Griseofulvin

Genetic Regulation of Griseofulvin Biosynthesis

The biosynthesis of this compound is subject to genetic regulation, involving transcriptional regulators and signaling pathways. ontosight.ai Within the gsf gene cluster, two putative transcription factors, gsfR1 and gsfR2, have been identified, although their precise functions have been a subject of investigation. nih.govnih.govmdpi.com Studies involving gene deletions have provided insights into their roles. For instance, deletion of the gsfR1 gene in P. griseofulvum has been shown to increase this compound biosynthesis by enhancing the expression of the gsfA gene under certain conditions, suggesting gsfR1 can act as a negative regulator. nih.govresearchgate.net However, under different culture conditions, such as high concentrations of nitrogen and complex sugars or media supplemented with peptone, gsfR1 appears to positively regulate this compound biosynthesis, indicating its response can vary depending on external stimuli, particularly the availability of carbon and nitrogen. nih.govresearchgate.net The gsfR2 gene, in contrast, may be involved in different metabolic pathways. nih.govmdpi.com The promoter region of gsfR1 suggests regulation by global regulators responsive to environmental cues like carbon and nitrogen availability. nih.govresearchgate.net

Genetic Engineering Approaches in Producer Fungi

Disruption of Fungal Microtubule Function and Mitosis

A key mechanism by which this compound exerts its fungistatic effect is by targeting fungal microtubules, essential components of the cytoskeleton involved in various cellular processes, including cell division. drugbank.commsdvetmanual.compatsnap.com By interfering with microtubule function, this compound disrupts the formation and operation of the mitotic spindle, which is crucial for chromosome segregation during mitosis. msdvetmanual.compatsnap.com This disruption ultimately leads to the inhibition of fungal cell division. patsnap.com The biological activity of this compound towards fungi is characterized by nuclear and mitotic abnormalities, followed by distortions in hyphal morphology. nih.govdroracle.ai

Binding to Alpha and Beta Tubulin

This compound is understood to bind to tubulin, the protein subunit that polymerizes to form microtubules. drugbank.compatsnap.com Specifically, it is thought to bind to both alpha and beta tubulin subunits. drugbank.commdpi.com Studies have suggested potential binding sites for this compound in tubulin, including one that may overlap with the binding site of paclitaxel and another located at the interface of alpha and beta tubulin. mdpi.commdpi.com This binding interferes with the normal function of microtubules. wikipedia.orgmdpi.com

Inhibition of Spindle Microtubule Dynamics and Polymerization

This compound inhibits microtubule polymerization, particularly affecting the dynamics of spindle microtubules. patsnap.commdpi.comaacrjournals.org While high concentrations of this compound (>100 µM) may be required to inhibit microtubule polymerization in vitro, lower concentrations (1-20 µM) have been shown to strongly suppress the dynamic instability of microtubules. droracle.aipnas.orgpnas.orgnih.govnih.gov This suppression of dynamic instability, which is vital for spindle assembly and function, is considered a primary mechanism by which this compound inhibits mitosis. mdpi.compnas.orgpnas.org The drug acts directly at the plus ends of microtubules, increasing their stability and suppressing their shortening rate. mdpi.com

Induction of Mitotic Arrest at Metaphase

The disruption of spindle microtubule function by this compound leads to the arrest of fungal cell division at the metaphase stage of mitosis. drugbank.comdroracle.aipnas.org This occurs because the proper formation and function of the mitotic spindle are necessary for chromosomes to align correctly at the metaphase plate and subsequently segregate into daughter cells. patsnap.com By interfering with these processes, this compound prevents the cell from progressing through mitosis, resulting in mitotic arrest and inhibition of fungal growth. drugbank.comdroracle.aipnas.org Cytological effects observed in various cell systems treated with this compound include C-mitoses, multipolar mitoses, and multinuclearity. nih.govdroracle.ai

Inhibition of Nucleic Acid Synthesis

Beyond its effects on microtubules, this compound is also thought to inhibit nucleic acid synthesis in fungi. drugbank.commsdvetmanual.comdroracle.ai Research has indicated that during growth inhibition, this compound can temporarily halt the net synthesis of nucleic acids and decrease the incorporation of precursors like uridine and thymidine into fungal nucleic acids. nih.gov This interference with DNA and RNA synthesis further contributes to its fungistatic activity. msdvetmanual.compatsnap.com

Antitumor Mechanisms of Action

This compound has demonstrated significant antitumor activity against a variety of cancer cell types, including cervical cancer, breast cancer, non-small-cell lung cancer, colorectal cancer, and adrenocortical cancer. frontiersin.orgnih.gov Its antitumor effects are mediated through several key mechanisms that target the fundamental processes of cancer cell growth and division. frontiersin.orgnih.gov

Inhibition of Cancer Cell Division and Proliferation

This compound inhibits the proliferation of various tumor cells by affecting the function of spindle microtubules during mitosis. frontiersin.orgnih.gov This inhibition of cell division contributes significantly to its antitumor effects. Studies have shown that this compound can inhibit the proliferation of cancer cells from lung, colorectal, breast, cervical, and liver tissues. frontiersin.orgnih.gov The concentrations of this compound necessary for the inhibition of cell proliferation are similar to those required for the induction of multipolar spindles and mitotic arrest. aacrjournals.org

Induction of Mitotic Arrest and Cell Death in Cancer Cells

A key antitumor mechanism of this compound involves the induction of mitotic arrest, primarily at the G2/M phase of the cell cycle, and subsequent cell death in cancer cells. frontiersin.orgiiarjournals.orgnih.govekb.eg This arrest is associated with various mitotic abnormalities, such as misaligned chromosomes and the formation of multipolar spindles. ekb.egresearchgate.net Studies have shown that this compound induces G2/M phase arrest in a dose-dependent manner in certain cancer cell lines. frontiersin.org The mechanisms underlying this compound-induced G2/M arrest include the induction of abnormal mitotic spindle formation, elevation of cyclin B1/cdc2 kinase activity, and down-regulation of myt-1 protein expression. iiarjournals.orgnih.gov Following mitotic arrest, this compound can induce apoptosis, a form of programmed cell death, in various tumor cells. frontiersin.orgnih.goviiarjournals.org Mechanisms of this compound-induced apoptosis include caspase 3 activation, Bcl-2 hyperphosphorylation, and inhibition of the normal function of Bcl-2 associated with Bax. iiarjournals.orgnih.gov this compound has been shown to induce apoptosis in colorectal cancer cells by increasing the expression of caspase-3, PARP, and Bax, while decreasing Bcl-2 protein expression. frontiersin.org In human testicular germ cell tumor cells, this compound can induce apoptosis by activating the expression of Cx43, caspase-9, and caspase-3. frontiersin.org

Table 1: Effects of this compound on Cell Cycle and Apoptosis in Cancer Cells

Interaction with Mitotic Spindle Microtubules in Cancer Cells

This compound exerts its antitumor effects, in part, by interacting with mitotic spindle microtubules. frontiersin.orgekb.egresearchgate.netmdpi.com It is known to disrupt cell microtubule dynamics and cause cell death in cancer cells through binding to tubulin protein. mdpi.com While high concentrations (>100 μM) of this compound may be required to inhibit microtubule polymerization in vitro, much lower concentrations (1-20 μM) can effectively suppress the dynamic instability of microtubules. iiarjournals.orgpnas.orgnih.gov This suppression of spindle microtubule dynamics is considered a primary mechanism by which this compound inhibits mitosis in human cells, similar to the actions of other antimitotic drugs like vinca alkaloids and taxanes. iiarjournals.orgpnas.orgnih.govnih.gov this compound has been suggested to bind to tubulin at sites that overlap with the binding site of paclitaxel or within microtubule dimers. frontiersin.orgresearchgate.netnih.gov

Inhibition of Centrosomal Clustering

Many tumor cells contain supernumerary centrosomes, which can lead to the formation of multipolar mitotic spindles and chromosome segregation defects. To maintain mitotic stability, these multiple centrosomes often cluster into two functional spindle poles. aacrjournals.orgnih.govacs.org this compound has been identified as an inhibitor of this centrosomal clustering in cancer cells. aacrjournals.orgnih.govaacrjournals.orgfocusbiomolecules.com By inhibiting centrosome coalescence, this compound forces tumor cells with supernumerary centrosomes to undergo multipolar mitoses, which subsequently leads to apoptosis. aacrjournals.orgnih.govaacrjournals.orgfocusbiomolecules.com This inhibition of centrosomal clustering by this compound is not limited to mitotic cells but can also occur during interphase. aacrjournals.orgnih.gov The mechanism may involve the disruption of the interphase microtubule network. aacrjournals.org

Activation of Tumor Suppressor Protein p53

This compound has been shown to activate the tumor suppressor protein p53. aacrjournals.orgekb.egnih.govbohrium.com Activated p53 plays a critical role in the cellular response to stress, including DNA damage and oncogene activation, by inducing cell cycle arrest or apoptosis. wikipedia.orgcusabio.comyoutube.com Increased p53 accumulation in the nucleus of cancer cells treated with this compound has been observed, indicating that these cells are undergoing apoptosis. ekb.egresearchgate.netresearchgate.netmdpi.com The activation of p53 by this compound contributes to its ability to induce mitotic arrest and subsequent cell death in cancer cells. aacrjournals.orgekb.egnih.govbohrium.com

Activation of Wnt Pathway in Myeloma

Exaggerated Wnt/β-catenin signaling has been observed in lymphoma and multiple myeloma (MM), suggesting that targeting this pathway could be a therapeutic approach. This compound, which is chemically related to known Wnt inhibitors, has shown potential in this regard. Studies have found that this compound can inhibit the Wnt/β-catenin signaling pathway in myeloma cell lines and induce apoptosis. iiarjournals.orgnih.govfrontiersin.orgnih.gov In vitro and in vivo studies indicate that this compound can inhibit the proliferation of myeloma cells and significantly reduce tumor growth by influencing the Wnt pathway and decreasing the phosphorylation of the β-catenin pathway. frontiersin.org

Induction of Apoptosis in Cancer Cell Lines

This compound has demonstrated the ability to induce apoptosis in a variety of cancer cell lines. nih.govnih.govmedchemexpress.comtoku-e.comresearchgate.net This effect has been observed in multiple myeloma, lymphoma, colorectal cancer, liver cancer, and leukemia cells. iiarjournals.orgnih.govmedchemexpress.comiiarjournals.org The induction of apoptosis is often dose-dependent. iiarjournals.orgmedchemexpress.comiiarjournals.org For instance, this compound significantly induced apoptosis in various myeloma and lymphoma cell lines in a dose-dependent manner, while healthy control cells were less sensitive. iiarjournals.orgnih.goviiarjournals.org In colorectal cancer cells, this compound induced apoptosis by increasing the expression of caspase-3, PARP, and Bax, while decreasing Bcl-2 expression. nih.gov this compound-promoted abnormal microtubule stabilization has been shown to initiate a cascade of events leading to apoptosis. iiarjournals.orgiiarjournals.org

The half-maximal inhibitory concentration (IC₅₀) values for this compound vary depending on the cancer cell line. The following table summarizes some reported IC₅₀ values:

This compound can also induce G₂/M cell cycle arrest in cancer cells, contributing to its anti-tumor effects. iiarjournals.orgmedchemexpress.com Higher doses (>20 µM) in HT 29 colorectal adenocarcinoma cells initiated significant G₂/M arrest. iiarjournals.org

Inhibition of Cancer Cell Migration, Invasion, and Adhesion

This compound has shown inhibitory effects on the migration, invasion, and adhesion of tumor cells. nih.govresearchgate.net Studies have demonstrated that this compound can significantly inhibit the longitudinal migration of cells at higher concentrations. nih.gov The inhibition rate of cell adhesion ability has also been shown to increase with increasing this compound concentration. nih.gov

Antiviral Mechanisms of Action

Inhibition of Hepatitis C Virus Replication by Disrupting Microtubule Polymerization

This compound has been shown to suppress Hepatitis C Virus (HCV) replication in vitro. nih.goviiarjournals.orgresearchgate.netniph.go.jpekb.egfishersci.camdpi.com This antiviral effect is thought to be related to its interaction with microtubules. iiarjournals.orgniph.go.jpekb.egmdpi.comnih.gov this compound can inhibit microtubule polymerization and arrest human cells in the G₂/M phase. niph.go.jpekb.eg It is speculated that this inhibition of microtubule polymerization may influence the formation of the HCV-RNA replication complex. niph.go.jp Studies using Huh7/Rep-Feo cells (a hepatoma cell line containing HCV replicons) showed dose-dependent antiviral effects with this compound. niph.go.jp Immunostaining of Huh7.5.1/JFH-1 cells (cells persistently infected with HCV) treated with this compound revealed a substantial reduction in HCV NS3 protein expression, indicating suppression of HCV replication. niph.go.jp

Potential Interactions with SARS-CoV-2 Targets (Main Protease, RdRp, Spike Protein Receptor-Binding Domain, ACE2 Receptor)

Computational studies have explored the potential of this compound and its derivatives as therapeutic agents for COVID-19 by examining their interactions with key SARS-CoV-2 targets. iiarjournals.orgfishersci.canih.govdntb.gov.uanih.gov Molecular docking analysis revealed that this compound has binding potential with the SARS-CoV-2 main protease, RNA-dependent RNA polymerase (RdRp), spike protein receptor-binding domain (RBD), and the human host angiotensin-converting enzyme 2 (ACE2). iiarjournals.orgnih.govdntb.gov.uanih.govdoaj.org this compound showed the highest docking score with the main protease of SARS-CoV-2 in one study. nih.govdntb.gov.uanih.govresearchgate.net These findings suggest that this compound may have inhibitory effects on SARS-CoV-2 entry and viral replication, although these are based on computational approaches and warrant further investigation. nih.govdntb.gov.ua

Anti-Inflammatory and Immunomodulatory Potential

Beyond its antifungal and potential antineoplastic and antiviral effects, this compound has also demonstrated anti-inflammatory and immunomodulatory properties. nih.govtaylorandfrancis.comiiarjournals.orgnih.govfrontiersin.orgekb.egresearchgate.net It has shown effectiveness in treating non-fungal skin inflammation conditions, such as pigmented purpuric dermatosis and lichen planus. nih.govnih.gov this compound has been shown to induce inhibitory effects on vascular cell adhesion molecule 1 (VCAM-1) in human dermal microvascular endothelial cells stimulated with TNF-alpha and IL-1. nih.gov These observations suggest a potential role for this compound in modulating inflammatory responses. taylorandfrancis.comnih.gov

Cardiovascular Effects: Vasodilation and Capillary Blood Flow Improvement

This compound has been observed to potentially influence the cardiovascular system, specifically by contributing to vascular vasodilation and improving capillary blood flow. wikipedia.orgnih.govchem960.comguidetopharmacology.orgreadthedocs.io While these effects have been noted, the precise molecular mechanism underlying this compound's impact on blood pressure and blood flow is not yet fully elucidated. nih.gov One hypothesis suggests that this compound may interact with ACE2, potentially enhancing its function, which could contribute to vasodilation and tissue protection. nih.gov

Interaction with Keratin Intermediate Filament Proteins (K8 and K18)

Studies indicate that this compound and its metabolites, specifically 6-desmethylthis compound (6-DMG) and 4-desmethylthis compound (4-DMG), exhibit favorable interactions with cytokeratin intermediate filament proteins K8 and K18. wikipedia.orgchem960.comguidetopharmacology.org These interactions are considered potentially responsible for observed liver injury and the formation of Mallory bodies in hepatocytes of humans, mice, and rats treated with this compound. wikipedia.orgchem960.comguidetopharmacology.org Molecular docking analysis has been used to evaluate the binding affinities of this compound and its metabolites with K8 and K18 across different species. chem960.com

The binding energy values from molecular docking studies illustrate the interactions between this compound, its metabolites, and keratin proteins. For instance, this compound showed binding energies towards K8 ranging from -3.17 to -4.6 kcal/mol. Higher binding energies towards K18 were noted in rat and mouse models compared to humans, which might explain the differences in the severity of hepatitis observed between these species. chem960.comguidetopharmacology.org this compound has also been shown to induce the phosphorylation of K8 (at serine residues 79 and 436) and K18 (at serine residue 33).

Note: Binding energy ranges for metabolites represent favorable interactions with K8 and K18 across species. Specific values for each metabolite and species within the cited range were not consistently detailed for inclusion in this summary table. wikipedia.orgchem960.comguidetopharmacology.org

Inhibition of Ferrochelatase (FECH) and its Metabolites

This compound acts as an inhibitor of ferrochelatase (FECH) as an off-target effect. FECH is a crucial enzyme in the heme biosynthesis pathway, catalyzing the insertion of ferrous iron into protoporphyrin IX (PPIX) to form heme. In vivo, this compound is metabolized to N-methylprotoporphyrin (NMPP), which is a potent inhibitor of FECH. Inhibition of FECH by this compound or NMPP has been shown to impact angiogenesis in various models. NMPP is described as a tight-binding competitive inhibitor of purified ferrochelatase with a nanomolar Ki value.

Impact of Substituents at Specific Positions (C-6, C-7, C-6', Carbonyl, Double Bond)

Substituents at various positions on the this compound core structure, as well as the presence and position of carbonyl groups and double bonds, have been shown to significantly affect antifungal activity. For instance, research on new this compound derivatives isolated from the mangrove-derived fungus Nigrospora sp. QQYB1 demonstrated that substituents at C-6, C-7, and C-6', along with the positions of the carbonyl and double bond, play a crucial role in their antifungal activity. nih.govnih.gov

Modifications at 4, 5, 2', 3', and 4' Positions

Modifications to the this compound structure at positions 4, 5, 2', 3', and 4' have been explored to understand their impact on anticancer activity. Studies indicate that modifications at the 4 and 5 positions often result in inactive molecules. researchgate.netnih.gov The presence of an enol ether at the 2' position and an sp2 hybridized 4' position appear to be important for activity. researchgate.netnih.gov

Identification of Potent Analogues (e.g., 2'-benzyloxy this compound)

Several analogues with enhanced anticancer potency have been identified. The 2'-benzyloxy and 2'-(4-methylbenzyloxy) analogues, as well as the oxime of the former, have shown significantly increased activity compared to this compound in inhibiting centrosomal clustering. researchgate.netnih.gov For example, the 2'-benzyloxy analogue has demonstrated a 25-fold increase in activity as a centrosome clustering inhibitor compared to this compound in certain cancer cell lines. researchgate.netnih.gov 2'-benzyloxy-2'-demethoxy-griseofulvin has also been highlighted as one of the most effective compounds against certain breast cancer cell lines. nih.govcore.ac.ukfrontiersin.org While these potent analogues show promise, challenges such as poor aqueous solubility and metabolic stability, similar to the parent compound, have been observed, prompting further analogue development to improve pharmacokinetic properties. researchgate.netnih.gov The 2'-benzylamine analogue has been identified as a promising compound with improved solubility and metabolic stability while retaining low micromolar in vitro anticancer potency. nih.gov

Molecular Docking and Dynamics Simulations for Target Binding Affinity

This compound, a spiro-containing antifungal antibiotic derived from Penicillium species, has been a subject of ongoing research not only for its antifungal properties but also for potential antibacterial and anticancer activities. Investigations into its structure-activity relationships (SAR) and the development of analogues aim to enhance its therapeutic efficacy and explore new applications.

Design of Novel Analogues with Enhanced Antibacterial Activity

The urgent need for innovative antibiotics has driven theoretical investigations into designing novel this compound analogues with enhanced antibacterial efficacy. Computational studies have been employed to design derivatives and evaluate their interactions with bacterial targets using in silico analysis. mdpi.comresearchgate.netresearchgate.net Researchers hypothesized that this compound and its newly designed derivatives might favorably interact with the FtsZ protein in bacterial cells, given its structural similarity to microtubules, the primary targets of this compound in eukaryotic cells. mdpi.comresearchgate.net

In silico studies investigating the binding affinities and stability towards potential bacterial targets revealed that newly designed this compound derivatives displayed robust binding affinities towards PBP2, tyrosine phosphatase, and FtsZ proteins. mdpi.comresearchgate.netresearchgate.net Molecular dynamics (MD) simulations further underscored the notable stability of these derivatives when engaged with the FtsZ protein. mdpi.comresearchgate.netresearchgate.net

Structure analysis of computationally designed derivatives indicated that the presence of substituents such as β-lactam moiety, hydrazine, sulfonyl group, chlorine, and methylenedioxy ring groups can be beneficial for antibacterial activity. mdpi.com Experimental testing of antibacterial activity for previously synthesized this compound derivatives has been performed on panels of gram-positive and gram-negative microorganisms using the microdilution method to determine minimal inhibitory (MIC) and minimal bactericidal (MBC) concentrations. researchgate.netresearchgate.net Some tested compounds exhibited potent antibacterial activity against studied bacteria, with MIC and MBC values often exceeding the activity of reference drugs like ampicillin and streptomycin. researchgate.netresearchgate.net

Preliminary SAR studies on related compounds, such as geodin derivatives which share the grisan backbone with this compound, have indicated that the introduction of halogenated benzyl groups, particularly fluorobenzyl, and substitution of the 4-OH group could be key factors in increasing antibacterial activities. mdpi.com

In Vitro Antifungal Spectrum (e.g., Microsporum, Epidermophyton, Trichophyton species)

In vitro studies have investigated the susceptibility of various dermatophyte species to this compound. These studies typically determine the minimum inhibitory concentration (MIC), which is the lowest concentration of the drug that inhibits visible fungal growth.

Research has shown that this compound exhibits antifungal activity against common dermatophytes, including species of Microsporum, Epidermophyton, and Trichophyton. For instance, studies have examined the susceptibility of Trichophyton mentagrophytes, T. verrucosum, Microsporum canis, and Epidermophyton floccosum to this compound, reporting MIC values within a certain range nih.gov. Another study evaluating the in vitro susceptibility of dermatophytes, including Microsporum canis, Microsporum gypseum, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton schoenleinii, and Epidermophyton floccosum, also determined MIC values for this compound researchgate.net. While some studies indicate that certain isolates, such as T. verrucosum, M. canis, and T. mentagrophytes, may exhibit relatively higher MIC values suggesting potential reduced susceptibility, the majority of isolates tested generally fall within a susceptible range nih.gov.

However, the in vitro efficacy can vary depending on the specific fungal species and the methodology used for susceptibility testing oup.commedicinearticle.com. For example, one study found that all Microsporum spp. and Epidermophyton spp. strains tested were resistant to fluconazole and this compound, while Trichophyton spp. showed varying resistance rates to different antifungals, including this compound (46.4% resistance in that specific study) oamjms.eu. Conversely, another study indicated that the MIC range for isolated dermatophytes against this compound was within the normal susceptibility range of a standard strain (Trichophyton mentagrophytes ATCC MYA – 4439), suggesting susceptibility of the isolates tested medicinearticle.com.

The following table summarizes representative in vitro susceptibility data for this compound against various dermatophyte species:

Note: MIC values and resistance rates can vary significantly between studies due to differences in methodologies, fungal isolates, and geographical locations.

In Vivo Efficacy Models (e.g., Guinea Pig Model of Trichophytosis)

In vivo models are crucial for evaluating the effectiveness of antifungal agents in a living system. The guinea pig model of dermatophytosis, particularly infection with Trichophyton mentagrophytes, is a widely used model for assessing the in vivo efficacy of antifungal drugs, including this compound karger.comkarger.comnih.govresearchgate.net.

Studies utilizing this model have demonstrated the in vivo antifungal activity of both topical and oral administration of this compound against Trichophyton mentagrophytes infections in guinea pigs karger.comkarger.com. For example, a study evaluating a novel topical formulation of this compound in a guinea pig model of trichophytosis showed effective cure of infected animals nih.gov. This model allows for the assessment of clinical and mycological cure, providing valuable data on the drug's effectiveness in reducing infection severity and eliminating the fungus from infected tissues karger.comresearchgate.net. The model typically involves inducing infection with a standardized inoculum of dermatophytes and then administering the antifungal treatment, monitoring the progression of the infection and the response to therapy through clinical scoring, microscopy, and fungal cultures karger.comresearchgate.net.

Efficacy in Specific Dermatophytosis (e.g., Tinea Capitis)

This compound has been a traditional treatment for tinea capitis, a common dermatophyte infection of the scalp, particularly in children ijcmph.compracticeupdate.comjwatch.org. Numerous studies and meta-analyses have investigated its efficacy in treating this condition.

While newer agents like terbinafine are increasingly used, often offering shorter treatment durations, this compound has remained an important option, especially for Microsporum infections ijcmph.comjwatch.org. Comparative studies have provided data on its cure rates in relation to other treatments (see Section 5.1.4).

Comparative Efficacy with Other Antifungal Agents (e.g., Terbinafine, Fluconazole, Azoles)

Comparative studies have evaluated the efficacy of this compound against other systemic antifungal agents commonly used for dermatophyte infections, such as terbinafine, fluconazole, and other azoles. These comparisons are important for determining the optimal treatment strategies for different types of dermatophytosis and causative species.

Comparisons with fluconazole have also been conducted. One study comparing this compound, terbinafine, and fluconazole for tinea capitis in children reported cure rates of 96% for this compound, 88% for terbinafine, and 84% for fluconazole researchgate.netnih.gov. Another study comparing this compound and fluconazole for tinea capitis found no significant difference in efficacy, although higher doses were associated with earlier cure practiceupdate.com.

Studies comparing this compound with azoles and allylamines for tinea corporis have suggested that azole and allylamine agents may have greater efficacy in some cases ijpmbs.com. However, the choice of antifungal agent often depends on the specific fungal species involved oamjms.euijcmph.comresearchgate.netresearchgate.net.

The following table summarizes comparative efficacy findings from selected studies:

In Vitro and In Vivo Antitumorigenic Effects

Studies have investigated the potential of this compound to inhibit the growth of tumor cells both in vitro and in vivo. This compound is known to interfere with microtubule function, a property that is relevant to cell division and could contribute to antitumor effects nih.govcapes.gov.br.

In vitro studies have demonstrated that this compound can inhibit the proliferation and induce apoptosis in various cancer cell lines. For example, it has been shown to inhibit the proliferation of human myeloma cell lines, mouse myeloma cell lines, and human lymphoma cell lines in a concentration-dependent manner, with reported IC50 values (the concentration required to inhibit cell growth by 50%) for different cell lines nih.goviiarjournals.org. Studies have also indicated that this compound can inhibit the proliferation of adrenocortical carcinoma cells and induce apoptosis in these cells in a dose-dependent manner in vitro nih.govuni-duesseldorf.de.

In vivo studies using animal models have also provided evidence of this compound's antitumorigenic effects. Research has shown that this compound can reduce the growth of myeloma in murine models nih.goviiarjournals.org. Additionally, in a nude mouse xenograft model, this compound was found to inhibit the growth of small-cell lung cancer cells nih.gov. These in vivo effects are thought to be mediated, in part, by influencing factors such as the expression of proteins involved in apoptosis and angiogenesis nih.gov.

Research suggests that this compound's antitumor effects may involve mechanisms related to the Wnt pathway and the inhibition of centrosomal clustering, which is a mechanism used by some cancer cells to manage supernumerary centrosomes nih.govnih.govuni-duesseldorf.de.

The following table summarizes some findings on the in vitro antitumorigenic effects of this compound:

Further research is ongoing to fully understand the mechanisms underlying the antitumorigenic effects of this compound and its potential therapeutic applications in oncology nih.govnih.goviiarjournals.orguni-duesseldorf.de.

Inhibition of Tumor Growth in Xenograft Mouse Models

Antiviral Activity in Cellular Models

This compound has demonstrated antiviral activity in cellular models, particularly against the hepatitis C virus (HCV). Studies have shown that this compound can inhibit the replication of the hepatitis C virus. frontiersin.orgnih.govekb.egnih.gov this compound suppresses HCV replication by arresting the human cell cycle at the G2/M phase and acting on microtubule polymerization. nih.gov It has been documented that the replication of a subgenomic hepatitis C virus genotype 1b (HCV-1b) replicon can be suppressed by this compound. nih.gov this compound decreased the replicon RNA titer in Huh7/Rep-Feo cells in vitro in a dose-dependent manner and was shown to induce G2/M cell cycle arrest in HCV replicon cells. nih.gov

Anti-Inflammatory Effects in Non-Fungal Skin Diseases

Research suggests that this compound possesses anti-inflammatory and immunomodulatory properties, which may contribute to its effects in non-fungal skin diseases. frontiersin.orgnih.govekb.egnih.gov Studies have reported the effectiveness of this compound in the treatment of non-fungal skin inflammation diseases, including lichen planus and chronic purpuric dermatosis. ekb.egnih.gov An older study suggested that this compound has an anti-inflammatory effect, estimated to be in the range of one-third to one-tenth of that of cortisone acetate. bmj.com This anti-inflammatory effect may explain some of the reported benefits of this compound in conditions other than ringworm infections. bmj.com

Angiogenic Inhibition in Preclinical Models (e.g., Choroidal Neovascularization)

This compound has shown potential as an inhibitor of angiogenesis in preclinical models, particularly in the context of ocular neovascularization, such as choroidal neovascularization (CNV). Ocular neovascularization is a key feature of blinding eye diseases like wet age-related macular degeneration (AMD). nih.govarvojournals.org Research has identified ferrochelatase (FECH), an enzyme in heme synthesis, as a mediator of ocular neovascularization. nih.govarvojournals.orgarvojournals.org this compound inhibits FECH as an off-target effect. nih.govarvojournals.orgarvojournals.org

In vitro studies using human retinal endothelial cells have shown that this compound and its active metabolite, N-methylprotoporphyrin (NMPP), dose-dependently inhibit the proliferation, migration, and tube formation of these cells. arvojournals.org this compound at concentrations of 50 µM or higher profoundly suppressed choroidal sprouting in an ex vivo assay. arvojournals.org

In the murine laser-induced choroidal neovascularization (L-CNV) model, this compound dose-dependently decreased CNV. arvojournals.org Intravitreal administration of 50 µM and 100 µM this compound reduced CNV volume by 28% and 67%, respectively. arvojournals.org Oral administration of 0.5% and 1% (w/w) this compound in food also reduced CNV volume by 33% and 42%, respectively. arvojournals.org this compound also inhibited neovascularization and decreased the avascular area in the mouse oxygen-induced retinopathy (OIR) model, a model of retinal angiogenesis. arvojournals.orgresearchgate.net These findings suggest that this compound has significant anti-angiogenic potential in the eye at clinically achievable concentrations. arvojournals.org

Combinations with Other Therapeutic Agents (e.g., Prednisolone, Vincristine)

Research has investigated the efficacy of combining this compound with other drugs, particularly in cases where an inflammatory response complicates a fungal infection or in exploring potential anti-proliferative effects.

Combinations with Prednisolone

Prednisolone, a corticosteroid with anti-inflammatory properties, has been studied in combination with this compound for the treatment of inflammatory tinea capitis, such as kerion celsi. oup.comnih.govresearchgate.netnih.govresearchgate.net Kerion celsi is a severe inflammatory reaction to dermatophyte infections of the scalp, often seen in children, and can potentially lead to scarring alopecia if untreated. oup.com

A randomized, comparative trial evaluated the efficacy of oral this compound combined with oral prednisolone versus oral this compound alone in treating kerion celsi. oup.comnih.govresearchgate.net In this study, both groups received oral this compound for 8 weeks. oup.comnih.govresearchgate.net The combination group also received oral prednisolone in tapering doses for 3–4 weeks. oup.comnih.govresearchgate.net At the final evaluation at week 12, both treatment groups showed a 100% cure rate, with no significant difference observed in terms of clinical or mycological cure between the combination therapy and this compound alone. oup.comnih.govresearchgate.net This suggests that while both regimens were effective, the addition of prednisolone did not provide significant additional objective or subjective improvement in this specific context. oup.comnih.govresearchgate.net

Another study involving children with inflammatory tinea capitis treated with a combination of this compound and oral corticosteroids reported a fall in positive mycology from 100% to 16% at the end of 8 weeks. jpmi.org.pk In this study, 25% of patients achieved complete resolution of inflammation, initiation of hair growth, and negative mycological examination. jpmi.org.pk

Combinations with Vincristine

Vincristine is a vinca alkaloid chemotherapy medication known to bind to tubulin and interfere with microtubule function, similar to this compound's mechanism of action in fungi. nih.govnih.govuni.luguidetopharmacology.orgwikipedia.orgmdpi.com Research has explored the potential for synergistic effects when this compound is combined with vincristine, particularly in the context of cancer cell proliferation, given their shared target on microtubules. nih.gov

In in vitro experiments focusing on human breast cancer cells (MCF-7), this compound demonstrated a significant inhibitory effect on cell proliferation. nih.gov When this compound was used in combination with vincristine, a synergistic effect was observed in inhibiting MCF-7 cell proliferation. nih.gov Specifically, when this compound at 10 µM was combined with vincristine at 0.5 nM or 1 nM, the inhibitory effects on MCF-7 proliferation were reported as 84% and 92%, respectively. nih.gov This suggests that combining this compound with vincristine can enhance the therapeutic effect on these cancer cells. nih.gov The mechanism underlying this synergy may be related to their combined impact on microtubule dynamics and the activation of tumor suppressor proteins like p53. nih.gov

Nano- and Microcrystal Formulations

Particle size reduction to the nanoscale or microscale is a common strategy to enhance the dissolution rate and, consequently, the bioavailability of poorly soluble drugs. Studies on this compound have explored the use of nano- and microsuspensions, particularly for subcutaneous administration, as an alternative to the conventional oral route which is associated with low bioavailability. nih.govtaylorandfrancis.comtandfonline.com

Liposomal Formulations

Liposomes are versatile drug carriers that can encapsulate both hydrophilic and lipophilic drugs, offering potential benefits such as improved solubility, enhanced tissue penetration, and reduced toxicity. ijfmr.comijfmr.com For this compound, liposomal formulations have been investigated to enhance its delivery, particularly for topical applications in treating cutaneous fungal infections. ijfmr.com

Studies examining the oral bioavailability of this compound-loaded liposomes in rats have highlighted the impact of formulation parameters like encapsulation efficiency and liposome size. nih.govmdpi.com Encapsulation within liposomes was found to increase this compound bioavailability by 1.7 to 2.0 times compared to an aqueous suspension. nih.govmdpi.com A significant enhancement (approximately two-fold) in bioavailability was observed with liposomes exhibiting higher drug encapsulation efficiency. nih.govmdpi.com Furthermore, smaller liposome sizes (142 nm and 357 nm) resulted in approximately three times higher bioavailability compared to larger liposomes (813 nm). nih.govmdpi.com However, reducing the size below 400 nm did not lead to a further increase in uptake or bioavailability. nih.govmdpi.com These findings underscore the critical role of optimizing encapsulation efficiency and liposome size in the design of this compound liposomal formulations for improved oral bioavailability. nih.govmdpi.com The development of liposome-loaded topical films containing this compound is also being explored as a strategy for enhanced transdermal delivery and improved treatment of skin infections. ijfmr.comijfmr.com

Vaterite Carriers for Topical Delivery

Vaterite, a calcium carbonate polymorph, has emerged as a promising carrier for the topical delivery of this compound, especially for targeting fungal infections within hair follicles, which are often difficult to treat with conventional topical formulations due to this compound's poor skin permeation. researchgate.netnih.govacs.orgnih.gov

Novel topical formulations utilizing micron-sized vaterite carriers have been developed to improve the incorporation and delivery of this compound to hair follicles, thereby increasing its dermal bioavailability. researchgate.netnih.govacs.orgnih.gov In vivo studies in rats have demonstrated the successful penetration of these this compound-loaded vaterite carriers into hair follicles. nih.gov Evaluation in a guinea pig model of trichophytosis showed that the vaterite-based this compound formulation provided a more rapid and effective therapeutic outcome compared to free this compound or isoconazole, requiring fewer treatment procedures. acs.orgnih.gov Research also indicates that ultrasound can assist the delivery of these carriers, with studies showing no significant cytotoxicity to fibroblasts in vitro or dermal toxicity in healthy rabbits in vivo. acs.orgnih.gov

Poly(lactic-co-glycolide) (PLGA) Microparticles

Poly(lactic-co-glycolide) (PLGA) is a widely used biodegradable polymer matrix for creating sustained-release drug delivery systems. researchgate.netnih.gov PLGA microparticles have been investigated for their potential to provide prolonged release of this compound, particularly in applications requiring sustained local drug levels.

A notable application area is the use of this compound-loaded PLGA microparticles for the treatment of ocular neovascularization, a key pathological feature of wet age-related macular degeneration (AMD). researchgate.netnih.govprf.orgarvojournals.orgpurdue.eduarvojournals.org Given that current AMD treatments often involve frequent intravitreal injections, a sustained-release formulation of this compound, which has shown antiangiogenic properties, could offer a significant advantage. prf.orgarvojournals.org

Studies have focused on developing this compound-loaded PLGA microparticles suitable for intravitreal injection. researchgate.netnih.govarvojournals.org The incorporation of additives such as magnesium hydroxide has been explored to modulate the drug release kinetics from the PLGA matrix. researchgate.netnih.govpurdue.eduarvojournals.org In vitro studies have demonstrated that these formulations can achieve sustained release of this compound for over 30 days. researchgate.netnih.govpurdue.eduarvojournals.org In vivo evaluation in a murine model of laser-induced choroidal neovascularization (CNV) showed that intravitreally injected this compound-loaded PLGA microparticles effectively reduced CNV lesion volume for at least 6 weeks, a sustained effect not observed with free this compound. researchgate.netnih.govarvojournals.orgpurdue.edu These findings suggest that PLGA microparticles can provide a prolonged antiangiogenic effect, positioning this formulation as a potential long-acting therapeutic option for ocular neovascularization. nih.govarvojournals.orgpurdue.edu

The in vitro release profiles of this compound from PLGA microparticles can be influenced by the composition of the formulation, as illustrated by data showing the effect of varying magnesium hydroxide content:

This data indicates that formulations with lower magnesium hydroxide content, such as 2% w/w, exhibit a reduced initial burst release and provide a more extended release of this compound. purdue.eduarvojournals.org

Association with Liver Injury and Mallory Body Formation

This compound has been associated with liver injury and the formation of Mallory bodies (MBs) in hepatocytes frontiersin.orgmdpi.comresearchgate.nettandfonline.commdpi.com. Mallory bodies are aggregates primarily composed of intermediate filament proteins, such as keratins 8 and 18 (K8/K18) mdpi.comresearchgate.netnih.gov. Studies, particularly in rodents, have shown that this compound treatment induces the formation of these bodies mdpi.comresearchgate.nettandfonline.comnih.gov.

The mechanism involves this compound and its metabolites, including 6-desmethylthis compound (6-DMG) and 4-desmethylthis compound (4-DMG), interacting favorably with cytokeratin intermediate filament proteins K8 and K18 mdpi.comnih.gov. This binding can alter keratin solubility and phosphorylation on specific sites, leading to protein misfolding and the formation of aggregates mdpi.comresearchgate.net. Research using molecular docking analysis has indicated that this compound metabolites have stronger interactions with K8 and K18 than the parent compound mdpi.comnih.gov. This disruption of the keratin cytoskeleton is believed to contribute to liver injury mdpi.comresearchgate.net.

In mice, a this compound-containing diet has been shown to induce Mallory body formation, potentially linked to the overexpression of the Krt8 gene and the binding of this compound to K8 and K18 in hepatocytes mdpi.comresearchgate.net. These interactions change keratin solubility and phosphorylation, causing protein misfolding mdpi.comresearchgate.net. While Mallory bodies are characteristic of alcoholic hepatitis in humans, they can be induced in mice by chronic this compound intoxication, providing a model for studying the molecular mechanisms of keratin's role in response to chemical injuries researchgate.netnih.gov. Studies in mice have shown that this compound intoxication leads to changes in keratin solubility and increased phosphorylation of specific keratin sites (K8 pS79, K8 pS436, and K18 pS33), particularly in insoluble protein fractions researchgate.net.

Disturbance of Porphyrin Metabolism

This compound is known to disturb porphyrin metabolism frontiersin.orgupenn.edunih.govscilit.com. This disturbance is characterized by the accumulation of porphyrins, particularly protoporphyrin, in the liver and, in some cases, in circulating red blood cells upenn.edu. Early experiments in mice demonstrated that oral administration of this compound led to a marked disturbance of porphyrin metabolism within 24 hours, primarily causing massive fecal excretion of protoporphyrin and liver accumulation of protoporphyrin upenn.edu. This indicated a hepatic type of porphyria upenn.edu. After several days of treatment in mice, a significant increase in protoporphyrin was also observed in peripheral red blood cells, suggesting a mixed hepatic-erythropoietic distribution upenn.edu.

The porphyrinogenic effect in mice may result from the inhibition of ferrochelatase and a compensatory induction of δ-aminolevulinic acid synthase (ALA synthase) nih.gov. A green pigment that inhibited ferrochelatase was isolated from the livers of this compound-treated mice, with chromatographic characteristics identical to N-methyl protoporphyrin iarc.fr. This compound-induced accumulation of porphyrins in mouse liver has been followed by cell damage, necrotic, and inflammatory processes nih.goviarc.fr. While this compound therapy can disturb porphyrin metabolism in humans, the effect is considered moderate compared to the mouse model nih.goviarc.fr.

Interference with Chromosomal Distribution and Aneuploidy

This compound is recognized for its ability to interfere with chromosomal distribution and induce aneuploidy iarc.froup.comresearchgate.netoup.com. This effect is primarily attributed to its interaction with microtubules, which are essential components of the mitotic spindle responsible for chromosome segregation during cell division mdpi.comiarc.fr. This compound acts as a spindle poison, disrupting the formation and function of spindle microtubules nih.gov.

Studies have shown that this compound can induce micronuclei containing whole chromosomes (kinetochore-positive) in isolated human lymphocytes, indicating aneuploidic events iarc.fr. It has also been observed to alter the cell cycle of lymphocytes, increasing the percentage of triploid cells iarc.fr. In mice, this compound has been shown to induce aneuploidy and polyploidy in germ cells, particularly oocytes, in a time- and dose-dependent manner oup.comresearchgate.netoup.com. It can cause mitotic arrest of oocytes in metaphase I at high doses, and while these cells may overcome the block, they often form polyploid zygotes iarc.fr. Even at lower doses, the frequency of hyperploid cells can be substantially increased iarc.fr.

Research in orally treated mice has provided evidence that this compound induces both cell cycle delay and aneuploidy in bone marrow cells oup.comresearchgate.net. A statistically significant increase in the average generation time in bone marrow cells of mice treated with 666 and 2000 mg/kg this compound suggested interference with cell cycle progression researchgate.net. Frequencies of hyperploid cells were significantly higher in treated groups compared to controls, although the effect was not always dose-dependent within the tested range oup.comresearchgate.net.

The mechanism involves this compound binding to tubulin, interfering with the normal polymerization of microtubule protein iarc.fr. This colchicine-like effect can disturb the correct distribution of chromosomes during cell division iarc.fr.

Immunological Basis of Severe Cutaneous Adverse Reactions (SCARs)

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), are rare but potentially life-threatening reactions associated with various drugs, including this compound npra.gov.mynih.govnih.govjmust.org. While the pathophysiology of how drugs induce SCARs is not fully understood, these reactions are generally considered delayed type IV hypersensitivity reactions triggered by a T-cell-mediated drug-specific immune response npra.gov.mynih.gov.

The clinical heterogeneity of SCARs may be attributed to the activation of different effector or regulatory cells that produce specific cytokines npra.gov.my. This compound-induced SCARs, such as SJS, TEN, and AGEP, have been reported npra.gov.myrjptonline.org. The time-to-onset of symptoms following this compound use has been reported to range from days to weeks npra.gov.my. Recovery is typically documented after discontinuing this compound and providing supportive treatment npra.gov.my.

Enhanced Solubility and Metabolic Stability

This compound is classified as a Class II drug according to the Biopharmaceutics Classification System (BCS), indicating low solubility and high permeability acs.org. Its poor water solubility limits its absorption and bioavailability, hindering in vivo research and reducing its druggability frontiersin.org. Strategies to improve solubility and metabolic stability include structural modifications such as the conversion of aryl methyl ethers into aryl difluoromethyl ethers and the conversion of the C-ring ketone into polar oximes nih.govresearchgate.netdtu.dk. The formation of polar oximes appears to be a promising strategy for improving the properties of this compound analogues nih.govresearchgate.net. Studies have shown that certain derivatives, such as the 2'-benzylamine analogue, exhibit significantly increased solubility and improved metabolic stability compared to this compound and its more potent anticancer analogue, 2'-benzyloxy this compound researchgate.net. Complexation with cyclodextrin derivatives, particularly HP-γ-cyclodextrin, has also demonstrated a substantial increase in this compound's water solubility, with one study reporting a 477-fold increase mdpi.com. This complexation also led to improved pharmacokinetic properties in vivo, including increased Cmax and AUC, and a longer half-life mdpi.com.

Here is a table summarizing data on the improved solubility and metabolic stability of some this compound analogues:

Increased Potency and Selectivity for Specific Targets

Structural modifications of this compound have also aimed at increasing its potency and selectivity for specific targets, particularly in the context of cancer therapy. Studies have prepared new this compound derivatives with good antitumor activity through structural modification frontiersin.org. For instance, the 2'-demethoxy-2'-propoxy analog was found to be more potent in Chinese hamster V79 cells, suggesting that the anticancer effect could be enhanced through structural modification dtu.dk. Experimental studies have reported that this compound analogues with a sulfonyl group in the 2' or 3' position showed significant activity against oral squamous carcinoma and a triple-negative breast cancer cell line resistant to microtubule inhibitors mdpi.com. Modifications at the 2'-benzyloxy position have also remarkably enhanced anticancer activity compared to the parent compound mdpi.com. Computational studies exploring interactions with different human beta-tubulin isotypes suggest that certain derivatives may have favorable interactions and significant affinity, potentially offering a strategy for targeting drug-resistant cancer cells nih.govmdpi.com.

Continued Investigation in Cancer Therapy

This compound has garnered significant attention for its potential as an anticancer agent, owing to its ability to inhibit cell proliferation, induce apoptosis, and affect microtubule function in cancer cells nih.govfrontiersin.orgnih.gov. It has shown inhibitory effects on cancer cell division and may induce cell death through interaction with the mitotic spindle microtubule nih.gov. This compound can inhibit the proliferation, migration, and invasion of tumor cells, induce apoptosis, and inhibit tumor growth frontiersin.org. Studies have demonstrated its significant antitumor activity against various cancers, including cervical cancer, breast cancer, non-small-cell lung cancer, colorectal cancer, and adrenocortical cancer frontiersin.org. Its mechanisms of action in cancer cells include interfering with the cell cycle, inducing apoptosis, regulating signaling pathways like Wnt/β-catenin, NF-κB, and cGAS-STING, and affecting the expression of proteins such as p53, Bcl-2, Bax, and cytochrome C frontiersin.org. This compound has also been shown to inhibit centrosomal clustering, a strategy used by many cancer cells to avoid lethal multipolar cell divisions dtu.dksciencedaily.com. The combination of this compound with other therapies, such as radiotherapy or certain chemotherapy drugs like vincristine or nocodazole, has shown synergistic effects in enhancing therapeutic outcomes in cancer models frontiersin.orgnih.govresearchgate.net. Future research in this area includes developing this compound composites or GF-loaded nanomaterials to improve bioavailability for cancer treatment frontiersin.org.

Exploration in Viral Infections (e.g., SARS-CoV-2)

Beyond its antifungal use, this compound has shown antiviral properties, notably inhibiting the replication of the hepatitis C virus (HCV) by interfering with microtubule polymerization frontiersin.orgnih.govtandfonline.comresearchgate.net. More recently, the potential of repurposing this compound for the treatment of SARS-CoV-2 infection has been explored, primarily through computational studies mdpi.comnih.govresearchgate.netnih.govresearchgate.netijnrd.orgmdpi.com. Molecular docking analyses have revealed that this compound and its derivatives have good binding potential with key SARS-CoV-2 targets, including the main protease, RNA-dependent RNA polymerase (RdRp), and the spike protein receptor-binding domain (RBD), suggesting potential inhibitory effects on viral entry and replication mdpi.comnih.govresearchgate.netnih.govresearchgate.netmdpi.com. Furthermore, this compound may enhance ACE2 function, which could contribute to relieving COVID-19 symptoms mdpi.comnih.govresearchgate.net. These findings suggest that this compound and its derivatives may be considered when designing future therapeutic options for SARS-CoV-2 infection researchgate.netnih.govresearchgate.net.

Here is a table summarizing some potential applications of this compound and its derivatives in emerging disease areas: