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Thiazolide Prodrug Esters and Derived Peptides: Synthesis and Activity.

ABSTRACT: 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.

SUBMITTER: Stachulski AV

PROVIDER: S-EPMC10436260 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Thiazolide Prodrug Esters and Derived Peptides: Synthesis and Activity.

Stachulski Andrew V AV Rossignol Jean-Francois JF Pate Sophie S Taujanskas Joshua J Iggo Jonathan A JA Aerts Rudi R Pascal Etienne E Piacentini Sara S La Frazia Simone S Santoro M Gabriella MG van Vooren Lieven L Sintubin Liesje L Cooper Mark M Swift Karl K O'Neill Paul M PM

ACS bio & med chem Au 20230411 4

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 solubilit ...[more]

PMID: 37599793

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