The options for treating fungal infections are more limited than those for treating bacterial infections. Amphotericin B has been used for decades to control serious fungal infections, but it exhibits significant nephrotoxicity. Fluconazole has been approved with a high safety profile to treat local and systemic infections, but recent reports point out that the clinical successes of these drugs are declining against yeast, particularly against Candida infection [1].Candida albicans is the leading cause of severe Candida infections, and fluconazole-resistant C. albicansis more prevalent than previously believed [2]. The mechanism of azole resistance is due to reduced intracellular accumulation caused by overexpression of drug efflux pumps Mdr1p and Cdr1p/Cdr2p, as well as the presence of ERG11 point mutations [3]. The annual incidence of Candida infections is estimated at 1.56 million, with 0.99 million deaths [4]. These estimates pose a threat to the antifungal drugs that are currently on the market. The development of potent antifungals is significantly hampered by the fact that fungal cells resemble human cells more than those of other microorganisms, including bacteria [5]. Molecules toxic to fungi are probably toxic to humans, thus, an integrated strategy in antifungal design is essential to combat emerging resistant microorganisms.

Self-assembling amphiphiles have been used to mimic biological systems, such as protein and lipid assembly, and their self-assembly enables them to carry out highly specific cellular functions [6]. Hence, amphiphiles have found a wide range of applications, including the food industry, cosmetics, pharmacy, drug delivery, gene therapy, tissue engineering, and so forth [7]. For example, a hydrogel scaffold made of polymers with an amphiphilic network has been shown to be effective against drug-resistant bacteria and can be used to manage clinical wounds [8]., [9]., [10].. Among the amphiphiles, cationic amphiphiles (CA) have been effective in targeting the negative surface charges of bacterial membranes [11]. Barman et al. have shown that positional isomerization of isoamphipathic compounds has a greater impact on antibacterial activity and toxicity [12]. De et al. found that an amphiphile with two cationic head groups and two tails separated by a distinct hydrophobic spacer had low hematotoxicity but strong antibacterial activity against methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii[13]. Park et al. demonstrated that amphiphiles with lower logP values and a higher hydrophilic-lipophilic balance are easier to incorporate into bacterial cell membranes and display bacteriostatic and/or bactericidal effects [14]. Riahifard et al. showed that cyclic peptides exhibit higher antimicrobial activity than their linear counterparts [15]. The hydrophobicity, main-chain flexibility, and structure of ionenes have been found to influence their hemocompatibility and antibacterial activity [16]. Yuan et al. showed that the antimicrobial activity of ammonium-imidazolium oligomers was influenced by their structural components, such as hydrophobicity, number of charged units, linkers, and ending groups [17]. The findings in the field clearly suggest that the structure of CA has a decisive influence on its activity and biocompatibility. In this context, we synthesized a series of cationic amphiphiles from 2-morpholinoethanol (MEtOH) and evaluated the influence of hydrophilic-lipophilic balance (HLB) in combating C. albicans.

Morpholine and its derivatives have been reported with a number of pharmacological properties, including antifungal, anthelmintic, and bactericidal activity, as well as being identified as a key structural component in the antibacterial drug Linezolid [18]. Wang et al. demonstrated corrosion inhibition and preliminary antibacterial activity from the monomer 4-dodecyl-4-(3-hydroxypropyl)morpholin-4-ium and its Gemini surfactant [19]. The coatings prepared with N-substituted morpholine amine incorporated block polymer showed promising antifouling properties [20]. Quaternary ammonium salts formed by N-alkylation of N-methyl morpholine demonstrated alkyl chain length-dependent antibacterial action against S. aureus, with molecules with long alkyl chains exhibiting high bactericidal activity but being heavily toxic to Artemia salina [21]. Although the morpholine group has shown great promise as a chemical structure for the development of new antimicrobials, its toxicity must be considered during the design process. In this study, we used 2-morpholinoethanol, which has a polar side chain unlikeN-methylmorpholine, and N-alkylated it using alkylbromide to form cationic N-alkylated MEtOH (NAMEtOH). The influence of N-alkyl chain length on NAMEtOH self-assembly was studied using fluorimetry to determine the critical micellar concentration (CMC). The optimal N-alkylation of MEtOH for anticandida activity without damaging mammalian cells was reported by assessing the minimal inhibitory concentration (MIC). Further, the hemolytic concentration (HC) and the mechanism of action against C. albicans were described. The findings reveal that the N18MEtOH is hemocompatible yet effective in damaging C. albicans membranes and inducing ROS accumulation to kill the cells.