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

0446744 - ÚOCHB 2016 RIV DE eng J - Journal Article
Česnek, Michal - Jansa, Petr - Šmídková, Markéta - Mertlíková-Kaiserová, Helena - Dračínský, Martin - Brust, T. F. - Pávek, P. - Trejtnar, F. - Watts, V. J. - Janeba, Zlatko
Bisamidate Prodrugs of 2-Substituted 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA, adefovir) as Selective Inhibitors of Adenylate Cyclase Toxin from Bordetella pertussis.
ChemMedChem. Roč. 10, č. 8 (2015), s. 1351-1364. ISSN 1860-7179. E-ISSN 1860-7187
R&D Projects: GA MV VG20102015046
Institutional support: RVO:61388963
Keywords : adenylate cyclase toxin * bisamidates * Bordetella pertussis * nucleosides * phosphonates
Subject RIV: CC - Organic Chemistry
Impact factor: 2.980, year: 2015

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.
Permanent Link: http://hdl.handle.net/11104/0248752