Design of Two Alternative Routes for the Synthesis of Naftifine and Analogues as Potential Antifungal Agents.

Two practical and efficient approaches have been implemented as alternative procedures for the synthesis of naftifine and novel diversely substituted analogues and in good to excellent yields, mediated by Mannich-type reactions as the key step of the processes. In these approaches, the γ-aminoalcohols and were obtained as the key intermediates and their subsequent dehydration catalyzed either by Brønsted acids like H₂SO₄ and HCl or Lewis acid like AlCl₃, respectively, led to naftifine, along with the target allylamines and . The antifungal assay results showed that intermediates (bearing both a β-aminoketo- and -methyl functionalities in their structures) and products were the most active. Particularly, structures , 1, and the allylamine showed the lowest MIC values, in the 0.5-7.8 µg/mL range, against the dermatophytes and . Interesting enough, compound bearing a 4-Br as the substituent of the phenyl ring, also displayed high activity against and with MIC = 7.8 µg/mL, being fungicide rather than fungistatic with a relevant MFC value = 15.6 µg/mL against .