Periodontitis and its systemic sequelae remain a major public health problem and the development of a safe, cost-efficient therapy will benefit healthcare worldwide. The adherence of Porphyromonas gingivalis to Streptococcus gordonii facilitates colonization of the oral cavity by P. gingivalis and contributes to the development of periodontal disease. It was previously shown that a synthetic peptide derived from the streptococcal protein potently inhibits this interaction and prevents formation of P. gingivalis biofilms. However, peptides are not ideal therapeutic agents due to preparation costs and hydrolytic instability. Consequently, our approach is to rationally-design small-molecule peptidomimetics that inhibit P. gingivalis adherence to S. gordonii. The inhibitors are based on the principle of click chemistry whereby two inhibitory small-molecule fragments are joined through a click reaction to produce an enhanced inhibitor. Our first generation inhibitors were based on 2-azidomethyl-4,5-disubstuted oxazoles and substituted arylacetylenic click components. We now report on the synthesis and bioassay of a ‘second generation’ of click biofilm inhibitors based on azidoarylsulfonyloxazoles and acetylenic triazine components. The click products are composed of a new arylsulfonylmethyl spacer and utilize acetylenic triazines as the coupling partners. The synthesis of the inhibitors and the in vitro bioassay studies of the compounds will be presented.

Second generation inhibitors of Porphyromonas gingivalis biofilm formation

253rd National Meeting (2017)

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