Research Article: The solid-state conformation of the topical anti­fungal agent O-naphthalen-2-yl N-methyl-N-(3-methyl­phen­yl)carbamo­thio­ate

Date Published: November 01, 2018

Publisher: International Union of Crystallography

Author(s): Douglas M. Ho, Michael J. Zdilla.


Large flat colorless needles of tolnaftate have been obtained from Tinactin, and have been shown to contain a 50:50 mixture of the (+ap,−sp,+ac,−ac) and (−ap,+sp,−ac,+ac) conformers. This finding fills a long-standing void in the structural chemistry of this classic anti­fungal compound, and suggests that prior theoretical models used to explain the spectroscopy, bioactivity, and mode of binding of tolnaftate to squalene epoxidase are probably inappropriate or suspect.

Partial Text

O-Naphthalen-2-yl N-methyl-N-(3-methyl­phen­yl)carbamo­thi­o­ate, (I), is a synthetic thio­carbamate from the 1960s with anti­mycotic activity (Noguchi et al., 1961 ▸, 1963 ▸). It is perhaps most readily recognized by the generic name tolnaftate and is primarily used to treat fungal skin infections, such as athlete’s foot (tinea pedis), jock itch (tinea cruris), and ringworm (tinea capitis and tinea corporis). Tolnaftate is a squalene epoxidase inhibitor used to disrupt the biosynthesis of ergosterol, resulting in a toxic accumulation of squalene and ultimately fungal cell death (Morita & Nozawa, 1985 ▸; Ryder et al., 1986 ▸; Barrett-Bee et al., 1986 ▸). It was launched for human use in 1965 by Schering Corporation as the active pharmaceutical ingredient (API) in Tinactin (Sittig, 1988 ▸). Schering Corporation subsequently merged with Plough in 1971 and Merck in 2009. Today, Tinactin is marketed by Bayer which acquired Merck’s consumer care products in 2014. Tolnaftate is present in numerous anti­fungal products worldwide either as the sole active ingredient or in combination with one or more other APIs.

Some readers may have already surmised from §1 and §2.1, that this study is a spin-off from a STEM outreach project for informal chemical and crystallographic education, i.e. for grades 6–12 pre-college students, homeschoolers, hobbyists, and amateur scientists. Chemistry is often introduced to this audience in the digestible and relatable form of common mol­ecules and common household chemicals. One of the design criteria for our outreach project was to base it on a less commonly recognized common mol­ecule. We believe that tolnaftate fits that criterion. It has been found in numerous households for over 50 years, yet most individuals have no notion of its structural identity and make-up. Another design criterion was cost, i.e. the chemical source was required to be relatively inexpensive and readily available to the targeted audience. The Bayer Tinactin Liquid Spray used in this study was purchased from a retail store for less than 6 US dollars. Other generic sprays can also be purchased for 3–4 US dollars. A single can of Tinactin can provide 2 ml aliquots for a class of roughly 75 students at a cost of 8 cents per student (or 150 students at 4 cents per student, if they work in pairs). We hope that the results and discussion provided below will be educational and simulating for those inter­ested in STEM, and meaningful and entertaining for our academic and industrial colleagues as well.

The take-home message for amateur scientists and science enthusiasts is that opportunities for scientific adventures and discoveries in a home setting do indeed exist and may even be publishable. All of the wet chemistry presented in this paper were done in a common household kitchen and all of the structure solution, refinement, and manuscript preparation were carried out with readily available freeware using public computers in local libraries. Exploring science in the 21st Century can be that simple. Also, be willing to investigate opportunities at local colleges and universities where specialized equipment like an X-ray diffractometer might be available through various outreach programs. Adult supervision and guidance are, of course, encouraged for any projects involving minors or other pre-college individuals.