Diaminopimelic acid (DAP) analogs bearing isoxazoline moiety as selective inhibitors against meso-diaminopimelate dehydrogenase (m-Ddh) from Porphyromonas gingivalis.

Autor: Ma H; Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA., Stone VN; Philips Institute for Oral Health Research, Virginia Commonwealth University, 521 North 11th Street, Richmond, VA 23298, USA; Department of Microbiology and Immunology, Virginia Commonwealth University, 1101 East Marshall Street, Richmond, VA 23298, USA., Wang H; Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA., Kellogg GE; Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA; Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA., Xu P; Philips Institute for Oral Health Research, Virginia Commonwealth University, 521 North 11th Street, Richmond, VA 23298, USA; Department of Microbiology and Immunology, Virginia Commonwealth University, 1101 East Marshall Street, Richmond, VA 23298, USA., Zhang Y; Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA. Electronic address: yzhang2@vcu.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2017 Aug 15; Vol. 27 (16), pp. 3840-3844. Date of Electronic Publication: 2017 Jun 22.
DOI: 10.1016/j.bmcl.2017.06.056
Abstrakt: Two diastereomeric analogs (1 and 2) of diaminopimelic acid (DAP) bearing an isoxazoline moiety were synthesized and evaluated for their inhibitory activities against meso-diaminopimelate dehydrogenase (m-Ddh) from the periodontal pathogen, Porphyromonas gingivalis. Compound 2 showed promising inhibitory activity against m-Ddh with an IC 50 value of 14.9µM at pH 7.8. The two compounds were further tested for their antibacterial activities against a panel of periodontal pathogens, and compound 2 was shown to be selectively potent to P. gingivalis strains W83 and ATCC 33277 with minimum inhibitory concentration (MIC) values of 773µM and 1.875mM, respectively. Molecular modeling studies revealed that the inversion of chirality at the C-5 position of these compounds was the primary reason for their different biological profiles. Based on these preliminary results, we believe that compound 2 has properties consistent with it being a lead compound for developing novel pathogen selective antibiotics to treat periodontal diseases.
(Published by Elsevier Ltd.)
Databáze: MEDLINE
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