Počet záznamů: 1

Bisamidate Prodrugs of 2-Substituted 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA, adefovir) as Selective Inhibitors of Adenylate Cyclase Toxin from Bordetella pertussis

SYSNO ASEP	0446744
Druh ASEP	J - Článek v odborném periodiku
Zařazení RIV	J - Článek v odborném periodiku
Poddruh J	Článek ve WOS
Název	Bisamidate Prodrugs of 2-Substituted 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA, adefovir) as Selective Inhibitors of Adenylate Cyclase Toxin from Bordetella pertussis
Tvůrce(i)	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, ORCID}
Celkový počet autorů	10
Zdroj.dok.	ChemMedChem. - : Wiley - ISSN 1860-7179 Roč. 10, č. 8 (2015), s. 1351-1364
Poč.str.	14 s.
Jazyk dok.	eng - angličtina
Země vyd.	DE - Německo
Klíč. slova	adenylate cyclase toxin ; bisamidates ; Bordetella pertussis ; nucleosides ; phosphonates
Vědní obor RIV	CC - Organická chemie
CEP	VG20102015046 GA MV - Ministerstvo vnitra
Institucionální podpora	UOCHB-X - RVO:61388963
UT WOS	000358516200008
EID SCOPUS	84937968759
DOI	10.1002/cmdc.201500183
Anotace	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.
Pracoviště	Ústav organické chemie a biochemie
Kontakt	asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434
Rok sběru	2016

Počet záznamů: 1