Griseofulvin

Griseofulvin is synthesized through a biosynthetic pathway involving the combination of one acetyl coenzyme A and six malonyl coenzyme A molecules to form a heptaketide backbone . The industrial production of this compound typically involves fermentation processes using Penicillium species . The compound can also be prepared through chemical synthesis, although this method is less common due to the complexity and cost involved .

Griseofulvin undergoes various chemical reactions, including oxidation, reduction, and substitution reactions. Common reagents used in these reactions include oxidizing agents like hydrogen peroxide and reducing agents such as sodium borohydride . Major products formed from these reactions include desmethylthis compound derivatives, which have been studied for their potential biological activities .

Griseofulvin is an antifungal polyketide metabolite derived from ascomycetes, initially isolated from Penicillium griseofulvum in 1939 . Since its commercial introduction in 1959, it has been used to treat dermatophyte infections . Beyond its antifungal properties, this compound has gained interest for its potential in disrupting mitosis and cell division in cancer cells, inhibiting hepatitis C virus replication, enhancing ACE2 function, promoting vascular vasodilation, and improving capillary blood flow .

Antifungal Applications

This compound is used as an antifungal drug to treat ringworm and dermatophyte infections in humans and animals . It is also the drug of choice for tinea capitis, onychomycosis, and other superficial fungal infections .

Antitumor Applications

This compound has garnered attention as a potential agent in cancer chemotherapy due to its low toxicity . It inhibits tumor growth and cancer cell proliferation by suppressing spindle microtubule dynamics, inducing mitotic arrest, and causing cell death in multipolar spindles, without harming fibroblasts and keratinocytes with normal centrosome composition . this compound binds to the αβ intra-dimer tubulin interface, leading to mitotic abnormalities like misaligned chromosomes and multipolar spindles, resulting in fragmented nuclei and apoptosis .

Antiviral Applications

This compound may inhibit hepatitis C virus replication by interfering with microtubule polymerization in human cells . Molecular docking analysis suggests that this compound and its derivatives can bind to SARS-CoV-2 main protease, RNA-dependent RNA polymerase (RdRp), and spike protein receptor-binding domain (RBD), suggesting potential inhibitory effects on SARS-CoV-2 entry and viral replication .

Other Applications

This compound is used as a crop protectant in agriculture to prevent fungal colonization and infection .

Anti-malarial Applications

This compound impairs the intraerythrocytic development of P. falciparum . In vitro studies showed that P. falciparum could not grow in human red blood cells from subjects taking this compound . While initial studies showed promise, subsequent clinical trials showed no significant inhibition of parasite growth when subjects were treated with this compound .

Acne Treatment

This compound has been investigated for treating acne vulgaris . Clinical trials have shown improvement in inflammatory acne lesions (papules and pustules) but less significant effects on non-inflamed lesions (comedones, cysts, and nodules) .

Case Study 1: Pediatric Tinea Capitis

A study reported successful treatment of recalcitrant pediatric tinea capitis using this compound . After 10 weeks of treatment, skin lesions nearly disappeared, and remarkable hair regrowth was observed .

Research Finding: Anti-malarial Activity

Ex vivo studies demonstrated that red blood cells (RBCs) collected from subjects who had been orally administered clinical doses of this compound accumulated the drug in levels sufficient to impair parasite growth .
Pharmacokinetic profiling showed that this compound levels in plasma and RBCs peaked within one day of drug intake, with RBC levels (59–143 μg/L) comparable to those required in vitro to inhibit parasite growth . RBCs from a subject given a single 2,000 mg dose inhibited parasite growth for up to 2 days, with parasite growth inhibition gradually declining as plasma and RBC levels of this compound decreased .

Research Finding: Acne Vulgaris Treatment

Griseofulvin exerts its antifungal effects by inhibiting fungal cell mitosis at metaphase . It binds to tubulin, a protein that forms microtubules, and disrupts the formation of the mitotic spindle, preventing the separation of chromosomes during cell division . This action makes the fungal cells unable to replicate and spread . This compound also binds to keratin in human cells, making the keratin resistant to fungal invasion .

Griseofulvin is often compared to other antifungal agents such as terbinafine and itraconazole . Unlike this compound, which inhibits mitosis, terbinafine works by inhibiting the enzyme squalene epoxidase, leading to the accumulation of toxic squalene in fungal cells . Itraconazole, on the other hand, inhibits the synthesis of ergosterol, an essential component of fungal cell membranes . These differences in mechanisms of action highlight the uniqueness of this compound in targeting fungal cell division .

Similar compounds to this compound include:

• Terbinafine
• Itraconazole
• Fluconazole
• Ketoconazole

This compound’s unique mechanism of action and its ability to bind to keratin make it a valuable antifungal agent, particularly for treating dermatophyte infections .

Griseofulvin is an antifungal agent derived from the mold Penicillium griseofulvum, primarily used to treat dermatophyte infections. Since its introduction in 1959, it has been recognized for its fungistatic properties, inhibiting fungal growth by interfering with mitosis and cell division. Recent studies have expanded its potential applications, suggesting roles in cancer treatment and viral infections.

This compound exerts its antifungal effects by binding to tubulin, disrupting the mitotic spindle formation during cell division. This action not only inhibits fungal growth but also has implications for human cells, particularly in cancer research. Additionally, molecular docking studies indicate that this compound may bind effectively to proteins involved in the SARS-CoV-2 lifecycle, suggesting potential antiviral properties against COVID-19 .

Table 1: Mechanisms of this compound Action

Antifungal Efficacy

This compound is primarily indicated for dermatophyte infections such as tinea capitis and tinea corporis. A meta-analysis comparing this compound to terbinafine showed that both treatments are effective, with this compound being particularly effective against infections caused by Microsporum species .

Case Studies

• Tinea Capitis Treatment : A study involving 175 patients treated with this compound showed a clearance rate of 13.6% among those with tinea corporis caused by Trichophyton rubrum. Side effects were minimal and transient .
• Cancer Research : In a cohort study examining the long-term effects of this compound, one patient developed chronic granulocytic leukemia after treatment for skin infections. This raised concerns regarding potential carcinogenic effects, warranting further investigation into long-term use .

Table 2: Summary of Clinical Findings on this compound

Additional Biological Activities

Recent research has suggested that this compound may have additional biological activities beyond antifungal effects:

• Antiviral Properties : this compound shows promise in inhibiting the replication of hepatitis C virus and SARS-CoV-2, indicating a potential role in treating viral infections .
• Anti-Plasmodial Activity : Studies have shown that this compound can impair the growth of Plasmodium falciparum, the parasite responsible for malaria, through mechanisms involving heme metabolism disruption .

Table 3: Broader Biological Activities of this compound

Basic Research Questions

Q. What are the key challenges in optimizing Griseofulvin synthesis for scalable production, and what methodological approaches address them?

this compound synthesis involves a nonreducing polyketide synthase (gsfA) to form the heptaketide backbone, followed by methylation via O-methyltransferases (gsfB/gsfC) . Challenges include low yields in benzophenone intermediate formation and regioselective methylation. Methodological improvements include:

• Enzyme engineering : Modifying gsfA/gfsB activity to enhance catalytic efficiency .
• Chemoenzymatic routes : Combining microbial synthesis with chemical steps (e.g., alcoholysis of griseofulvic acid) to improve scalability .
• Crystallographic analysis : Using X-ray diffraction (space group P41, Z=4) to guide stereochemical control .

Q. How does this compound’s poor aqueous solubility impact preclinical studies, and what formulation strategies mitigate this limitation?

this compound’s solubility in aqueous buffers is ≤8.63·10⁻⁷ mol/L, necessitating advanced formulation techniques :

• Ultramicrosizing : Reduces particle size to 1–2 µm, achieving bioequivalence with lower doses .
• Solid dispersions : Incorporation into PEG matrices increases dissolution rates by 3–5× via fusion/solvent methods .
• Liposomal encapsulation : Enhances GI absorption (2.6× higher C_max vs. suspensions) . Methodological validation includes FT-IR spectroscopy and DSC to confirm amorphous state stability .

Q. What experimental models are used to study this compound’s antifungal mechanism, and how do they reconcile conflicting data on microtubule disruption vs. nucleic acid synthesis inhibition?

this compound’s fungistatic action involves microtubule binding (α/β-tubulin) and mitotic arrest . Contradictions arise from species-specific effects:

• In vitro fungal models : Microsporum spp. show microtubule depolymerization, while Trichophyton spp. exhibit RNA synthesis inhibition .
• Yeast assays : S. cerevisiae studies reveal SGS1 gene repression, linking mitotic disruption to genomic instability .
• Human cell lines : HeLa cells demonstrate metaphase arrest via suppression of microtubule dynamic instability (IC₅₀ = 20 µM) .

Advanced Research Questions

Q. How can researchers resolve contradictory structure-activity relationship (SAR) data for this compound analogs targeting cancer cells?

Disparate SAR data arise from divergent assays (e.g., fungal vs. mammalian microtubule affinity) . Methodological solutions include:

• 2D NMR/X-ray crystallography : Confirm stereochemical assignments (e.g., 4/6-methoxy positional isomers) .
• Phenotypic screening : Centrosomal clustering inhibition (IC₅₀ = 5 µM) identifies analogs with dual antifungal/anticancer activity .
• Dynamic instability assays : Quantify microtubule rescue/frequency rates to differentiate mechanisms from vinca alkaloids .

Q. What experimental designs are critical for evaluating this compound’s ecological toxicity in agricultural or environmental contexts?

Ecotoxicity studies require multispecies assays:

• Soil microbiota : 16S rRNA sequencing reveals bacterial dominance shifts (bacteria > actinomycetes > fungi) at 1,000 mg/kg .
• Enzyme inhibition : Dose-dependent urease suppression (IC₅₀ = 200 mg/L) and dehydrogenase biphasic effects .
• Plant models : Arabidopsis root elongation assays show minimal phytotoxicity below 200 mg/L .

Q. How does this compound’s pharmacokinetic profile influence its repurposing for oncology, and what combination therapies are methodologically viable?

this compound’s low oral bioavailability (27–72.5%) and hepatic metabolism to 6-DMG limit monotherapy efficacy . Strategies include:

• Adjuvant combinations : Synergy with taxanes (e.g., paclitaxel) via complementary microtubule stabilization/destabilization .
• Nanocarrier systems : PEGylated liposomes improve tumor targeting and reduce hepatic first-pass metabolism .
• Metabolite profiling : LC-MS/MS quantifies 6-DMG levels to optimize dosing schedules .

Q. What advanced techniques elucidate this compound’s species-specific efficacy against dermatophytes (e.g., Microsporum vs. Trichophyton)?

Mechanistic divergence is probed via:

• Proteomic profiling : Tubulin isoform expression differences in Microsporum (β-tubulin dominance) vs. Trichophyton (α-tubulin mutations) .
• Sweat simulation assays : Stratum corneum "wick effect" enhances drug transfer in Microsporum-infected models .
• Comparative genomics : Trichophyton CYP450 upregulation correlates with this compound resistance .

Q. Methodological Notes

• Data validation : Cross-reference IR spectra (2000–700 cm⁻¹) and 60 MHz ¹H NMR to confirm analog identity .
• Ethical compliance : Adhere to ECHA guidelines for ecotoxicity data reproduction .
• Clinical relevance : Prioritize in vivo PK/PD models over static in vitro MIC assays .