Posaconazole is a synthetic, broad-spectrum, second generation triazole with antifungal activity. It has potent in vitro and in vivo trypanocidal activity. It was discovered by Schering-Plough and it is a structural analog of itraconazole. It has promising anti-cancer properties. Posaconazole is slightly soluble in DMSO but is practically insoluble in water.
|Mechanism of Action||Posaconazole blocks ergosterol synthesis, by inhibiting the enzyme lanosterol 14 α-demethylase. The result is an accumulation of methylated sterol precursors. It also inhibits CYP3A4, but does not inhibit the activity of other CYP enzymes thus it may have the potential for fewer drug interactions.|
Broad-spectrum antifungal activity including yeast (Candida) and fungi (Aspergillus spp. Scedosporium, Fusarium spp. Zygomycetes spp). It is effective against a parasitological cure in a murine model of Chagas disease caused by Trypanosoma cruzi. Triazole resistance is increasing among fungal pathogens including Candida spp. due to multiple molecular mechanisms.
Posaconazole was involved in a 10-year study of 19,000 clinically important strains of yeast and mold with 200 medical centers participating. Strains were tested using CLSI broth microdilution methods with RPMI 1640 medium, with MIC50 (0.063 ug/ml) and MIC90 (1 µg/ml) for all fungal isolates in the database. . For both yeasts and molds, MIC90 was 1 µg/ml. The compound was active against Candida and Aspergillus isolates that are resistant to Fluconazole, Voriconazole, and Amphotericin B (Sabatelli et al, 2006).
The in vivo efficacy of Poscanazole was studied in a murine model against 4 Aspergillus fumigatus isolates with MICs values of 0.03-16 mg/L. Resistance mechanisms included substitutions in the cyp51A gene. (Mavridou et al, 2010).
As a trypanocidal agent, it can act synergistically with Amiodarone. It disrupts Ca2+ homeostasis in T. cruzi (Benaim et al, 2006). The antiproliferative synergism of the compounds was characterized using electron microscopy (Veiga-Santos P et al, 2012) and this association is promising against T. cruzi.
|Cancer Applications||Deregulation of the Hedgehog (Hh) pathway signaling pathway, a highly conserved developmental pathway, leads to disorders and cancers such as basal cell carcinoma. Under normal conditions, binding of a Hh ligand, relieves its inhibition of Smoothened (SMO), a transmembranae protein. Posaconazole inhibits the Hh pathway that by a similar mechanism to itraconazole. It is a promising compound for Hh-dependent cancers (Chen B et al, 2016).|
|Solubility||Slightly soluble in DMSO. Practically insoluble in water.|
Benaim G et al (2006) Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with Posaconazole. J. Med. Chem. 49(3):892-899 PMID 16451055
Chen CK (2010) Structural characterization of CYP51 from Trypanosoma cruzi and Trypanosoma brucei bound to the antifungal drugs Posaconazole and fluconazole. PLoS Negl Trop Dis. 4(4):e651 PMID 20386598
Chen B et al (2016) Posaconazole, a second-generation triazole antifungal drug, inhibits the hedgehog signaling pathway and progression of basal cell carcinoma. Mol Cancer Ther . 15(5):866-876
Harbrecht R (2004) Posconazole: A potent, extended-spectrum triazole anti-fungal for the treatment of serious fungal infections. Int. J. Clin. Pract. 58(6):612-624
Mavridou E, Brüggemann RJ, Melchers WJ, Mouton JW, Verweij PE (2010) Efficacy of Posaconazole against three clinical Aspergillus fumigatus isolates with mutations in the cyp51A gene. Antimicrob. Agents Chemother. 54(2):860-865 PMID 19917751
Nomeir AA et al (2008) Posaconazole (Noxafil, SCH 56592), a new azole antifungal drug, was a discovery based on the isolation and mass spectral characterization of a circulating metabolite of an earlier lead (SCH 51048). J Mass Spectrom. 43(4):509-517 PMID 18059003
Sabatelli F et al (2006) In vitro activities of Posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts. Antimicrob. Agents Chemother. 50(6):2009-2015 PMID 16723559