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

Hongguang Ma; Victoria N Stone; Huiqun Wang; Glen E Kellogg; Ping Xu; Yan Zhang

doi:10.1016/j.bmcl.2017.06.056

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

Bioorg Med Chem Lett. 2017 Aug 15;27(16):3840-3844. doi: 10.1016/j.bmcl.2017.06.056. Epub 2017 Jun 22.

Authors

Hongguang Ma¹, Victoria N Stone², Huiqun Wang¹, Glen E Kellogg³, Ping Xu², Yan Zhang⁴

Affiliations

¹ Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA.
² 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.
³ 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.
⁴ Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA. Electronic address: yzhang2@vcu.edu.

Abstract

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 IC₅₀ 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.

Keywords: Antibacterial activity; Diaminopimelic acid; Molecular modeling; meso-Diaminopimelate dehydrogenase inhibitor.

Published by Elsevier Ltd.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Oxidoreductases / antagonists & inhibitors*
Amino Acid Oxidoreductases / metabolism
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Diaminopimelic Acid / chemical synthesis
Diaminopimelic Acid / chemistry
Diaminopimelic Acid / pharmacology*
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Isoxazoles / chemistry
Isoxazoles / pharmacology*
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Porphyromonas gingivalis / drug effects*
Porphyromonas gingivalis / enzymology
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Enzyme Inhibitors
Isoxazoles
Diaminopimelic Acid
Amino Acid Oxidoreductases
diaminopimelate dehydrogenase

Grants and funding

R01 DE023078/DE/NIDCR NIH HHS/United States