Tameryn Stringer

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. Preliminary results show that the type of ancillary ligand as well as the substituents on the aromatic ring of the salicylaldiminato thiosemicarbazone ligand influences the antiparasitic activity of these complexes.

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. The quinoline compounds show enhanced activity compared to the ferrocene compounds against this parasite. Compound 5 displays the most promising activity against the NF54 strain. Compounds 5 and 6 are effective at inhibiting β-hematin formation perhaps due to an increased number of quinoline moieties. The trimeric (12) and tetrameric (13) ferrocenyl compounds also inhibit β-hematin formation, albeit to a lesser degree compared to the quinoline thioureas. The compounds were also screened against the G3 strain of Trichomonas vaginalis and here the ferrocene-containing compounds show a slightly higher parasite growth inhibition compared to the quinoline thioureas. The quinoline compounds were also found to be more cytotoxic compared to the ferrocenyl compounds. Compound 6 displays good cytotoxicity against WHCO1 oesophageal cancer cells.

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. F, Cl, Br, I, NO2, OMe and (t)Bu for HL(2-8), respectively. Ligand HL(9) is also a salicylaldimine-containing ligand with substitutions in both 3- and 5-positions of the salicylaldimine moiety, i.e. N-(2-((2-hydroxy-3,5-di-tert-butylphenyl)methyl-imino)ethyl)-7-chloroquinolin-4-amine, while HL(10) is N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) The half sandwich metal complexes that have been investigated are [Ru(η(6)-cym)(L(1-8))Cl] (Ru-1-Ru-8, cym = p-cymene), [Os(η(6)-cym)(L(1-3,5,7))Cl] (Os-1-Os-3, Os-5, and Os-7), [M(η(6)-cym)(HL(9))Cl2] (M = Ru, Ru-HL(9); M = Os, Os-HL(9)) and [M(η(6)-cym)(L(10))Cl]Cl (M = Ru, Ru-10; M = Os, Os-10). In complexes Ru-1-Ru-8 and Ru-10, Os-1-Os-3, Os-5 and Os-7 and Os-10, the ligands were found to coordinate as bidentate N,O- and N,N-chelates, while in complexes Ru-HL(9) and Os-HL(9), monodentate coordination of the ligands through the quinoline nitrogen was established. The antimalarial activity of the new ligands and complexes was evaluated against chloroquine sensitive (NF54 and D10) and chloroquine resistant (Dd2) Plasmodium falciparum malaria parasite strains. Coordination of ruthenium and osmium arene moieties to the ligands resulted in lower antiplasmodial activities relative to the free ligands, but the resistance index is better for the ruthenium complexes compared to chloroquine. Overall, osmium complexes appeared to be less active than the corresponding ruthenium complexes.

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. falciparum, as well as for their cytotoxicity against Chinese Hamster Ovarian (CHO) cells. The ferrocenyl-containing quinolines displayed activities in the low nanomolar range (6-36 nM), and showed selectivity towards parasites. β-Haematin inhibition assays suggest that the compounds may in part act via the inhibition of haemozoin formation, while microsomal metabolic stability studies reveal that the ferrocenyl-containing quinolines are rapidly metabolised in liver microsomes. Further, antitrichomonal screening against the metronidazole-sensitive (G3) strain of the mucosal pathogen T. vaginalis revealed that the quinoline-based compounds displayed superior parasite growth inhibition when compared to the ferrocenylamines. The library was also tested E. coli and on Lactobacilli spp. found as part of the normal flora of the human microbiome and no effect on growth in vitro was observed, supporting the observation that these compounds are specific for eukaryotic pathogens.

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. Selected metal complexes were further screened against the multidrug-resistant (K1) strain. In general, the 2-phenylbenzimidazole ligands showed weak antiplasmodial activities (IC50 ∼ 17.66-22.32 μM) while an enhancement of antiplasmodial activity was observed upon coordination of the ligands with either ruthenium, iridium or rhodium. The new cyclometallated complexes were found to be active against both parasite strains, with IC50 values in the low to submicromolar range (0.12-5.17 μM). In addition, the metal complexes have relatively low cytotoxicity against mammalian Chinese Hamster Ovarian (CHO) cells.