Griseofulvin

Comparative Hepatotoxicity of Fluconazole, Ketoconazole, Itraconazole, Terbinafine, and Griseofulvin in Rats.[Pubmed:28261269]

J Toxicol. 2017;2017:6746989.

Oral ketoconazole was recently the subject of regulatory safety warnings because of its association with increased risk of inducing hepatic injury. However, the relative hepatotoxicity of antifungal agents has not been clearly established. The aim of this study was to compare the hepatotoxicity induced by five commonly prescribed oral antifungal agents. Rats were treated with therapeutic oral doses of Griseofulvin, fluconazole, itraconazole, ketoconazole, and terbinafine. After 14 days, only ketoconazole had significantly higher ALT levels (p = 0.0017) and AST levels (p = 0.0008) than the control group. After 28 days, ALT levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, Griseofulvin, and terbinafine, respectively. The AST levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, terbinafine, and Griseofulvin, respectively. All drugs significantly elevated ALP levels after 14 days and 28 days of treatment (p < 0.0001). The liver enzyme levels suggested that ketoconazole had the highest risk in causing liver injury followed by itraconazole, fluconazole, terbinafine, and Griseofulvin. However, histopathological changes revealed that fluconazole was the most hepatotoxic, followed by ketoconazole, itraconazole, terbinafine, and Griseofulvin, respectively. Given the poor correlation between liver enzymes and the extent of liver injury, it is important to confirm liver injury through histological examination.

Synthesis and formulation studies of griseofulvin analogues with improved solubility and metabolic stability.[Pubmed:28258034]

Eur J Med Chem. 2017 Apr 21;130:240-247.

Griseofulvin (1) is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Comprehensive SAR studies have led to the identification of 2'-benzyloxy Griseofulvin 2, a more potent analogue with low micromolar anticancer potency in vitro. Analogue 2 was also shown to retard tumor growth through inhibition of centrosomal clustering in murine xenograft models of colon cancer and multiple myeloma. However, similar to Griseofulvin, compound 2 exhibited poor metabolic stability and aqueous solubility. In order to improve the poor pharmacokinetic properties, 11 Griseofulvin analogues were synthesized and evaluated for biological activity and physiological stabilities including SGF, plasma, and metabolic stability. Finally, the most promising compounds were investigated in respect to thermodynamic solubility and formulation studies. The 2'-benzylamine analogue 10 proved to be the most promising compound with low muM in vitro anticancer potency, a 200-fold increase in PBS solubility over compound 2, and with improved metabolic stability. Furthermore, this analogue proved compatible with formulations suitable for both oral and intravenous administration. Finally, 2'-benzylamine analogue 10 was confirmed to induce G2/M cell cycle arrest in vitro.

Griseofulvin Derivative and Indole Alkaloids from Penicillium griseofulvum CPCC 400528.[Pubmed:28117586]

J Nat Prod. 2017 Feb 24;80(2):371-376.

A new Griseofulvin derivative, 4'-demethoxy-4'-N-isopentylisoGriseofulvin (1), three new indole alkaloids, 2-demethylcyclopiamide E (2), 2-demethylsperadine F (3), and clopiamine C (4), and five known metabolites (5-9) were isolated from Penicillium griseofulvum CPCC 400528. Compound 1 is the first reported Griseofulvin analogue with an N-isopentane group and the first example of a naturally occurring N-containing Griseofulvin analogue. Their structures and absolute configurations were elucidated through extensive spectroscopic analyses, calculated ECD, and single-crystal X-ray diffraction (Cu Kalpha). The possible biogenetic pathway of 1-3 was proposed. Compounds 1, 2, and 5 exhibited anti-HIV activities with IC50 values of 33.2, 20.5, and 12.6 muM, respectively.

Griseofulvin impairs intraerythrocytic growth of Plasmodium falciparum through ferrochelatase inhibition but lacks activity in an experimental human infection study.[Pubmed:28176804]

Sci Rep. 2017 Feb 8;7:41975.

Griseofulvin, an orally active antifungal drug used to treat dermatophyte infections, has a secondary effect of inducing cytochrome P450-mediated production of N-methyl protoporphyrin IX (N-MPP). N-MPP is a potent competitive inhibitor of the heme biosynthetic-enzyme ferrochelatase, and inhibits the growth of cultured erythrocyte stage Plasmodium falciparum. Novel drugs against Plasmodium are needed to achieve malaria elimination. Thus, we investigated whether Griseofulvin shows anti-plasmodial activity. We observed that the intraerythrocytic growth of P. falciparum is inhibited in red blood cells pretreated with Griseofulvin in vitro. Treatment with 100 muM Griseofulvin was sufficient to prevent parasite growth and induce the production of N-MPP. Inclusion of the ferrochelatase substrate PPIX blocked the inhibitory activity of Griseofulvin, suggesting that Griseofulvin exerts its activity through the N-MPP-dependent inhibition of ferrochelatase. In an ex-vivo study, red blood cells from Griseofulvin-treated subjects were refractory to the growth of cultured P. falciparum. However, in a clinical trial Griseofulvin failed to show either therapeutic or prophylactic effect in subjects infected with blood stage P. falciparum. Although the development of Griseofulvin as an antimalarial is not warranted, it represents a novel inhibitor of P. falciparum growth and acts via the N-MPP-dependent inhibition of ferrochelatase.

Griseofulvin(Gris-PEG; Grifulvin) is a spirocyclic fungal natural product used in treatment of fungal dermatophytes; Antifungal drug.

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