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

Abstract

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 H2SO4 and HCl or Lewis acid like AlCl3, 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, 18c, 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 MIC80 = 7.8 µg/mL, being fungicide rather than fungistatic with a relevant MFC value = 15.6 µg/mL against C. neoformans.

Visualisation of penetration of topical antifungal drug substances through mycosis‐infected nails by matrix‐assisted laser desorption ionisation mass spectrometry imaging

“…Antifungal nail lacquers, such as Loceryl ® and Ciclopoli ® used in this study, have been described to be the most suitable topical formulation to treat onychomycosis, 11 providing longer permanence of the formulation to the nail, which allows continuous release of the active agent, enhancing the penetration of the drug 12 . Topical antifungal solutions are also available, such as naftifine hydrochloride 1%, which can be effectively used against a broad spectrum of dermatophyte fungi of Trichophyton spp, which includes the Trichophyton rubrum , that can cause onychomycosis infections 13,14 …”

“…12 Topical antifungal solutions are also available, such as naftifine hydrochloride 1%, which can be effectively used against a broad spectrum of dermatophyte fungi of Trichophyton spp, which includes the Trichophyton rubrum, that can cause onychomycosis infections. 13,14 Molecular penetration of compounds into infected human nail plate has been investigated with the use of different approaches. 12,15,16 However, to the best of our knowledge, this is the first reported study where MALDI-MSI is applied to assess the spatial distribution of pharmaceutical compounds in nails.…”

Recent Applications of the Multicomponent Synthesis for Bioactive Pyrazole Derivatives

“…Moreover, the use of standard antifungal therapies has been limited due to problems of toxicity, low efficacy rates, and resistance to antifungal drugs [ 117 ]. These reasons have given rise to the design and production of new chemical libraries of aza-heterocycles with distinct action or multitargeted combination therapy [ 116 , 117 , 118 , 119 ]. In this way, several pyrazole-containing pyrimidines 52 , 1,4-dihydropyridines 53 , and imidazoles 54 were prepared via multicomponent synthetic approaches and discussed in Section 2.1 .…”

Styryl Group, a Friend or Foe in Medicinal Chemistry

“…We further exemplify the synthetic approaches for styryl group introduction using the FDA-approved drug, naftifine (1, exoderil®, Figure 2b). The key approaches that were followed in naftifine synthesis are the Heck arylation, [22] Grignard reaction, [23] boronic acid Mannich reaction, [24] a combination of Mannich-and aza-Pris reaction, [25] and using in-built styryl group bearing precursors (Figure 2b). [26] The styryl group has shown remarkable utility in the drug discovery arena and is a common moiety in FDA-approved drugs.…”