New Pyrimidinone-Fused 1,4-Naphthoquinone Derivatives Inhibit the Growth of Drug Resistant Oral Bacteria

• Main Authors: Kyungmin Kim, Daseul Kim, Hyunjin Lee, Tae Hoon Lee, Ki-Young Kim, Hakwon Kim
• Format: Article
• Language: English
• Published: MDPI AG 2020-06-01
• Series: Biomedicines
• Subjects: 1,4-napthoquinone; pyrimidinone; antibacterial activity; oral bacteria; dental caries
• Online Access: https://www.mdpi.com/2227-9059/8/6/160

Background: Dental caries is considered to be a preventable disease, and various antimicrobial agents have been developed for the prevention of dental disease. However, many bacteria show resistance to existing agents. Methods/Principal Findings: In this study, four known 1,4-naphthoquinones and newly synthesized 10 pyrimidinone-fused 1,4-naphthoquinones, i.e. KHQ 701, 702, 711, 712, 713, 714, 715, 716, 717 and 718, were evaluated for antimicrobial activity against <i>Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus mutans, Streptococcus sobrinus, Porphyromonas gingivalis, Actinomyces viscosus</i> and <i>Fusobacterium nucleatum.</i> Pyrimidinone-fused 1,4-naphthoquinones were synthesized in good yields through a series of chemical reactions from a commercially available 1,4-dihydroxynaphthoic acid. MIC values of KHQ 711, 712, 713, 714, 715, 716, 717 and 718 were 6.25–50 μg/mL against <i>E. faecalis</i> (CCARM 5511)<i>,</i> 6.25–25 μg/mL against <i>E. faecium</i> (KACC11954) and <i>S. aureus</i> (CCARM 3506), 1.56–25 μg/mL against <i>S. epidermidis</i> (KACC 13234), 3.125–100 μg/mL against <i>S. mutans</i> (KACC16833), 1.56–100 μg/mL against <i>S. sobrinus</i> (KCTC5809) and <i>P. gingivalis</i> (KCTC 5352), 3.125–50 μg/mL against <i>A. viscosus</i> (KCTC 9146) and 3.125–12.5 μg/mL against <i>F. nucleatum</i> (KCTC 2640) with a broth microdilution assay. A disk diffusion assay with KHQ derivatives also exhibited strong susceptibility with inhibition zones of 0.96 to 1.2 cm in size against <i>P. gingivalis</i>. Among the 10 compounds evaluated, KHQ 711, 712, 713, 715, 716 and 717 demonstrated strong antimicrobial activities against the 9 types of pathogenic oral bacteria. A pyrimidin-4-one moiety comprising a phenyl group at the C2 position and a benzyl group at the N3 position appears to be essential for physiological activity. Conclusion/Significance: Pyrimidinone-fused 1,4-naphthoquinones synthesized from simple starting compounds and four known 1,4-naphthoquinones were synthesized and showed strong antibacterial activity to the 9 common oral bacteria. These results suggest that these derivatives should be prospective for the treatment of dental diseases caused by oral bacteria, including drug-resistant strains.