• Dioxo-[14]aneN3S: a novel macrocyclic compound with antifungal activity against Candida genus

Invasive candidiasis is a major global health concern due to both the lack of effective systemic antifungals with low drawbacks and the increasing number of multi-drug resistant yeasts. Macrocyclic compounds, which tend to show highly favourable drug-like proprieties, have been identified as key-points in the correct functioning of a variety of fundamental biological systems. Thus, in the last years, macrocyclic scaffold-based pharmaceuticals have been developed for a diversity of medical applications. In this work, a novel macrocycle with in vitro activity against the Candida genus was synthesised and studied.

Dioxo-[14]aneN₃S (1-thia-4,8,12-triazacyclotetradecane-3,13-dione) was synthesised by reacting dimethyl thiodiglycolate with dipropylenetriamine in dry methanol at 40 ºC under nitrogen atmosphere for 7 days (η ≈ 77%). This procedure was based on Tabushi’s method for macrocyclization, to which some improvements were introduced. These upgrades increased the reaction yield by fourfold compared to other compounds obtained by the non-modified methodology. Structural characterisation and purity determination were achieved by FT-IR, 1D/2D NMR and ESI-MS techniques. The acid-base behaviour of dioxo-[14]aneN₃S in aqueous solution was studied by potentiometry and ¹H NMR spectroscopy. Despite this compound has three ionisable centres, only one protonation constant (log⁡ K₁^H = 9.43) was found under the adopted experimental conditions. For pH values below 8, the ionised species (HL⁺) is the major form of the macrocycle. Thus, according to the pH-partition hypothesis, dioxo-[14]aneN₃S has unfavourable characteristics for oral administration, but favourable acid-base behaviour for parenteral formulation.

The antifungal activity of dioxo-[14]aneN₃S was evaluated in vitro against several clinical isolates of multi-drug resistant Candida yeasts by broth microdilution method, according to the CLSI M27-A3 international guidelines. Compared to the reference antifungal fluconazole, dioxo-[14]aneN₃S shows higher activity, indicating that it has the potential to be developed as a promising antifungal agent.