Candida yeasts are the primary cause of invasive fungal infections, which are among the most severe fungal diseases since they have the potential to invade critical organs, including the heart, brain, and blood stream. A major therapeutic challenge lies in the growing tolerance of fungi to existing antifungal treatments, leading to reduced treatment efficacy [1]. The global incidence of invasive candidiasis (IC) is estimated at 1.57 million cases annually, resulting in approximately 995,000 deaths each year [2]. Among the diverse Candida species, Candida albicans is the predominant etiological agent of various forms of candidiasis and has been closely associated with nosocomial infections that exhibit high mortality rates [1], [3]. The increasing prevalence of these infections underscores the need for innovative therapeutic strategies that address antifungal resistance and maintain microbial balance [4].

The current antifungal therapy for Candida albicans infections encompasses several major drug classes. One class is the azoles, which include fluconazole, itraconazole, voriconazole, and posaconazole. These drugs inhibit the lanosterol 14α-demethylase enzyme, thereby blocking ergosterol biosynthesis. However, they face challenges such as resistance, hepatotoxicity, and poor solubility [5]; echinocandins (caspofungin, micafungin, and anidulafungin), which inhibit β-(1,3)-D-glucan synthase enzyme and compromise cell wall integrity. Unfortunately, they require intravenous administration and have limited tissue penetration [6]; (amphotericin B and nystatin), which bind ergosterol and cause membrane disruption yet are hampered by nephrotoxicity, infusion reactions, and formulation difficulties [7]. Other antifungal agents such as tolnaftate, a topical thiocarbamate derivative, that is effective against dermatophytes, but has negligible activity against Candida and is not applicable systemically [8]. Despite their utility, all classes exhibit limitations in potency, formulation, toxicity, or physicochemical properties, reinforcing the urgent need for novel antifungal agents with broader activity, improved safety, and enhanced delivery profiles. Furthermore, antifungal drugs often disrupt the protective role of the natural microbial flora, thereby exacerbating the risk of uncontrolled fungal proliferation [1].

Phenylpiperazine derivatives have gained significant attention as promising agents in the battle against microbial infections due to their notable antimicrobial properties [9]. These compounds demonstrate mechanisms of action that may effectively counteract fungal resistance pathways, positioning them as potential candidates for combating Candida-related infections. Their structural versatility facilitates optimization to enhance antifungal efficacy while minimizing adverse impacts on the host microbial flora [10], [11]. As a result, phenylpiperazine derivatives represent a valuable avenue for advancing antifungal therapies and improving clinical outcomes for patients affected by candidiasis [11].

Another promising area of innovation involves hydrogen sulphide, an endogenously produced gaseous signaling molecule with emerging antimicrobial potential. Hydrogen sulfide (H₂S) is a colorless gas with a distinctive odor similar to that of rotten eggs under standard temperature and pressure conditions [12]. While historically classified as a toxic compound, H₂S has more recently been recognized as an endogenous gaseous signaling molecule [13]. It represents the third member of the gasotransmitter family, alongside nitric oxide (NO) and carbon monoxide (CO) [14]. H₂S participates in numerous physiological and pathophysiological processes, primarily through mechanisms involving redox-dependent signaling pathways [15]. In mammalian systems, hydrogen sulfide (H₂S) is enzymatically synthesized by three primary enzymes, each exhibiting tissue-specific expression: cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (MPST) [13].

C. albicans is capable of producing H2S endogenously, which may regulate morphogenesis, biofilm development, and stress responses [16]. On the other hand, administered H2S, especially from synthetic donors, can exert inhibitory effects on fungal growth and virulence in a concentration-dependent manner [17], [18]. H2S can interfere with bacterial metabolism, particularly by targeting respiratory enzymes in microbial cells [19], [20]. It can modulate oxidative stress in bacteria, leading to cellular dysfunction and growth inhibition.

Furthermore, sulfur-containing organic compounds play a crucial role in the development of synthetic drugs, often serving as versatile and widely recognized “privileged scaffolds”. Among these, carbodithioates (dithiocarbamates) have garnered significant attention not only for their unique chemical properties and diverse applications, but also for their ability to act as H2S donors [21]. Importantly, dithiocarbamates have demonstrated significant biological activities, including antibacterial [22], antihistaminic [23], antiviral [24], anti-inflammatory [25], antioxidant [26], antifungal [27] and antitumor activities [28].

For example, compound I, which incorporates an N-(chlorobenzyl)piperazine carbodithioate moiety, was designed and synthesized as a potential antifungal agent [29]. In vitro bioassays against various Candida species, including C. albicans, C. parapsilosis, C. glabrata, C. tropicalis, and C. krusei, revealed that compound I exhibited the greatest antifungal potency, with MIC values ranging from 0.063 μg/mL to 0.5 μg/mL. Notably, compound I displayed activity 4 to 32 times higher than that of the reference antifungal, fluconazole.

Moreover, compound II, a newly synthesized kojic acid–phenylpiperazine hybrid incorporating a dithiocarbamate linker, was designed and synthesized as part of an effort to combat microbial resistance through multi-target mechanisms [30]. Its biological activity was also evaluated. Compound II exhibited the most pronounced antifungal activity against Candida albicans, with an MIC value of 64 μg/mL and an inhibition zone diameter of 14–15 mm.

These attributes have made the synthesis of dithiocarbamates a prominent focus of contemporary research, particularly for the development of novel antifungal agents, Fig. 1. [22].

Moreover; poor aqueous solubility remains a major challenge in drug development, as it often limits absorption and bioavailability of many therapeutic agents [31]. Among various nanocarrier systems, niosomes, which are vesicular carriers composed of non-ionic surfactants and cholesterol, have gained attention for improving drug solubility, stability, and controlled release characteristics [32], [33]. Modification of niosomal surfaces with polyethylene glycol (PEG) provides steric stabilization, reduces aggregation, and prolongs systemic circulation time, thereby enhancing formulation performance [34], [35]. PEG-Niosomes have been shown to improve entrapment efficiency, sustain drug release, and enhance pharmacokinetic behaviour compared with conventional niosomes [36], [37].

The objective of this study is to overcome the previous limitations associated with current antifungal therapies. The present work focuses on the exploration of novel antifungal scaffolds, particularly phenylpiperazine derivatives and sulfur-containing frameworks such as carbodithioates (Fig. 2), which demonstrate potential for improved antifungal performance. The study aims to design and develop tolnaftate-inspired agents that retain the essential pharmacophore of the reference drug, while incorporating strategic structural modifications to enhance target interactions and optimize physicochemical properties to achieve superior antifungal efficacy. In the proposed scaffold, the parent thiocarbamate moiety (N–C(=S)–O) of tolnaftate is replaced with a dithiocarbamate bioisostere (N–C(=S)–S). This transformation enables the dithiocarbamate scaffold to engage in π–sulfur interactions in the binding pocket. Furthermore, a phenylpiperazine ring system acts as a conformational spacer, providing the optimal orientation required for pharmacophore expression. (Fig. 2).

To further optimize therapeutic efficacy, the synthesized compounds are formulated as PEG-Niosomes which can enhance the dissolution of the poorly synthesized compounds [38], ensure controlled drug release [39], improve skin penetration, and increase local drug retention at the site of infection [40]. Such formulation strategies not only address solubility and bioavailability challenges associated with many conventional antifungals but also offer a promising platform for targeted and sustained antifungal delivery, potentially overcoming the limitations of existing therapies. The optimized formulation was characterized for particle size, zeta potential, morphology, and in-vitro release using Franz diffusion cells to assess its potential as an efficient nanocarrier system.

Unlike previous studies that focus on the direct fungicidal activity of dithiocarbamate-based antifungals, the present study introduces phenylpiperazine/dithiocarbamate hybrids as dual-function agents. These compounds not only exhibit potent antifungal activity against Candida albicans but also act as cysteine-triggered hydrogen sulfide donors, thereby targeting both fungal growth and virulence factors such as hyphal transition and biofilm formation. Furthermore, the tolnaftate-inspired design, combined with nanoparticle formulation, provides an innovative scaffold that has enhanced solubility, delivery, and multi-target activity compared to earlier dithiocarbamate derivatives.