Design and Synthesis of Quinoline, Cinchona Alkaloids and Other Potential Inhibitors or Leishmaniasis
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The synthesis and biological activity of Trypanothione mimics and a series of quinoline derivatives designed as potential antileishmanial chemotherapies is reported. The biosynthesis of trypanothione is a unique pathway for parasites such as Leishmania and trypanosomes. A structure-guided design of trypanothione mimics led to the identification of 4 target compounds. Compounds 93 and 94 were designed to mimic the left-hand side chain, while compounds 105 and 106 mimicked side chains of molecule 59. The selected side chain mimics have not been previously assessed for their potential as TryR inhibitors. The left-hand side chain mimics 93/94 were synthesised from thioamine 85 and bromopropylamine 89 in six steps and in an overall yield of 2.3%. Side chain mimics 105/106 were synthesised from cysteine methyl ester 103 in five steps and in an overall yield of 3.5%. Five mimics, 93, 94, 98, 105 and 106, were tested in vitro against Leishmania major, however none exhibited activity. Preliminary enzymatic assays of mimics 94 and 106 against Trypanothione synthase indicated a degree of activity for 94 (inhibition >45 ). The Doebner-Miller synthesis of quinolines under modified biphasic conditions was investigated. Crotonaldehyde, reacted readily with aniline to produce 2-methyl quinoline. However, cinnamaldehyde and other -substituted ,β-unsaturated aldehydes yielded complex mixtures with substituted anilines to provide only trace quantities of quinolines. The Doebner-Miller reaction under these conditions is only suitable for sterically accessible ,β-unsaturated aldehydes. A generalised SAR for quinolines active against leishmaniasis was developed from relevant literature. A series of 23 quinoline derivatives were generated using the Doebner-Miller reaction, nucleophilic addition of organometallic reagents to quinoline or palladium-catalyzed direct arylation of quinoline n-oxides. A total of 32 quinoline derivatives were designed varying from mono- to di-substituted quinolines, quinoline- N-oxides, and cinchona alkaloids. The derivatives 116-119, 125-127, 135-136, 147-149, 151-152, 160, 162, 165-166, 168-170 and 172-182 were screened against L. major infected macrophages and some SARs determined. Addition of a methoxy group at the 6-position of the quinoline promoted activity (c.f. 117 IC50 = 71.4 uM, 116 >200 M). Benzyl protection of the alcohol in the side chain of the cinchona alkaloid derivatives also led to improved activity (c.f. 170 IC50 = 1.83 uM, 172 10% at 24 uM). Compounds 169, 170 177, 117 gave IC50 values ranging from 0.49 uM to 71.4 uM. Maximal inhibitions were also found for compounds 165, 172, 176, 174 and 175 in the mid-low micromolar ranges. Cinchona alkaloid 177 (IC50 = 0.49 uM) was identified as the most potent compound from this series of compounds, and suggests cinchona derivatives have potential as chemotherapeutic agents for leishmaniasis.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
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