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Α,Α-Difluorophosphonohydroxamic Acid Derivatives Among the Best molecules Article α,α-Difluorophosphonohydroxamic Acid Derivatives among the Best Antibacterial Fosmidomycin Analogues Aurore Dreneau, Fanny S. Krebs, Mathilde Munier, Chheng Ngov , Denis Tritsch, Didier Lièvremont, Michel Rohmer and Catherine Grosdemange-Billiard * Laboratoire de Chimie et Biochimie de Molécules Bioactives, Université de Strasbourg/CNRS, UMR 7177, Institut Le Bel, 4 Rue Blaise Pascal, 67081 Strasbourg, France; [email protected] (A.D.); [email protected] (F.S.K.); [email protected] (M.M.); [email protected] (C.N.); [email protected] (D.T.); [email protected] (D.L.); [email protected] (M.R.) * Correspondence: [email protected]; Tel.: +33-368-851-349 Abstract: Three α,α-difluorophosphonate derivatives of fosmidomycin were synthesized from di- ethyl 1,1-difluorobut-3-enylphosphonate and were evaluated on Escherichia coli. Two of them are among the best 1-deoxy-D-xylulose 5-phosphate reductoisomerase inhibitors, with IC50 in the nM range, much better than fosmidomycin, the reference compound. They also showed an enhanced antimicrobial activity against E. coli on Petri dishes in comparison with the corresponding phosphates and the non-fluorinated phosphonate. Citation: Dreneau, A.; Krebs, F.S.; Munier, M.; Ngov, C.; Tritsch, D.; Keywords: α,α-difluorophosphonate; deoxyxylulose phosphate reductoisomerase; 1-deoxy-D- Lièvremont, D.; Rohmer, M.; xylulose 5-phosphate reductoisomerase (DXR); antimicrobial; fosmidomycin; isoprenoid biosynthesis; Grosdemange-Billiard, C. D α,α-Difluorophosphonohydroxamic 2-C-methyl- -erythritol 4-phosphate (MEP) pathway Acid Derivatives among the Best Antibacterial Fosmidomycin Analogues. Molecules 2021, 26, 5111. https://doi.org/10.3390/molecules 1. Introduction 26165111 Antimicrobial resistance affecting anyone in any country is rising to dangerously high levels in all parts of the world and has been recognized as a global health crisis by the Academic Editors: United Nations and the World Health Organization (WHO). As a result, the antibiotic Camilla Parmeggiani, treatment of a growing number of infections, e.g., tuberculosis, pneumonia, gonorrhea, and Camilla Matassini and salmonellosis, are becoming less and less effective. In 2017, WHO reported a list of twelve Francesca Cardona priority pathogens, mostly Gram-negative bacteria belonging to e.g., the Enterobacteriaceae or to other groups (e.g., Acinetobacter baumannii, Pseudomonas aeruginosa. ) for which it is Received: 28 July 2021 urgent to find new treatments [1]. Recently, a study of the European Centre for Disease Accepted: 22 August 2021 Prevention and Control (ECDPC) estimated that about 33,000 people died each year from an Published: 23 August 2021 infection due to antimicrobial-resistant bacteria, frequently while receiving health care i.e., from nosocomial infections [2]. It is therefore crucial and urgent to identify new targets in Publisher’s Note: MDPI stays neutral order to elaborate and develop new drugs. In this respect, the biosynthesis of isopentenyl with regard to jurisdictional claims in published maps and institutional affil- diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), the two precursors of all iations. isoprenoids, via the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway is an attractive prospect. In fact, this pathway is essential and present in many Gram-negative and Gram- positive bacteria as well as protozoans, e.g., Plasmodium species responsible for malaria [3]. As this pathway is absent in humans, each enzyme is a potential target to elaborate new antimicrobial compounds with expected minimal side effects for the patient. Part of our Copyright: © 2021 by the authors. work on the design of new antimicrobials is based on the inhibition of the second enzyme Licensee MDPI, Basel, Switzerland. of the MEP pathway, the 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), which This article is an open access article D distributed under the terms and catalyzes the conversion of 1-deoxy- -xylulose 5-phosphate (DXP) 1 into MEP 2 in the 2+ 2+ conditions of the Creative Commons presence of a divalent metal ion (Mg or Mn ) and NADPH as cofactors (Scheme1). Attribution (CC BY) license (https:// Indeed, fosmidomycin 3a and its N-acetyl homologue, FR-900098 3b, two natural creativecommons.org/licenses/by/ retrohydroxamate phosphonic acids isolated from Streptomyces spp., are selective inhibitors 4.0/). of DXR [4,5]. However, their use in antibiotherapy is limited due to their fast clearance and Molecules 2021, 26, 5111. https://doi.org/10.3390/molecules26165111 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 5111 2 of 15 the rapid emergence of resistance as observed with fosmidomycin [6,7]. In an attempt to improve the efficiency of such inhibitors, numerous analogues of fosmidomycin have been synthesized. From these results, it is clear that neither the retro-hydroxamate chelating moiety nor the phosphonate anchoring group can be replaced without a drastic loss of activity except for the inversion of the retrohydroxamate into a hydroxamate (compounds Molecules 2021, 26, 5111 2 of 15 4a,b, Scheme1)[ 8] and for the replacement of a phosphonate with a phosphate group (compounds 5a,b and 6a,b, Scheme1) as we previously reported [9]. Scheme 1. 1. TheThe 1-deoxyxylulose 1-deoxyxylulose 5-phosphate 5-phosphate reductoisomerase reductoisomerase (DXR) (DXR)and its inhibitors. and its inhibitors. Indeed,Even if fosmidomycin the phosphate 3a and derivatives its N-acetyl (compounds homologue,5a FR-900098,b, Scheme 3b,1 two) were natural previously shownretrohydroxamate to be more phosphonic potent inhibitors acids isolated of thefromSynechocystis Streptomyces spp.,DXR are than selective their inhibi- phosphonate analoguestors of DXR [4,5]. [10], However, this conclusion their use isin notantibi validotherapy for allis limited DXRs, due as to we their have fast clearance shown that they areand lessthe rapid efficient emergence against of resistance the E. coli asand observMycobacteriumed with fosmidomycin smegmatis [6,7].DXRs In an [attempt9]. Although a phosphonateto improve the groupefficiency is consideredof such inhibitors to be, isostericnumerous to analogues a phosphate of fosmidomycin group, some have differences suchbeen synthesized. as the pKa valuesFrom these and results, the C-O-P/C-C-P it is clear that bondneither angles the retro-hydroxamate might impact their chelat- binding in ing moiety nor the phosphonate anchoring group can be replaced without a drastic loss the enzyme active site. Introduction of fluorine atoms in α position of the phosphonate of activity except for the inversion of the retrohydroxamate into a hydroxamate (com- moietypounds results4a,b, Scheme in significant 1) [8] and changes for the replacement in biological of propertiesa phosphonate and with in metabolic a phosphate stability as comparedgroup (compounds with the 5a,b non-fluorinated and 6a,b, Scheme compounds 1) as we previously [11–13]. Van reported Calenbergh [9]. et al. reported the synthesisEven ofif the FR-900098 phosphate and derivatives its hydroxamic (compounds derivative 5a,b, in Scheme which 1) the were phosphonate previously has been replacedshown to withbe more a phosphatase-stable potent inhibitors of theα-monofluoromethylenephosphonate Synechocystis DXR than their phosphonate7 and ana-8 [14]. The racemiclogues, [10] mixtures this conclusion of these syntheticis not valid compounds for all DXRs, were as we evaluated have shownin vitro that theyand inare vivo less for their antimalarialefficient against potentials the E. coli and and were Mycobacterium shown to besmegmatis more effective DXRs [9]. than Although the reference a phospho- compounds 3anate,b .group The presence is considered of an to electron-withdrawing be isosteric to a phosphate substituent, group, some in particular differences fluorine, such as in the α the pKa values and the C-O-P/C-C-P bond angles might impact their binding in the en- position of the phosphonate moiety, resulted in the decrease of the pKa2 of such compounds (fromzyme active ca. 7.5 site. to Introduction ca. 6.4), almost of fluorine identical atoms to in that α position of a phosphate of the phosphonate group, whichmoiety is in the dianionicresults in significant form at the changes pH of thein biological enzymatic properties assay, whereas and in themetabolic phosphonate stability is as predominantly com- pared with the non-fluorinated compounds [11–13]. Van Calenbergh et al. reported the in a singly ionized form. By comparison with the α-monofluoromethylene group, which is synthesis of FR-900098 and its hydroxamic derivative in which the phosphonate has been isoacidic of a phosphate group [15], the α,α-difluoromethylene is an isopolar mimic of the replaced with a phosphatase-stable α-monofluoromethylenephosphonate 7 and 8 [14]. oxygenThe racemic component mixtures ofof thethese P-O-C synthetic linkage comp inounds phosphate were evaluated [16] and in has vitro been and used in vivo to prepare non-hydrolyzablefor their antimalarialphosphate potentials and analogues were shown of nucleotidesto be more effective [17], phosphatidylinositol than the reference [18], compounds 3a,b. The presence of an electron-withdrawing substituent, in particular flu- orine, in the α position of the phosphonate moiety, resulted in the decrease of the pKa2 of Molecules 2021, 26, 5111 3 of 15 such compounds (from ca. 7.5 to ca. 6.4), almost identical to that of a phosphate group, which is in the dianionic form at the pH of the enzymatic assay, whereas
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