Two practical and efficient approaches have been implemented as alternative procedures for the synthesis of naftifine and novel diversely substituted analogues
16 and
20 in good to excellent yields, mediated by Mannich-type reactions as the key step of the processes. In these approaches,
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Two practical and efficient approaches have been implemented as alternative procedures for the synthesis of naftifine and novel diversely substituted analogues
16 and
20 in good to excellent yields, mediated by Mannich-type reactions as the key step of the processes. In these approaches, the γ-aminoalcohols
15 and
19 were obtained as the key intermediates and their subsequent dehydration catalyzed either by Brønsted acids like H
2SO
4 and HCl or Lewis acid like AlCl
3, respectively, led to naftifine, along with the target allylamines
16 and
20. The antifungal assay results showed that intermediates
18 (bearing both a β-aminoketo- and
N-methyl functionalities in their structures) and products
20 were the most active. Particularly, structures
18b, 1
8c, and the allylamine
20c showed the lowest MIC values, in the 0.5–7.8 µg/mL range, against the dermatophytes
Trichophyton rubrum and
Trichophyton mentagrophytes. Interesting enough, compound
18b bearing a 4-Br as the substituent of the phenyl ring, also displayed high activity against
Candida albicans and
Cryptococcus neoformans with MIC
80 = 7.8 µg/mL, being fungicide rather than fungistatic with a relevant MFC value = 15.6 µg/mL against
C. neoformans.
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