Number of the records: 1
Bisamidate Prodrugs of 2-Substituted 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA, adefovir) as Selective Inhibitors of Adenylate Cyclase Toxin from Bordetella pertussis
- 1.
SYSNO ASEP 0446744 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Bisamidate Prodrugs of 2-Substituted 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA, adefovir) as Selective Inhibitors of Adenylate Cyclase Toxin from Bordetella pertussis Author(s) Česnek, Michal (UOCHB-X) RID, ORCID
Jansa, Petr (UOCHB-X) RID
Šmídková, Markéta (UOCHB-X) RID, ORCID
Mertlíková-Kaiserová, Helena (UOCHB-X) RID, ORCID
Dračínský, Martin (UOCHB-X) RID, ORCID
Brust, T. F. (US)
Pávek, P. (CZ)
Trejtnar, F. (CZ)
Watts, V. J. (US)
Janeba, Zlatko (UOCHB-X) RID, ORCIDNumber of authors 10 Source Title ChemMedChem. - : Wiley - ISSN 1860-7179
Roč. 10, č. 8 (2015), s. 1351-1364Number of pages 14 s. Language eng - English Country DE - Germany Keywords adenylate cyclase toxin ; bisamidates ; Bordetella pertussis ; nucleosides ; phosphonates Subject RIV CC - Organic Chemistry R&D Projects VG20102015046 GA MV - Ministry of Interior (MV) Institutional support UOCHB-X - RVO:61388963 UT WOS 000358516200008 EID SCOPUS 84937968759 DOI 10.1002/cmdc.201500183 Annotation Novel small-molecule agents to treat Bordetella pertussis infections are highly desirable, as pertussis (whooping cough) remains a serious health threat worldwide. In this study, a series of 2-substituted derivatives of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA, adefovir), in their isopropyl ester bis(L-phenylalanine) prodrug form, were designed and synthesized as potent inhibitors of adenylate cyclase toxin (ACT) isolated from B.pertussis. The series consists of PMEA analogues bearing either a linear or branched aliphatic chain or a heteroatom at the C2 position of the purine moiety. Compounds with a small C2 substituent showed high potency against ACT without cytotoxic effects as well as good selectivity over human adenylate cyclase isoforms AC1, AC2, and AC5. The most potent ACT inhibitor was found to be the bisamidate prodrug of the 2-fluoro PMEA derivative (IC50=0.145M). Although the bisamidate prodrugs reported herein exhibit overall lower activity than the bis(pivaloyloxymethyl) prodrug (adefovir dipivoxil), their toxicity and plasma stability profiles are superior. Furthermore, the bisamidate prodrug was shown to be more stable in plasma than in macrophage homogenate, indicating that the free phosphonate can be effectively distributed to target tissues, such as the lungs. Thus, ACT inhibitors based on acyclic nucleoside phosphonates may represent a new strategy to treat whooping cough. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Year of Publishing 2016
Number of the records: 1