SYNTHESIS OF NAD ANALOGS AS SELECTIVE INHIBITORS OF INOSINE MONOPHOSPHATE DEHYDROGENASE

C-nucleosides are composed of an aromatic moiety linked to a carbohydrate derivative thanks to a stable carbon-carbon bond rather than a hydrolysable carbon-nitrogen bond present in regular nucleosides. C-nucleosides are generally synthesized by two main approaches. In the first approach heterocyclic bases are built, starting from a functional group introduced at the anomeric position of the carbohydrate. The second approach is based on the direct attachment of aromatic or heterocylic moieties to the protected ribose derivative. Two C-nucleosides, tiazofurin and benzamide riboside, show a potent inhibitory activity against Inosine Monophosphate Dehydrogenase (IMPDH) when converted to their corresponding tiazofurin- and benzamide adenine dinucleotide (TAD and BAD). We will discuss the synthesis of TAD analogues containing a substituent at the C2 of adenine ring that inhibit IMPDH with Ki in 1-10 nM range. We will also report modified BAD analogues with inhibitory activity against NAD kinase and M. tuberculosis enoyl ACP reductase.