Acyloxybenzyl and Alkoxyalkyl Prodrugs of a Fosmidomycin Surrogate as Antimalarial and Antitubercular Agents.

Two classes of prodrugs of a fosmidomycin surrogate were synthesized and investigated for their ability to inhibit in vitro growth of P. falciparum and M. tuberculosis. To this end, a novel efficient synthesis route was developed involving a cross metathesis reaction as a key step. Alkoxyalkyl prodrugs show decent antimalarial activities, but acyloxybenzyl prodrugs proved to be the most interesting and show enhanced antimalarial and antitubercular activity. The most active antimalarial analogues show low nanomolar IC50 values.

[1]  C. Dowd,et al.  The Methylerythritol Phosphate Pathway: Promising Drug Targets in the Fight against Tuberculosis. , 2018, ACS infectious diseases.

[2]  B. Lell,et al.  Efficacy and Safety of Fosmidomycin–Piperaquine as Nonartemisinin-Based Combination Therapy for Uncomplicated Falciparum Malaria: A Single-Arm, Age De-escalation Proof-of-Concept Study in Gabon , 2017, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[3]  M. Groll,et al.  The Methylerythritol Phosphate Pathway to Isoprenoids. , 2017, Chemical reviews.

[4]  A. Pain,et al.  Emergence of Indigenous Artemisinin-Resistant Plasmodium falciparum in Africa. , 2017, The New England journal of medicine.

[5]  J. Balzarini,et al.  Membrane-permeable Triphosphate Prodrugs of Nucleoside Analogues. , 2016, Angewandte Chemie.

[6]  J. Balzarini,et al.  Lipophilic prodrugs of nucleoside triphosphates as biochemical probes and potential antivirals , 2015, Nature Communications.

[7]  J. Balzarini,et al.  Nucleoside Diphosphate Prodrugs: Nonsymmetric DiPPro-Nucleotides. , 2015, Journal of medicinal chemistry.

[8]  Johan Wouters,et al.  Synthesis and bioactivity of β-substituted fosmidomycin analogues targeting 1-deoxy-D-xylulose-5-phosphate reductoisomerase. , 2015, Journal of medicinal chemistry.

[9]  A. Bacher,et al.  Prodrugs of reverse fosmidomycin analogues. , 2015, Journal of medicinal chemistry.

[10]  Andrew S Murkin,et al.  Mechanism and inhibition of 1-deoxy-D-xylulose-5-phosphate reductoisomerase. , 2014, Bioorganic chemistry.

[11]  A. Hirsch,et al.  Development of inhibitors of the 2C-methyl-D-erythritol 4-phosphate (MEP) pathway enzymes as potential anti-infective agents. , 2014, Journal of medicinal chemistry.

[12]  R. Schinazi,et al.  Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs , 2014, Chemical reviews.

[13]  M. Rohmer,et al.  Growth inhibition of Mycobacterium smegmatis by prodrugs of deoxyxylulose phosphate reducto-isomerase inhibitors, promising anti-mycobacterial agents. , 2012, European journal of medicinal chemistry.

[14]  H. Boshoff,et al.  Antibacterial and antitubercular activity of fosmidomycin, FR900098, and their lipophilic analogs. , 2011, Bioorganic & medicinal chemistry letters.

[15]  D. Roos,et al.  Fosmidomycin Uptake into Plasmodium and Babesia-Infected Erythrocytes Is Facilitated by Parasite-Induced New Permeability Pathways , 2011, PloS one.

[16]  S. van Calenbergh,et al.  Synthesis and evaluation of alpha-halogenated analogues of 3-(acetylhydroxyamino)propylphosphonic acid (FR900098) as antimalarials. , 2010, Journal of medicinal chemistry.

[17]  K. Silamut,et al.  Artemisinin resistance in Plasmodium falciparum malaria. , 2009, The New England journal of medicine.

[18]  K. Hostetler.  Alkoxyalkyl prodrugs of acyclic nucleoside phosphonates enhance oral antiviral activity and reduce toxicity: current state of the art. , 2009, Antiviral research.

[19]  J. Balzarini,et al.  Bioreversible protection of nucleoside diphosphates. , 2008, Angewandte Chemie.

[20]  T. Parish,et al.  Bmc Microbiology , 2022 .

[21]  J. Wiesner,et al.  Double Ester Prodrugs of FR900098 Display Enhanced In‐Vitro Antimalarial Activity , 2007, Archiv der Pharmazie.

[22]  Nidhi Singh,et al.  Targeting the methyl erythritol phosphate (MEP) pathway for novel antimalarial, antibacterial and herbicidal drug discovery: inhibition of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) enzyme. , 2007, Current pharmaceutical design.

[23]  J. Karbwang,et al.  Pharmacokinetics and pharmacodynamics of fosmidomycin monotherapy and combination therapy with clindamycin in the treatment of multidrug resistant falciparum malaria , 2007, Malaria Journal.

[24]  J. Wiesner,et al.  Short-Course Regimens of Artesunate-Fosmidomycin in Treatment of Uncomplicated Plasmodium falciparum Malaria , 2005, Antimicrobial Agents and Chemotherapy.

[25]  Roland Lange,et al.  The crystal structure of E.coli 1-deoxy-D-xylulose-5-phosphate reductoisomerase in a ternary complex with the antimalarial compound fosmidomycin and NADPH reveals a tight-binding closed enzyme conformation. , 2005, Journal of molecular biology.

[26]  J. Wiesner,et al.  Fosmidomycin-clindamycin for Plasmodium falciparum Infections in African children. , 2004, The Journal of infectious diseases.

[27]  O. Berg,et al.  Biological Costs and Mechanisms of Fosfomycin Resistance in Escherichia coli , 2003, Antimicrobial Agents and Chemotherapy.

[28]  R. Grubbs,et al.  A general model for selectivity in olefin cross metathesis. , 2003, Journal of the American Chemical Society.

[29]  S. Furukawa,et al.  Fosmidomycin Resistance in Adenylate Cyclase Deficient (cya) Mutants of Escherichia coli , 2003, Bioscience, biotechnology, and biochemistry.

[30]  A. Hoveyda,et al.  Efficient and Recyclable Monomeric and Dendritic Ru-Based Metathesis Catalysts , 2000 .

[31]  M. Nishida,et al.  Pharmacokinetics of fosmidomycin, a new phosphonic acid antibiotic , 1982, Antimicrobial Agents and Chemotherapy.