Imidazonaphthyridine systems (part 2): Functionalization of the phenyl ring linked to the pyridine pharmacophore and its replacement by a pyridinone ring produces intriguing differences in cytocidal activity

We recently discovered that five- and pseudo-five-fused-ring derivatives in an imidazonaphthyridine series were promising hit compounds for the development of new DNA-intercalators. In this study, novel (dihydro)imidazo[1,6] and [1,7]naphthyridi(no)nes were prepared including pseudo-pentacycles. All the compounds synthesized were screened against four tumor cell lines. Compounds 3(b–d) showed significant in vitro cytotoxicity, and DNA intercalation properties were demonstrated at 25 μM. Imidazonaphthyridinones exhibited no DNA binding affinity despite significant growth inhibition activity. Interestingly, when a pyridinone pharmacophore was linked to the imidazo[1,2-a]pyridine scaffold, the geometric orientation of the link had a strong impact on the growth inhibition activity. From these results we conclude that the moderate cytotoxicity observed for these compounds is independent of their DNA-binding and topoisomerase inhibition activities.

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► Several rationally designed imidazonaphthyridin(on)es compounds were synthesized.
► Four of twenty-one new compounds displayed DNA-intercalation activity.
► The most potent compound had GI50 = 300 nM against HT-1080 and MCF-7 cancer cell line.
► Compounds 3(b–d) showed better activity than parent compound.
► Connection of pyridine chromophore is crucial in displaying DNA-intercalation activity.