Synthesis of halogenated benzimidazolyl-C-nucleosides and their activity against Leishmania major and Leishmania tropica

Here we report the short synthesis of "reversed" halogenated C-nucleoside (benzimidazole) analogs. Initially, 1,2; 3,4 vicinal diols of D-galactose were acetylated with two different ketones, acetone and cyclohexanone, to furnish acetylated galacto pyranose 1a and 1b, respectively. Subsequently, pyridinium chlorochromate (PCC) was used for the oxidation of C-6 hydroxy- of 1a and 1b to aldehyde 2a and 2b in good yields. Subsequently, the acetylated beta-D-galactopyranosyl C-6 aldehydes were reacted with halogen-substituted O-phenylenediamine to furnish reverse C-galactopyranosyl nucleosides 3a to 7a; 3b to 7b. Hitherto, this is the first report on the synthesis of pyranose-based reverse-position C-nucleosides. These newly synthesized C-nucleosides were identified as an anti-leishmanial agent, in vitro, against Leishmania major and Leishmania tropica. The halogen substitution on the benzimidazole moiety and lipophilicity of the acetylated group of C-nucleosides were found to be the key factors for anti-leishmanial activity. For instance, compound 3a, a non-halogenated analogue, was inactive while its bromine-substituted analogue 6a was considerably active against L. major and L. tropica with IC50 = 8.60 +/- 0.04 mu M and 8.3 +/- 0.4 mu M, respectively. Moreover, fluorinated nucleoside 4a with low lipophilicity was inactive but its analogue 4b was active against both strains L. major and L. tropica with IC50 = 24.7 +/- 0.3 mu M and 20.9 +/- 0.4 mu M, respectively.