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Acyloxyalkyl ester prodrugs of FR900098 with improved in vivo anti-malarial activity
Authors:Ortmann Regina  Wiesner Jochen  Reichenberg Armin  Henschker Dajana  Beck Ewald  Jomaa Hassan  Schlitzer Martin
Affiliation:1. Department für Pharmazie, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, D-81377 München, Germany;2. Biochemisches Institut, Justus-Liebig-Universität Gießen, Friedrichstrasse 24, D-35392 Gießen, Germany;1. Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China;2. Faculty of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan;1. Research Center for Advanced Computation, Xihua University, College of Science, Xihua University, Chengdu 610039, PR China;2. College of Rongchang, Southwest University, Chongqing 402460, PR China;3. Institute for Clean Energy & Advanced Materials, Southwest University, Chongqing 400715, PR China;1. Department of Chemistry, Physical Chemistry Division, CSIR–National Chemical Laboratory, Pune 411008, India;2. Indian Institute of Technology Bombay, Powai, Mumbai 400076, India;1. Cellular Therapy and Immunology, Manashi Chakrabarti Foundation, Kolkata, India;2. Department of Blood and Marrow Transplantation, Dharamshila Narayana Superspeciality Hospital and Research Centre, New Delhi, India;1. Department of Physics, Northeast Petroleum University, Daqing 163318, China;2. College of Electrical Engineering, Suihua University, Suihua, Heilongjiang 152000, China;3. Department of Physics, Harbin Institute of Technology, Harbin 150001, China
Abstract:FR900098 represents an improved derivative of the new antimalarial drug fosmidomycin and acts through inhibition of the 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase, an essential enzyme of the mevalonate independent pathway of isoprenoid biosynthesis. Prodrugs with increased activity after oral administration were obtained by chemical modification of the phosphonate moiety to yield acyloxyalkyl esters. The most successful compound demonstrated 2-fold increased activity in mice infected with the rodent malaria parasite Plasmodium vinckei.
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