Description
Tavaborole (Kerydin®), discovered and developed by Anacor,
was approved by the US FDA in July 2014. Tavaborole, topical
solution, 5% is an oxaborole antifungal indicated for the treatment
of onychomycosis of the toenails due to Trichophyton rubrum or
Trichophyton mentagrophytes. The mechanism of action of tavaborole is inhibition of fungal protein synthesis, which inhibits
an aminoacyl-transfer ribonucleic acid synthetase.
Uses
Tavaborole is a topical treatment of toenail onychomycosis.
Definition
ChEBI: A member of the class of benzoxaboroles that is 1,3-dihydro-1-hydroxy-2,1-benzoxaborole substituted at position 5 by a fluoro group. A topical antifungal agent used for the treatment of onychomycosis (fungal infection of the toenails and fingernails).
General Description
Tavaborole is a boron-based pharmaceutical agent. It has broad-spectrum oxaborole antifungal activity. Due to its low molecular weight, it facilitates maximal nail plate penetration than its predecessors.
Biochem/physiol Actions
Tavaborole (AN2690) is a potent antifungal that targets the post-transfer editing site of leucyl-tRNA synthetase (LeuRS). Tavaborole forms a covalent adduct with the 3′ adenosine of tRNA(leu) at the editing site of fungal, but not bacterial LeuRS, locking the enzyme in an inactive conformation. Tavaborole was recently approved for the treatment of onychomycosis of the toenail in adults.
Synthesis
Three syntheses of tavaborole (XXXII) have been
reported. The 26.9 g scale approach started
with 2-bromo-5-fluorophenyl methanol (257), which was treated
with ethyl vinyl ether (258) to produce o-bromobenzyl alcohol
derivative 259 in 82% yield. 259 was then converted into the
corresponding phenylboronic acid, followed by the one-pot deprotection and spontaneous cyclization upon treatment with
6 M hydrochloric acid, delivering tavaborole (XXXII) in 43%
yield.
in vitro
an2690 showed the most active against fungi and especially against the dermatophytes t. rubrum and t. mentagrophytes, the primary fungal pathogens causing onychomycosis. in addition, an2690 was identified as having a unique profile of in vitro antidermatophyte activity, maintenance of this activity in the presence of keratin, and exceedingly good penetration of human nails [1].
target
Trichophyton species
References
[1] baker sj, zhang yk, akama t, lau a, zhou h, hernandez v, mao w, alley mr, sanders v, plattner jj. discovery of a new boron-containing antifungal agent, 5-fluoro-1,3-dihydro-1-hydroxy-2,1- benzoxaborole (an2690), for the potential treatment of onychomycosis. j med chem. 2006;49(15):4447-50.
[2] hui x, baker sj, wester rc, barbadillo s, cashmore ak, sanders v, hold km, akama t, zhang yk, plattner jj, maibach hi. in vitro penetration of a novel oxaborole antifungal (an2690) into the human nail plate. j pharm sci. 2007;96(10):2622-31.
[3] markham a. tavaborole: first global approval. drugs. 2014;74(13):1555-8.
