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Reviews in Analytical Chemistry 2021; 40: 220–252 Review Article Giovanni D’Orazio*, Chiara Fanali, Chiara Dal Bosco, Alessandra Gentili, and Salvatore Fanali* Chiral separation and analysis of antifungal drugs by chromatographic and electromigration techniques: Results achieved in 2010–2020 https://doi.org/10.1515/revac-2021-0136 received December 16, 2020; accepted May 25, 2021 1 Introduction Abstract: The determination and separation of enantio- Antifungal substances were discovered almost 80 years mers is an interesting and important topic of research in ago by D. W. Woolley. Since 1958, chlormidazole was the fi - various elds, e.g., biochemistry, food science, pharma first specific drug that was commercialized in medical - ceutical industry, environment, etc. Although these com practice for topical application [1]. pounds possess identical physicochemical properties, a Fungal infections have emerged in the past 40 years ff pair of enantiomers often has di erent pharmacological, and are becoming a major public health alarming dis- toxicological, and metabolic activities. For this reason, ease. The increasing rate of invasive fungal infections - chiral discrimination by using chromatographic and electro [2,3] is due to the increased incidence of the immune- migration techniques has become an urgent need in the compromised patient population, including the rising pharmaceutical field. This review intends to offer the number of acquired immunodeficiency for the advent of “state of the art” about the separation of chiral antifungal HIV, cancer patients with chemotherapy, organ trans- drugs and several related precursors by both liquid and plant recipients receiving immunosuppressive therapy, gas chromatography, as well as electromigration methods. on the one hand; the increasing number of invasive This overview is organized into two sections. The first one devices (catheters, artificial joints, and valves), on the describes general considerations on chiral antifungal drugs. other hand. The second part deals with the main analytical methods for The azoles compounds are important synthetic medi- the enantiomeric discrimination of these drugs, including a cinal products so named for the presence of an imidazole brief description of chiral selectors and stationary phases. or triazole moiety in the molecule. They are well-known Moreover, many recent applications attesting the great due to their quite extensive potent activities towards interest of analytical chemists in the field of enantiomeric many pathogenic fungi. In addition, some of them exhibit separation are presented. additional antibacterial and antiparasitic properties. Keywords: antifungal drugs, chiral separation, electro- Thealmostacceptedactionmodeofazolecompounds migration methods, nano-LC, HPLC, SFC relies on the inhibition of Lanosterol 14α-demethylase (CYP51A1), a key enzyme in the ergosterol biosynthesis. The latter is a fundamental component of the plasma mem- brane structure and its depletion causes a weakening of the membrane. This is related both to the consequent change in theactivityofmanymembrane-bound enzymes associated * Corresponding author: Giovanni D’Orazio, Istituto per i Sistemi with nutrient transport and chitin synthesis and to the Biologici (ISB), CNR – Consiglio Nazionale delle Ricerche, α- - Monterotondo, 00015 Rome, Italy, e-mail: [email protected] accumulation of toxic 14 methylated sterols in mem * Corresponding author: Salvatore Fanali, Teaching Committee of branes [4,5]. Ph.D. School in Natural Science and Engineering, University of A great part of active substances, belonging to imi- Verona, Verona, Italy, e-mail: [email protected] dazole and triazole derivatives, shows optical isomerism, - Chiara Fanali: Faculty of Science, University Campus Bio Medico of like more than half of drugs on the market [6]. Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy Chiara Dal Bosco, Alessandra Gentili: Department of Chemistry, The enantiomers of the same molecule have identical University of Rome “La Sapienza“, Piazzale Aldo Moro 5, P. O. Box physical and chemical properties in an achiral environ- 34, Posta 62, 0018 Roma, Italy ment (e.g., air–water exchange, abiotic absorption, and Open Access. © 2021 Giovanni D’Orazio et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 International License. Chiral separation of antifungal drugs 221 transformation), but they enantioselectively interact with organisms and they can act as biological markers of envir- biological systems, e.g., enzymes, proteins, receptors, onmental toxicity: for example, (2R,4S)-propiconazole and other chiral molecules [7]. In this frame, the pharma- exhibited 2.43–23.47-fold higher fungicidal activity toward cological activity may also be related to just one enantiomer, Rhizoctoniasolani,Fulviafulva,Alternariasonali,and being the other one inactive or even toxic. Consequently, Botrytis cinerea than (2S,4S)-propiconazole [16].Asimilar enantiomers may have different pharmacokinetic processes trend was observed for (2R,4S)-difenoconazole, whose fun- as well as therapeutic effects. gicidal activity against Botrytis cinerea is about 24.2 times Although antifungal drugs, such as imidazole and higher than that of its (2S,4S)-stereoisomer [15]. triazole derivatives, are present as racemic mixtures in Although a different effect of drug enantiomers in medicinal products, a lot of applications demonstrated pharmaceutical and agrochemical applications is demon- different biological effects of each enantiomer. For instance, strated, the racemic form is still currently available on a bacteriostatic test indicated that R-(−)-fenticonazole shows the markets of both medical products and plant treat- the minimum inhibitory concentration (MIC) of the anti- ments. Furthermore, it is estimated that about 50–75% fungal effects [8] and (+)-(S)-fenticonazole exhibited a faster of racemic pesticide emissions are unnecessary and cause absorption and elimination in female rats than did (−)-(R)- environmental pollution [17]. To reduce the risks of side fenticonazole [9]. Although the genaconazole is adminis- effects or unspecific toxicities derived from the adminis- tered as a racemate, only RR form is the active enantiomer tration of the no-active enantiomer, the new trend of the while SS-form is the inactive one. The concentration trend industrial sector is focused on the preparation of enantio- for a time in human serum does not show appreciable dif- merically pure compounds: in this way, the same effect ferences [10]. R enantiomer of azole compounds, such as would be produced by half the dose of the racemic form. fluconazole, genaconazole, itraconazole, posaconazole, In this frame, the development of analytical methodolo- ravuconazole, voriconazole, and sertaconazole, is two times gies for the chiral separation and determination of single- more active than the S-form, which is considered inactive enantiomer forms and their impurities is highly required. [11]; (−) enantiomer of ketokonazole is more potent against In doing this, pharmacokinetics and pharmacodynamics some strains of fungi [12] since, as demonstrated after studies (including absorption, distribution, metabolism, administration of rac-ketoconazole to rats, the concentra- and excretion) are needed, for both pharmaceutical and tion of (+)-ketoconazole in plasma was two-fold higher environmental (agrochemical) applications. The determi- than that of (−)-ketoconazole [13]. nation of a racemic antifungals in biological fluids of In recent years, due to their excellent antifungal humans or animals treated with one dose of drug can activity and a relatively low environmental persistence, be useful to investigate the dose/effect relationship during triazole fungicides have also become an important cate- a therapeutic drug monitoring (TDM): this information can gory of fungicides with wide applicability in agriculture. guide the physician in optimizing the appropriate dose. In this respect, this molecules family, considered as pes- Through studies of the enantioselective behavior of ticides, was introduced for the treatment and protection chiral pesticides in agri-food products or in the environ- of plants, such as cereals, soybeans, fruits, and vegeta- ment, the absorption, transformation, and degradation bles since the mid-1970s. processes in various plants, soil, water, and aquatic life As above reported, it is known that most of the tria- are generally also evaluated. Thus, a better knowledge zole fungicides/pesticides used as a pharmaceutical drug of individual degradation or toxicological data of each are chiral, like approximately 30% of anthropogenic enantiomer could reduce the amount of pesticide avoiding agrochemicals. Moreover, their optical isomers exhibit unnecessary stereoisomer and be useful to evaluate the different bioactivity, toxicity, and degradation in the environmental risk and food safety. environment. For instance, the R-enantiomer of dinico- This article reports an overview of both recent HPLC nazole and uniconazole shows stronger fungicidal activi- and CE (coveringtheliteraturesince2010) and an as ties, whereas the S-enantiomer has higher plant growth exhaustive as possible review of GC, SFC, and miniaturized regulating activity [14]; the degradation of the difenocona- liquid chromatographic applications for chiral separations zole stereoisomers also showed stereoselectivity in vegeta- of antimycotic drugs. The effect of chromatographic/electro- bles and soil [15]. phoretic experimental