Chemoenzymatic Synthesis, Nanotization, and Anti-Aspergillus Activity of Optically Enriched Fluconazole Analogues

Abstract

Despite recent advances in diagnostic and therapeutic methods in antifungal research, aspergillosis still remains a leading cause of morbidity and mortality. One strategy to address this problem is to enhance the activity spectrum of known antifungals, and we now report the first successful application of Candida antarctica lipase (CAL) for the preparation of optically enriched fluconazole analogues. AntiAspergillus activity was observed for an optically enriched derivative, (Ϫ)-S-2-(2=,4=-difluorophenyl)-1-hexyl-amino-3-(1ٞ,2ٞ,4ٞ)triazol-1ٞ-yl-propan-2-ol, which exhibits MIC values of 15.6 g/ml and 7.8 g/disc in broth microdilution and disc diffusion assays, respectively. This compound is tolerated by mammalian erythrocytes and cell lines (A549 and U87) at concentrations of up to 1,000 g/ml. When incorporated into dextran nanoparticles, the novel, optically enriched fluconazole analogue exhibited improved antifungal activity against Aspergillus fumigatus (MIC, 1.63 g/ml).These results not only demonstrate the ability of biocatalytic approaches to yield novel, optically enriched fluconazole derivatives but also suggest that enantiomerically pure fluconazole derivatives, and their nanotized counterparts, exhibiting antiAspergillus activity may have reduced toxicity. KEYWORDS chemoenzymatic synthesis, fluconazole, antifungal agents, AspergillusA spergillosis remains a significant threat to public health, and in spite of continuous efforts to improve timely diagnosis and clinical therapies, mortality caused by this disease remains unacceptably high (1, 2). Current therapeutic options for treating Aspergillus-induced disorders include antifungal agents such as polyenes, azoles, and echinocandins (3, 4). Thus, the discovery of new antifungal compounds remains important given the need to address the development of drug resistance in pathogenic fungi (5-7). One approach to accomplishing this goal is to prepare new derivatives of existing drugs with broad-spectrum activity and enhanced pharmacokinetic properties. As part of our ongoing efforts to use lipases (8-12), which catalyze reactions with high degrees of chemo-, regio-, and stereoselectivity in organic synthesis, we became interested in preparing new antifungals using biocatalysis.Fluconazole, introduced in 1990, is a bis-triazole antifungal drug which possesses

Additive with a tendency to synergy interaction between <i>Citrus aurantium</i> essential oil and fluconazole against <i>Aspergillus niger</i>

“…: Candida, Blastomyces, Epidermophyton spp., Microsporum spp., Trichophyton spp. Flukonazol stosuje się także w profilaktyce zakażeń grzybiczych [10,11].…”

Nanomaterial-Based Antifungal Therapies to Combat Fungal Diseases Aspergillosis, Coccidioidomycosis, Mucormycosis, and Candidiasis

“…These studies suggest that L/C NPs, used as drug delivery systems, are comparable to marketed ophthalmic suspension by showing no differences in antifungal effects. Malhotra et al [117] encapsulated fluconazole analogs in O-alkylated dextran nanoparticles as a drug delivery system to characterize its antifungal effect against A. fumigatus. The analog encapsulated in O-decyl-derivatized NPs inhibited the growth of A. fumigatus at an effective concentration of 3.16 µg/mL.…”

“…ZnONPs Growth inhibition at 20 µg/mL [33] Higher inhibition zone than AmB (resistant strain) [103] 51% growth inhibition at 100 µg/mL [104] Growth inhibition at 26.7 µg/mL [107] SeNPs Growth inhibition at 250 µg/mL [109] Growth inhibition at 100 µg/mL [112] N-Hexa Growth reduction at 10 ppm [114] Natamicyin encapsulated L/C NPs Similar growth inhibition than natamycin [115] AmB encapsulated L/C NPs Growth inhibition at 0.12 µg/mL [116] AmB entrapped lipid NPs Growth inhibition at 0.025 µg/mL [75] AmB loaded PLGA NPs 50% growth inhibition at 0.03 µg/mL [119] AmB-PMA NPs Growth inhibition with 300 µg of AmB [120] AmB leaded PEG NLC Growth inhibition at 1.25 µg/mL [122] Fluconazole encapsulated O-alkylated dextran Growth inhibition at 3.16 µg/mL [117] Natamycin SLNPs Better inhibition zones than natamycin [121] Abbreviations: CChG: Cross-linked chitosan biguanidine; 5FU: 5-fluorouracil; PLA: poly (lactic acid); pMWCNT-CD: polyurethane cyclodextrin co-polymerized phosphorylated multiwalled carbon nanotube; N-Hexa: nanocomposite-containing hexaconazole: L/C: lecithin/chitosan; AmB: amphotericin B; PLGA: poly(D, L-lactide-co-glycolide acid; PMA: polymethacrylic acid; PEG-NLC: polyethylene glycol nanostructures lipid carrier; SLNP: solid lipid nanoparticles.…”

Scalable Preparation of Methylated Ando-Type Horner–Wadsworth–Emmons Reagent

“…As shown in Scheme , α-alkylation of these types of reagents (step 1) followed by an HWE reaction (step 2) will generate trisubstituted Z -α,β-unsaturated systems 3 . These enoates are ubiquitous in synthetic organic chemistry, because they are versatile synthetic intermediates. − …”