Structure-Activity Relationship Studies of ME1111, a Novel Antifungal Agent for Topical Treatment of Onychomycosis

Chemistry Medicinal Chemistry Infectious Diseases Pharmacy Medicine
onychomycosis antifungal agent structure-activity relationship topical treatment ME1111 nail permeability keratin binding

Structure-Activity Relationship Studies of ME1111—A Novel Antifungal Agent for Topical Treatment of Onychomycosis

Background

Onychomycosis is a globally prevalent disease affecting approximately 5.5% of the world’s population. Among its subtypes, distal-lateral subungual onychomycosis (DLSO) is the most common. The treatment of onychomycosis typically relies on oral and topical medications. However, oral drugs such as terbinafine and itraconazole carry risks of hepatotoxicity and drug interactions, while topical agents like ciclopirox and amorolfine, though safer, are less effective. Therefore, there is an urgent need to develop a highly effective and safe topical antifungal agent.

To develop novel antifungal agents with high nail permeability and low keratin affinity, researchers at Meiji Seika Pharma Co., Ltd. conducted a systematic study. They first established an efficient ex vivo evaluation method using bovine hoof slices and human nails to screen an in-house compound library. Through this approach, they identified a compound with a phenyl-pyrazole skeleton and further optimized it through structure-activity relationship (SAR) studies, leading to the development of ME1111.

Source of the Study

This research was conducted by Naomi Takei-Masuda, Maiko Iida, Makoto Ohyama, Kaori Kaneda, Kenji Ueda, and Yuji Tabata from Meiji Seika Pharma Co., Ltd. and was published online on November 14, 2024, in The Journal of Antibiotics.

Research Process and Results

1. Compound Library Screening and Primary Screening

The research team first screened Meiji Seika Pharma Co., Ltd.’s in-house compound library (approximately 150,000 compounds) for growth inhibitory activity against Trichophyton mentagrophytes, a primary causative agent of onychomycosis. At a concentration of 5 µg/mL, 14,176 compounds (approximately 10% of the library) were identified, showing over 80% growth inhibition of T. mentagrophytes.

2. Secondary Screening: Bovine Hoof Permeability and Antifungal Activity Evaluation

To further identify compounds with high nail permeability, the team developed an ex vivo evaluation method using bovine hoof slices as a substitute for human nails. Through this method, 99 candidate compounds were identified, demonstrating good permeability and antifungal activity on bovine hoof slices.

3. Tertiary Screening: Human Nail Permeability and Antifungal Activity Evaluation

In the tertiary screening, the team evaluated the candidate compounds using human nails. Five compounds were ultimately selected, with compound 1 showing the highest antifungal activity and human nail permeability. The Turchub assay confirmed the permeability and antifungal activity of compound 1 in human nails.

4. Structure-Activity Relationship (SAR) Studies

The team conducted systematic SAR studies on compound 1 and its derivatives, focusing on the effects of substituents on the phenyl-pyrazole skeleton on antifungal activity and nail permeability. The study found that the hydroxyl group (OH) on the phenyl ring was crucial for antifungal activity, while substituents on the pyrazole ring significantly influenced the compound’s antifungal activity and permeability. Through a series of SAR studies, the team ultimately identified ME1111 (compound 28) as the best candidate.

5. Mechanism of Action of ME1111

The team further investigated the mechanism of action of ME1111, revealing that it selectively inhibits the succinate dehydrogenase of T. mentagrophytes while having minimal effects on the human homolog, ensuring the drug’s safety.

Research Conclusions and Significance

Through systematic compound screening and SAR studies, the research successfully developed ME1111, a novel topical antifungal agent. ME1111 exhibits high nail permeability, potent antifungal activity, and low toxicity to humans, demonstrating promising clinical applications. This study not only provides a new treatment option for onychomycosis but also offers valuable insights for the future development of antifungal drugs.

Research Highlights

  1. Efficient Screening Method: The team developed an ex vivo screening method based on bovine hoof slices and human nails, enabling efficient evaluation of compound nail permeability and antifungal activity.
  2. Structure-Activity Relationship Studies: Through systematic SAR studies, the team successfully optimized the compound structure, ultimately identifying ME1111 as the best candidate.
  3. Mechanism of Action: The team elucidated the mechanism of action of ME1111, providing theoretical support for its clinical application.

Additional Valuable Information

This study was supported by Meiji Seika Pharma Co., Ltd. The research team particularly thanked Dr. Sojiro Shiokawa and Dr. Takeshi Furuuchi for their valuable comments during manuscript preparation, as well as Dr. Takashi Murata for his support in compound instrumental analysis.

Through this research, Meiji Seika Pharma Co., Ltd. not only developed a novel antifungal agent but also provided important technical and methodological support for the future development of antifungal drugs.