TECHNICAL FIELD

The presently-disclosed subject matter relates to antimicrobial compounds, compositions, methods of making, and methods of use thereof. The presently-disclosed subject matter also relates to antimicrobial control ofPorphyromonas gingivalis. The presently-disclosed subject matter further relates to treatment of periodontal disease.

BACKGROUND

Periodontal disease is a chronic inflammatory disease that is triggered by oral pathogenic bacteria (e.g.,Porphyromonas gingivalis) and leads to tooth loss if untreated. This disease affects half of adult population in the United States and its prevalence significantly increases with aging.1, 2In addition to the oral local sequelae, periodontal disease has also been associated as a risk factor for diabetes, cardiovascular diseases, stroke, as well as arthritis.3-5P. gingivalisis a Gram-negative bacterium that is associated with periodontal disease.6-9Evidence indicates thatP. gingivaliscan invade oral epithelial cells and modulate innate responses that lead to oral dysbiosis and unresolved chronic inflammation.10-13

Although it has been suggested that local and systemic antibiotics can be used as adjunctive therapy for controlling periodontal disease,14-16there are no clear understanding and/or guidelines when it comes to selecting an antibiotic regimen for targeting specific periodontopathogens, without perturbing the normal oral commensal bacteria.17, 18This pitfall can result in poor efficacy against the targeted pathogens, which can be either resistant or poorly susceptible against the antibiotic(s) selected.19

In addition, the extensive use of antibiotics can result in development of drug-resistant bacteria, which can impact the effectiveness of the treatment. Thus, it is paramount that development of novel antibacterial agents for the treatment of periodontal disease become a priority.

Zafirlukast is an FDA-approved drug used for the effective inhibition of airway inflammation in the case of asthma treatment.28, 29Recently published work emphasized the use of zafirlukast as a treatment option forMycobacterium tuberculosisand West Nile virus infections.30, 31The antibacterial activity of the zafirlukast against two oral pathogens,P. gingivalisandStreptococcusmutants, was also reported in recent literature.32

In the instant invention, chemically modified zafirlukast provided better agents for treating oral infections compared to this parent drug scaffold (FIG.1). In zafirlukast, both a cyclopentyl carbamate attached to an N-methylindole and an arylsulfonamide scaffold are linked via a decorated benzoyl ring, which offers a unique opportunity for structure-activity relationship (SAR) studies. Herein, the synthesis of multiple zafirlukast derivatives is reported, where modifications on the indole (e.g., removal or replacement of the cyclopentyl carbamate by a nitro group, and removal of the methyl group from the indole amine), the arylsulfonamide (e.g., removal of the methyl substituent), as well as the benzoyl ring (e.g., change in its substituents and their substitution patterns) were made. The antibacterial activity of these zafirlukast derivatives againstP. gingivalisand various other oral bacteria is also disclosed herein. In addition, the cytotoxic effect of these zafirlukast derivatives against human oral epithelial cells is disclosed herein.

