ABSTRACT
Thiol-Olefin Co-Oxygenation (TOCO) methodology has been applied to the synthesis of a small library of weak base and polar 1,2,4-trioxanes. The 1,2,4-trioxane units synthesised exhibit remarkable stability as they survive base catalysed hydrolysis and mixed anhydride/amine coupling reactions. This unique stability feature has enabled a range of novel substitution patterns to be incorporated within the spiro 1,2,4-trioxane unit. Selected analogues express potent in vitro nM antimalarial activity, low cytotoxicity and oral activity in the Plasmodium berghei mouse model of malaria.
Subject(s)
Alkenes/chemistry , Antimalarials/pharmacology , Heterocyclic Compounds/pharmacology , Malaria/drug therapy , Propanols/chemistry , Sulfhydryl Compounds/chemistry , Amides/chemistry , Animals , Antimalarials/chemical synthesis , Antimalarials/chemistry , Crystallography, X-Ray , Disease Models, Animal , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Mice , Models, Molecular , Molecular Structure , Oxidation-Reduction , Oxygen/chemistry , Parasitic Sensitivity Tests , Plasmodium berghei/drug effects , Stereoisomerism , Sulfides/chemistry , Sulfones/chemistryABSTRACT
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
[reaction: see text] Thiol-olefin co-oxygenation (TOCO) of substituted allylic alcohols generates alpha-hydroxyperoxides that can be condensed in situ with various ketones to afford a series of functionalized 1,2,4-trioxanes in good yields. Manipulation of the phenylsulfenyl group in 4a allows for convenient modification to the spiro-trioxane substituents, and we describe, for the first time, the preparation of a new class of antimalarial prodrug.
Subject(s)
Alkenes/chemistry , Antimalarials/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Sulfhydryl Compounds/chemistry , Alkenes/pharmacology , Antimalarials/pharmacology , Combinatorial Chemistry Techniques , Heterocyclic Compounds/pharmacology , Molecular Structure , Oxidation-Reduction , Sulfhydryl Compounds/pharmacologyABSTRACT
Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial that can cause adverse side effects including agranulocytosis and liver damage. The observed drug toxicity is believed to involve the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which can bind to cellular macromolecules and initiate hypersensitivity reactions. We proposed that interchange of the 3' hydroxyl and the 4' Mannich side-chain function of amodiaquine would provide a new series of analogues that cannot form toxic quinoneimine metabolites via cytochrome P450-mediated metabolism. By a simple two-step procedure, 10 isomeric amodiaquine analogues were prepared and subsequently examined against the chloroquine resistant K1 and sensitive HB3 strains of Plasmodium falciparum in vitro. Several analogues displayed potent antimalarial activity against both strains. On the basis of the results of in vitro testing, isoquine (ISQ1 (3a)) (IC(50) = 6.01 nM +/- 8.0 versus K1 strain), the direct isomer of amodiaquine, was selected for in vivo antimalarial assessment. The potent in vitro antimalarial activity of isoquine was translated into excellent oral in vivo ED(50) activity of 1.6 and 3.7 mg/kg against the P. yoelii NS strain compared to 7.9 and 7.4 mg/kg for amodiaquine. Subsequent metabolism studies in the rat model demonstrated that isoquine does not undergo in vivo bioactivation, as evidenced by the complete lack of glutathione metabolites in bile. In sharp contrast to amodiaquine, isoquine (and Phase I metabolites) undergoes clearance by Phase II glucuronidation. On the basis of these promising initial studies, isoquine (ISQ1 (3a)) represents a new second generation lead worthy of further investigation as a cost-effective and potentially safer alternative to amodiaquine.
