title: Synthesis and antimalarial evaluation of prodrugs of novel fosmidomycin analogues.
abstract: The continuous development of drug resistance by Plasmodium falciparum, the agent responsible for the most severe forms of malaria, creates the need for the development of novel drugs to fight this disease. Fosmidomycin is an effective antimalarial and potent antibiotic, known to act by inhibiting the enzyme 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR), essential for the synthesis of isoprenoids in eubacteria and plasmodia, but not in humans. In this study, novel constrained cyclic prodrug analogues of fosmidomycin were synthesized. One, in which the hydroxamate function is incorporated into a six-membered ring, was found have higher antimalarial activity than fosmidomycin against the chloroquine and mefloquine resistant P. falciparum Dd2 strain. In addition, it showed very low cytotoxicity against cultured human cells.
authors.affiliation: LAQV, REQUIMTE, Department of Chemistry, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, Quinta da Torre, 2829-516 Caparica, Portugal. Electronic address: amfp@fct.unl.pt.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Faísca Phillips
authors.affiliation: Medical Parasitology Department, GHTM, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da Junqueira n° 100, 1349-008 Lisboa, Portugal.
authors.forename: Fátima
authors.initials: F
authors.lastname: Nogueira
authors.affiliation: Medical Parasitology Department, GHTM, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da Junqueira n° 100, 1349-008 Lisboa, Portugal.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Murtinheira
authors.affiliation: LAQV, REQUIMTE, Department of Chemistry, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, Quinta da Torre, 2829-516 Caparica, Portugal. Electronic address: mtb@fct.unl.pt.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Barros
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D011355:Prodrugs; D005578:Fosfomycin; C024640:fosmidomycin
keywords: Antimalarial; Fosmidomycin; Hydroxamates; Phospha-Michael; Phosphonates