ABSTRACT
N-tert-Butyl isoquine (4) (GSK369796) is a 4-aminoquinoline drug candidate selected and developed as part of a public-private partnership between academics at Liverpool, MMV, and GSK pharmaceuticals. This molecule was rationally designed based on chemical, toxicological, pharmacokinetic, and pharmacodynamic considerations and was selected based on excellent activity against Plasmodium falciparum in vitro and rodent malaria parasites in vivo. The optimized chemistry delivered this novel synthetic quinoline in a two-step procedure from cheap and readily available starting materials. The molecule has a full industry standard preclinical development program allowing first into humans to proceed. Employing chloroquine (1) and amodiaquine (2) as comparator molecules in the preclinical plan, the first preclinical dossier of pharmacokinetic, toxicity, and safety pharmacology has also been established for the 4-aminoquinoline antimalarial class. These studies have revealed preclinical liabilities that have never translated into the human experience. This has resulted in the availability of critical information to other drug development teams interested in developing antimalarials within this class.
Subject(s)
Aminoquinolines/pharmacology , Antimalarials/pharmacology , Benzylamines/pharmacology , Aminoquinolines/chemical synthesis , Aminoquinolines/chemistry , Aminoquinolines/pharmacokinetics , Aminoquinolines/toxicity , Amodiaquine/analogs & derivatives , Animals , Antimalarials/chemical synthesis , Antimalarials/pharmacokinetics , Antimalarials/toxicity , Benzylamines/chemical synthesis , Benzylamines/chemistry , Benzylamines/toxicity , Cytochrome P-450 Enzyme Inhibitors , Dogs , Drug Evaluation, Preclinical , Drug Resistance , Female , Haplorhini , Heme/chemistry , Humans , Malaria/drug therapy , Mice , Models, Molecular , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Plasmodium yoelii , Rats , Structure-Activity RelationshipABSTRACT
The development of drug resistance to affordable drugs has contributed to a global increase in the number of deaths from malaria. This unacceptable situation has stimulated research for new drugs active against multidrug-resistant Plasmodium falciparum parasites. In this regard, we show here that deshydroxy-1-imino derivatives of acridine (i.e., dihydroacridinediones) are selective antimalarial drugs acting as potent (nanomolar K(i)) inhibitors of parasite mitochondrial bc(1) complex. Inhibition of the bc(1) complex led to a collapse of the mitochondrial membrane potential, resulting in cell death (IC(50) approximately 15 nM). The selectivity of one of the dihydroacridinediones against the parasite enzyme was some 5000-fold higher than for the human bc(1) complex, significantly higher ( approximately 200 fold) than that observed with atovaquone, a licensed bc(1)-specific antimalarial drug. Experiments performed with yeast manifesting mutations in the bc(1) complex reveal that binding is directed to the quinol oxidation site (Q(o)) of the bc(1) complex. This is supported by favorable binding energies for in silico docking of dihydroacridinediones to P. falciparum bc(1) Q(o). Dihydroacridinediones represent an entirely new class of bc(1) inhibitors and the potential of these compounds as novel antimalarial drugs is discussed.
Subject(s)
Acridines/pharmacology , Antimalarials/pharmacology , Electron Transport Complex III/antagonists & inhibitors , Malaria/parasitology , Mitochondria/drug effects , Mitochondria/enzymology , Plasmodium falciparum/drug effects , Acridines/chemistry , Animals , Antimalarials/chemistry , Atovaquone/pharmacology , Cattle , Drug Synergism , Heme/metabolism , Hemeproteins/metabolism , Humans , Male , Membrane Potential, Mitochondrial/drug effects , Oxidation-Reduction/drug effects , Parasitic Sensitivity Tests , Rats , Rats, Wistar , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/metabolismABSTRACT
The cyclotriphosphazene P(3)N(3)Cl(6) reacts with six equivalents of DMAP (4-(dimethylamino)pyridine) in superheated chloroform to form crystals of composition [P(3)N(3)(DMAP)(6)]Cl(6).19CHCl(3) comprising [P(3)N(3)(DMAP)(6)](6+) ions, which host five chloride ions in basket-type cavities on either side of the ring and at equatorial positions via tetradentate ortho-H-donor arrangements.
ABSTRACT
Urea-functionalized porphyrins with amino acid substituents bind sugar derivatives strongly in non-polar solution.
Subject(s)
Carbohydrates/chemistry , Porphyrins/chemistry , Urea/chemistry , Amino Acids/chemistry , Carbohydrate Metabolism , Kinetics , Porphyrins/chemical synthesis , Porphyrins/metabolism , Protein Binding , Spectrometry, Fluorescence , Spectrophotometry, Ultraviolet , Titrimetry/methodsABSTRACT
A synthesis of meso-substituted porphyrins in anionic sodium dodecyl sulfate micelles has been developed. Polar, functionalized aromatic aldehydes condense reversibly with pyrrole in the micellar phase. Oxidation of the porphyrinogen then provides functionalized porphyrins in yields of 10-48%. Hydrophobic aldehydes condense irreversibly to give low yields at practical substrate concentrations. Synthesis in D(2)O solution results in per-beta-deuterated porphyrins. A two-phase model is used to rationalize the dependence of porphyrin yield on reactant and surfactant concentration. Micelles are viewed as potential wells which promote porphyrinogen assembly by binding products more tightly than reactants.
