title: Bisamidate Prodrugs of 2-Substituted 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA, adefovir) as Selective Inhibitors of Adenylate Cyclase Toxin from Bordetella pertussis.
abstract: 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 =0.145 μM). 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.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i. Flemingovo nám. 2, 166 10 Prague 6 (Czech Republic).
authors.forename: Michal
authors.initials: M
authors.lastname: Česnek
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i. Flemingovo nám. 2, 166 10 Prague 6 (Czech Republic).
authors.forename: Petr
authors.initials: P
authors.lastname: Jansa
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i. Flemingovo nám. 2, 166 10 Prague 6 (Czech Republic).
authors.forename: Markéta
authors.initials: M
authors.lastname: Šmídková
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i. Flemingovo nám. 2, 166 10 Prague 6 (Czech Republic).
authors.forename: Helena
authors.initials: H
authors.lastname: Mertlíková-Kaiserová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i. Flemingovo nám. 2, 166 10 Prague 6 (Czech Republic).
authors.forename: Martin
authors.initials: M
authors.lastname: Dračínský
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN, 47907 (USA).
authors.forename: Tarsis F
authors.initials: TF
authors.lastname: Brust
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 500 05 Hradec Králové (Czech Republic).|Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hněvotínská 5, 775 15 Olomouc (Czech Republic).
authors.forename: Petr
authors.initials: P
authors.lastname: Pávek
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 500 05 Hradec Králové (Czech Republic).
authors.forename: František
authors.initials: F
authors.lastname: Trejtnar
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN, 47907 (USA).
authors.forename: Val J
authors.initials: VJ
authors.lastname: Watts
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i. Flemingovo nám. 2, 166 10 Prague 6 (Czech Republic). janeba@uochb.cas.cz.
authors.forename: Zlatko
authors.initials: Z
authors.lastname: Janeba
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D037361:Adenylate Cyclase Toxin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001886:Bordetella pertussis / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006207:Half-Life; D006801:Humans; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011355:Prodrugs / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar
chemical_list: D037361:Adenylate Cyclase Toxin; D063065:Organophosphonates; D011355:Prodrugs; D020033:Protein Isoforms; D000225:Adenine; C106812:adefovir dipivoxil
keywords: Bordetella pertussis; PMEA; adenylate cyclase toxin; bisamidates; nucleosides; phosphonates; prodrugs