Tethered dimers as NAD synthetase inhibitors with antibacterial activity

Sadanandan E. Velu, Walter A. Cristofoli, Gabriel J. Garcia, Christie G. Brouillette, Milton C. Pierson, Chi Hao Luan, Lawrence J. DeLucas, Wayne J. Brouillette*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    20 Scopus citations

    Abstract

    The solution-phase parallel synthesis of tethered dimers was employed to identify lead inhibitors of bacterial NAD synthetase. Active dimers contained two aromatic end groups joined by a polymethylene linker, with one end group containing a permanent positive charge. Effective inhibitors of NAD synthetase also inhibited the growth of Gram-positive (but not Gram-negative) bacteria, including antibiotic-resistant strains. The desmethyl precursors of active inhibitors lacked a permanent positive charge and were inactive as either enzyme inhibitors or antibacterial agents. Similarly, a close structural analogue of the most active inhibitors contained two additional ether oxygens in the tether and was inactive in both assays. These results are consistent with the premise that NAD synthetase inhibition is responsible for the antibacterial actions and support further studies on NAD synthetase as a new target for antibacterial agents.

    Original languageEnglish (US)
    Pages (from-to)3371-3381
    Number of pages11
    JournalJournal of Medicinal Chemistry
    Volume46
    Issue number15
    DOIs
    StatePublished - Jul 17 2003

    ASJC Scopus subject areas

    • Molecular Medicine
    • Drug Discovery

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