Thiazolide Prodrug Esters and Derived Peptides: Synthesis and Activity

被引：0

作者：

Stachulski, Andrew V. ^{[1
]}

Rossignol, Jean-Francois ^{[2
]}

Pate, Sophie ^{[1
]}

Taujanskas, Joshua ^{[1
]}

Iggo, Jonathan A. ^{[1
]}

Aerts, Rudi ^{[3
]}

Pascal, Etienne ^{[3
]}

Piacentini, Sara ^{[4
]}

La Frazia, Simone ^{[4
]}

Santoro, M. Gabriella ^{[4
,5
]}

van Vooren, Lieven ^{[6
]}

Sintubin, Liesje ^{[6
]}

Cooper, Mark ^{[7
]}

Swift, Karl ^{[7
]}

O'Neill, Paul M. ^{[1
]}

机构：

[1] Univ Liverpool, Dept Chem, Donnan & Robert Robinson Labs, Liverpool L69 7ZD, England

[2] Romark Labs LC, Tampa, FL 33609 USA

[3] Romark Belgium BVBA, B-3400 Landen, Belgium

[4] Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy

[5] CNR, Inst Translat Pharmacol, I-00133 Rome, Italy

[6] Ardena Gent NV, B-9030 Mariakerke, Belgium

[7] Bio Techne, Bristol BS11 9QD, England

来源：

ACS BIO & MED CHEM AU | 2023年 / 3卷 / 04期

关键词：

antiviral; prodrug; time-course; NMR; rearrangement; influenza A; clinical; trials; HEPATITIS-B-VIRUS; POTENT INHIBITORS; DOUBLE-BLIND; NITAZOXANIDE; DERIVATIVES; TIZOXANIDE;

D O I：

10.1021/acsbiomedchemau.2c00083

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Amino acid ester prodrugs of the thiazolides, introduced to improve the pharmacokinetic parameters of the parent drugs, proved to be stable as their salts but were unstable at pH > 5. Although some of the instability was due to simple hydrolysis, we have found that the main end products of the degradation were peptides formed by rearrangement. These peptides were stable solids: they maintained significant antiviral activity, and in general, they showed improved pharmacokinetics (better solubility and reduced clearance) compared to the parent thiazolides. We describe the preparation and evaluation of these peptides.

引用

页码：327 / 334

页数：8

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