1,2,4-Thiadiazole acyclic nucleoside phosphonates as inhibitors of cysteine dependent enzymes cathepsin K and GSK-3ß.
Bioorg Med Chem
; 32: 115998, 2021 02 15.
Article
em En
| MEDLINE
| ID: mdl-33440320
ABSTRACT
In analogy to antiviral acyclic nucleoside phosphonates, a series of 5-amino-3-oxo-1,2,4-thiadiazol-3(2H)-ones bearing a 2-phosphonomethoxyethyl (PME) or 3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) group at the position 2 of the heterocyclic moiety has been synthesized. Diisopropyl esters of PME- and HPMP-amines have been converted to the N-substituted ureas and then reacted with benzoyl, ethoxycarbonyl, and Fmoc isothiocyanates to give the corresponding thiobiurets, which were oxidatively cyclized to diisopropyl esters of 5-amino-3-oxo-2-PME- or 2-HPMP- 1,2,4-thiadiazol-3(2H)-ones. The phosphonate ester groups were cleaved with bromotrimethylsilane, yielding N5-protected phosphonic acids. The subsequent attempts to remove the protecting group from N5 under alkaline conditions resulted in the cleavage of the 1,2,4-thiadiazole ring. Similarly, compounds with a previously unprotected 5-amino-1,2,4-thiadiazolone base moiety were stable only in the form of phosphonate esters. The series of twenty-one newly prepared 1,2,4-thiadiazol-3(2H)-ones were explored as potential inhibitors of cysteine-dependent enzymes - human cathepsin K (CatK) and glycogen synthase kinase 3ß (GSK-3ß). Several compounds exhibited an inhibitory activity toward both enzymes in the low micromolar range. The inhibitory potency of some of them toward GSK-3ß was similar to that of the thiadiazole GSK-3ß inhibitor tideglusib, whereas others exhibited more favorable toxicity profile while retaining good inhibitory activity.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tiadiazóis
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Inibidores Enzimáticos
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Catepsina K
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Organofosfonatos
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Glicogênio Sintase Quinase 3 beta
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Antineoplásicos
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Nucleosídeos
Limite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Ano de publicação:
2021
Tipo de documento:
Article