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Chemical and biological aspects of posaconazole as a classic antifungal agent with non-classical properties: highlighting a tetrahydrofuran-based drug toward generation of new drugs

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Abstract

Posaconazole (PSZ, SCH 56592), is a new generation of orally active triazole antifungal agent with a tetrahydrofuran center, derived from itraconazole (ITZ). This drug has a broader spectrum of activity respect to the dioxolane-based triazoles. Structurally, PSZ molecule with four chiral centers and long side chain has a complicated structure. In this review, we describe general aspects of PSZ, including chemistry, pharmacological properties, mechanism of action, synthetic strategies, synthesis of key intermediates, structure-antifungal activity relationships, and the design of its prodrugs. Finally, the non-classical properties of PSZ including antitrypanosomal, antileishmanial and hedgehog (Hh) signaling pathway inhibitory activities will be discussed. By highlighting the information and experiences gained with PSZ, we can better move toward newer compounds of this generation.

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Abbreviations

9-BBN:

9-Borabicyclo[3,3,1]nonane

BCC:

Basal cell carcinoma

BINAP:

2,2′-Bis(diary1phosphino)-1,l′-binaphthyl

BOB:

Benzyloxybutyrate

BSA:

Bovine serum albumin

CD:

Chagas disease

DBCP:

Dibenzylchlorophosphate

DCM:

Dichloromethane

DIBAL-H:

Diisobutylaluminum hydride

DIPEA:

Diisopropylethylamine

DMAP:

N′,N′-(dimethylamino)pyridine

DMF:

N,N-dimethylformamide

DMSO:

Dimethyl sulfoxide

FLZ:

Fluconazole

GVHD:

Graft versus host disease

HATU:

1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5b]pyridinium 3-oxide hexafluorophosphate

Hh:

Hedgehog

HSGT:

Hematopoietic stem cell transplantation

ITZ:

Itraconazole

LAH:

Lithium aluminum hydride

LT:

Long-tail

MB:

Medulloblastoma

MD:

Molecular dynamic

MTBE:

Methyl tertiary-butyl ether

NBS:

N-Bromosuccinimide

NMM:

N-Methylmorpholine

OXZ:

(4R)-(+)-4-benzyl-2-oxazolidinone

PSZ:

Posaconazole

SAR:

Structure-activity relationship

SOB:

4-Silyloxybutyrates

SMO:

Smoothened

ST:

Short-tail

TBAF:

Tetrabutylammonium fluoride

TBSCl:

tert-Butyldimethylsilyl chloride

TEA:

Triethylamine

THF:

Tetrahydrofuran

VRZ:

Voriconazole

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Authors and Affiliations

  1. Department of Medicinal Chemistry and Radiopharmacy, Faculty of Pharmacy, Baqiyatallah University of Medical Sciences, Tehran, Iran

    Sakineh Dadashpour

  2. Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

    Elham Ghobadi & Saeed Emami

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  1. Sakineh Dadashpour
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Correspondence to Saeed Emami.

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Dadashpour, S., Ghobadi, E. & Emami, S. Chemical and biological aspects of posaconazole as a classic antifungal agent with non-classical properties: highlighting a tetrahydrofuran-based drug toward generation of new drugs. Med Chem Res 31, 833–850 (2022). https://doi.org/10.1007/s00044-022-02901-2

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