ABSTRACT
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.e. the NF54 CQ-sensitive and K1 CQ-resistant strain as well as against the G3 isolate of Trichomonas vaginalis. The monomeric salicylaldimine quinolines exhibited good activity against the NF54 strain and the dimeric salicylaldimine quinolines exhibited no cross resistance across the two strains. The binuclear 5-chloro Rh(i) complex displayed the best activity against the Trichomonas vaginalis parasite, possibly a consequence of its enhanced lipophilicity. The compounds were also screened for cytotoxicity in vitro against WHCO1 oesophageal cancer cells. The monomeric salicylaldimine quinolines exhibited high selectivity towards malaria parasites compared to cancer cells, while the dimeric compounds were less selective.
Subject(s)
Antiparasitic Agents/pharmacology , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Quinolines/pharmacology , Rhodium/pharmacology , Trichomonas Vaginitis/drug therapy , Trichomonas vaginalis/drug effects , Antiparasitic Agents/chemical synthesis , Antiparasitic Agents/chemistry , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Female , Humans , Polyamines/chemical synthesis , Polyamines/chemistry , Polyamines/pharmacology , Quinolines/chemical synthesis , Quinolines/chemistry , Rhodium/chemistry , Structure-Activity RelationshipABSTRACT
New polynuclear organometallic Platinum Group Metal (PGM) complexes containing di- and tripyridyl ester ligands have been synthesised and characterised using analytical and spectroscopic techniques including (1)H, (13)C NMR and infrared spectroscopy. Reaction of these polypyridyl ester ligands with either [Ru(p-cymene)Cl2]2, [Rh(C5Me5)Cl2]2 or [Ir(C5Me5)Cl2]2 dimers yielded the corresponding di- or trinuclear organometallic complexes. The polyaromatic ester ligands act as monodentate donors to each metal centre and this coordination mode was confirmed upon elucidation of the molecular structures for two of the dinuclear complexes. The di- and trinuclear PGM complexes synthesized were evaluated for inhibitory effects on the human protozoal parasites Plasmodium falciparum strain NF54 (chloroquine sensitive), Trichomonas vaginalis strain G3 and the human ovarian cancer cell lines, A2780 (cisplatin-sensitive) and A2780cisR (cisplatin-resistant) cell lines. All of the complexes were observed to have moderate to high antiplasmodial activities and the compounds with the best activities were evaluated for their ability to inhibit formation of synthetic hemozoin in a cell free medium. The in vitro antitumor evaluation of these complexes revealed that the trinuclear pyridyl ester complexes demonstrated moderate activities against the two tumor cell lines and were also less toxic to model non-tumorous cells.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antiparasitic Agents/chemical synthesis , Antiparasitic Agents/pharmacology , Organometallic Compounds/chemical synthesis , Organometallic Compounds/pharmacology , Pyridines/chemistry , Antineoplastic Agents/chemistry , Antiparasitic Agents/chemistry , Cell Line, Tumor , Chemistry Techniques, Synthetic , Humans , Iridium/chemistry , Models, Molecular , Molecular Conformation , Organometallic Compounds/chemistry , Plasmodium falciparum/drug effects , Rhodium/chemistry , Ruthenium/chemistry , Solubility , Trichomonas vaginalis/drug effectsABSTRACT
In the present study, we carried out a structure-activity analysis in Trichomonas vaginalis of a series of adenosine and uridine analogues. The most potent compounds were found to be 2' and 3' modified adenosine analogues some of which are potent inhibitors of S-adenosylhomocysteine hydrolase. The 9-(2-deoxy-2-fluoro-ß,D-arabinofuranosyl)adenine compound was more potent than metronidazole, a current FDA approved and commonly prescribed drug for treatment of trichomoniasis. Its IC(50) was 0.09 µM compared to 0.72 µM for metronidazole.
Subject(s)
Adenosine/analogs & derivatives , Adenosine/chemical synthesis , Adenosylhomocysteinase/antagonists & inhibitors , Antiprotozoal Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Protozoan Proteins/antagonists & inhibitors , Trichomonas vaginalis/drug effects , Uridine/chemical synthesis , Adenosine/pharmacology , Adenosylhomocysteinase/metabolism , Animals , Antiprotozoal Agents/pharmacology , CHO Cells , Cell Culture Techniques , Cell Survival/drug effects , Cricetinae , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Metronidazole/pharmacology , Protozoan Proteins/metabolism , Structure-Activity Relationship , Trichomonas vaginalis/growth & development , Uridine/analogs & derivatives , Uridine/pharmacologyABSTRACT
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.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Coordination Complexes/chemical synthesis , Palladium , Thiosemicarbazones/chemical synthesis , Trichomonas vaginalis/drug effects , Antiprotozoal Agents/pharmacology , Coordination Complexes/pharmacology , Crystallography, X-Ray , Inhibitory Concentration 50 , Models, Molecular , Molecular Conformation , Thiosemicarbazones/pharmacologyABSTRACT
Trypanosoma brucei and Trichomonas vaginalis are both parasitic protozoans that are known to share many similar biochemical pathways. Aristeromycin, as well as 5'-iodovinyl and 5'-oxime analogues of adenosine, are potent inhibitors of AdoHcy hydrolase in T. brucei, an enzyme that catalyses the hydrolysis of AdoHcy to adenosine and L-homocysteine. To help determine the role of this enzyme in T. vaginalis, we have tested a library of 5'-modified adenosine derivatives, including 5'-deoxy-5'-(iodomethylene)-adenosine and related 6-N-cyclopropyl analogues. Our results indicate that these inhibitors are effective at inhibiting the growth of T. vaginalis, by as much as 95%.