acid (GNA) components, like nucleosides and nucleotides, is still very limited. Herein we report on the preparation of the uracil nucleoside (1) and nucleotide ester GNA (2). The compounds are functionalised with a luminescent phenanthrenyl group.

N,O-Chelating quinoline-based half-sandwich organorhodium and -iridium complexes: synthesis, antiplasmodial activity and preliminary evaluation as transfer hydrogenation catalysts for the reduction of NAD.

Two Rh(iii) and Ir(iii) half-sandwich quinoline-based complexes were synthesised and evaluated for their in vitro antiplasmodial activity against the chloroquine-sensitive NF54 and multi-drug resistant K1 strains of the human malaria parasite, Plasmodium falciparum. These half-sandwich organometallic complexes can also facilitate transfer hydrogenation, by converting β-nicotinamide adenine dinucleotide (NAD) to its reduced form (NADH) in the presence of sodium formate. Co-administration of the iridium(iii) complex with sodium formate enhances the antiplasmodial activity in the chloroquine-resistant (K1) strain of Plasmodium falciparum, intimating that metal-mediated transfer hydrogenations can be achieved in malarial parasitic cells.

Ferroquine-derived polyamines that target resistant Plasmodium falciparum.

Rising resistance to conventional therapies for malaria has led to the search for novel drugs and strategies with distinct mechanisms of action that may overcome this. Ferroquine is currently the gold standard as far as antimalarial metal-based drugs are concerned and is currently in phase IIb clinical trials as part of the MMV pipeline (in partnership with Sanofi) of antimalarials. It is assumed to inhibit haemozoin formation like chloroquine and maintain its activity in the resistant strain.

Antiplasmodial Activity and In Vivo Bio-Distribution of Chloroquine Molecules Released with a 4-(4-Ethynylphenyl)-Triazole Moiety from Organometallo-Cobalamins.

We have explored the possibility of using organometallic derivatives of cobalamin as a scaffold for the delivery of the same antimalarial drug to both erythro- and hepatocytes. This hybrid molecule approach, intended as a possible tool for the development of multi-stage antimalarial agents, pivots on the preparation of azide-functionalized drugs which, after coupling to the vitamin, are released with a 4-(4-ethynylphenyl)-triazole functionality. Three chloroquine and one imidazolopiperazine derivative (based on the KAF156 structure) were selected as model drugs.

Evaluation of PTA-derived ruthenium(II) and iridium(III) quinoline complexes against chloroquine-sensitive and resistant strains of the Plasmodium falciparum malaria parasite.

Cationic 1,3,5‑triaza‑phosphaadamantane (PTA) quinoline ruthenium(II) and iridium(III) complexes were successfully synthesized and characterized using standard spectroscopic and analytical techniques. The complexes were evaluated for their in vitro antiplasmodial activities against the chloroquine-sensitive (CQS) NF54 and chloroquine-resistant (CQR) K1 strains of the Plasmodium falciparum species of the malaria parasite and were found to exhibit good activities in the sensitive strain but moderate activities in the resistant strain, suggesting a resistance mechanism similar to chloroquine (CQ). Selected samples were screened for their ability to inhibit synthetic haemozoin formation and were found to be inhibitors with similar activity to CQ.

Structure-activity relationship studies of antiplasmodial cyclometallated ruthenium(II), rhodium(III) and iridium(III) complexes of 2-phenylbenzimidazoles.

Benzimidazoles, such as albendazole, thiabendazole and omeprazole have antiplasmodial activity against Plasmodium falciparum and are widely used as scaffolds for metal-based drug research. Incorporating substituents with various lipophilic and electronic properties can influence trans-membrane interactions and concomitantly improve the biological activity. To study structure-activity relationships, a series of 2-phenylbenzimidazoles and their corresponding Ru(II), Ir(III) and Rh(III) cyclometallated complexes were synthesised and evaluated for antiplasmodial activity against the chloroquine-sensitive (NF54) strain of the human malaria parasite Plasmodium falciparum.

Impact of various lipophilic substituents on ruthenium(II), rhodium(III) and iridium(III) salicylaldimine-based complexes: synthesis, in vitro cytotoxicity studies and DNA interactions.

A series of bidentate salicylaldimine ligands was prepared and reacted with either [RuCl(µ-Cl)(p-cymene)], [RhCl(µ-Cl)(Cp*)] or [IrCl(µ-Cl)(Cp*)]. All of the compounds were characterised using an array of spectroscopic and analytical techniques, namely, nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy and mass spectrometry. Single crystal X-ray diffraction (XRD) was used to confirm the bidentate coordination mode of the salicylaldimine ligand to the metal centre.

Antimicrobial activity of organometallic isonicotinyl and pyrazinyl ferrocenyl-derived complexes.

Isonicotinyl and pyrazinyl ferrocenyl-derived complexes were prepared using various hydrazides and ferrocenyl aldehydes. Three heterobimetallic complexes were also synthesized from the Schiff base-derived isonicotinyl ferrocene complex using various platinum group metal dimers based on ruthenium, rhodium and iridium. All complexes were evaluated in vitro for antimycobacterial and antiparasitic activity.

Bioisosteric ferrocenyl-containing quinolines with antiplasmodial and antitrichomonal properties.

Bioisosteric ferrocenyl-containing quinolines and ferrocenylamines containing organosilanes and their carbon analogues, were prepared and fully characterised. The molecular structures of two ferrocenyl-containing quinolines, determined using single-crystal X-ray diffraction, revealed that the compounds crystallise in a folded conformation. The compounds were screened for their antiplasmodial activity against the chloroquine-sensitive (NF54) and CQ-resistant (Dd2) strains of P.

Mono- and multimeric ferrocene congeners of quinoline-based polyamines as potential antiparasitics.

A series of mono- and multimeric polyamine-containing ferrocenyl complexes containing a quinoline motif were prepared. The complexes were characterised by standard techniques. The molecular structure of the monomeric salicylaldimine derivative was elucidated using single crystal X-ray diffraction and was consistent with the proposed structure.

Antimalarial activity of ruthenium(II) and osmium(II) arene complexes with mono- and bidentate chloroquine analogue ligands.

Eight new ruthenium and five new osmium p-cymene half-sandwich complexes have been synthesized, characterized and evaluated for antimalarial activity. All complexes contain ligands that are based on a 4-chloroquinoline framework related to the antimalarial drug chloroquine. Ligands HL(1-8) are salicylaldimine derivatives, where HL(1) = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine, and HL(2-8) contain non-hydrogen substituents in the 3-position of the salicylaldimine ring, viz.

Polyamine quinoline rhodium complexes: synthesis and pharmacological evaluation as antiparasitic agents against Plasmodium falciparum and Trichomonas vaginalis.

A series of mono- and bis-salicylaldimine ligands and their corresponding Rh(i) complexes were prepared. The compounds were characterised using standard spectroscopic techniques including NMR, IR spectroscopy and mass spectrometry. The salicylaldimine ligands and complexes were screened for antiparasitic activity against two strains of Plasmodium falciparum i.

Improved antiparasitic activity by incorporation of organosilane entities into half-sandwich ruthenium(II) and rhodium(III) thiosemicarbazone complexes.

A series of ferrocenyl- and aryl-functionalised organosilane thiosemicarbazone compounds was obtained via a nucleophilic substitution reaction with an amine-terminated organosilane. The thiosemicarbazone (TSC) ligands were further reacted with either a ruthenium dimer [(η(6-i)PrC6H4Me)Ru(μ-Cl)Cl]2 or a rhodium dimer [(Cp*)Rh(μ-Cl)Cl]2 to yield a series of cationic mono- and binuclear complexes. The thiosemicarbazone ligands, as well as their metal complexes, were characterised using NMR and IR spectroscopy, and mass spectrometry.

Synthesis, characterization, antiparasitic and cytotoxic evaluation of thioureas conjugated to polyamine scaffolds.

A series of mono- and multimeric 4-amino-7-chloroquinoline and ferrocenyl thioureas have been prepared by the reaction of a 7-chloroquinoline methyl ester and a ferrocenylimine methyl ester with various amines. These compounds were characterized using standard spectroscopic and analytical techniques. The compounds were evaluated against the NF54 (CQ-sensitive) and Dd2 (CQ-resistant) strains of Plasmodium falciparum.

Synthesis and in vitro evaluation of palladium(II) salicylaldiminato thiosemicarbazone complexes against Trichomonas vaginalis.

Eight mononuclear Pd(II) complexes containing salicylaldiminato thiosemicarbazones (saltsc-R; where R=H (1), 3-OMe (2), 3-(t)Bu (3) and 5-Cl (4)) as dinegative tridentate ligands were prepared by the reaction of the corresponding thiosemicarbazone with the precursor Pd(L)(2)Cl(2) (L=phosphatriazaadamantane or 4-picoline) in the presence of a weak base. These complexes (9-16) were characterised by a range of spectroscopic and analytical techniques including NMR spectroscopy and X-ray diffraction. These complexes along with four other Pd(II) analogues (5-8) were screened for activity in vitro against the Trichomonas vaginalis parasite.