Bacterial resistance is eroding the clinical utility of existing antibiotics necessitating the discovery of new agents. Bacterial type II topoisomerase is a clinically validated, highly effective, and proven drug target. This target is amenable to inhibition by diverse classes of inhibitors with alternative and distinct binding sites to quinolone antibiotics, thus enabling the development of agents that lack cross-resistance to quinolones. Described here are novel bacterial topoisomerase inhibitors (NBTIs), which are a new class of gyrase and topo IV inhibitors and consist of three distinct structural moieties. The substitution of the linker moiety led to discovery of potent broad-spectrum NBTIs with reduced off-target activity (hERG IC 50 > 18 μM) and improved physical properties. AM8191 is bactericidal and selectively inhibits DNA synthesis and Staphylococcus aureus gyrase (IC 50 = 1.02 μM) and topo IV (IC 50 = 10.4 μM). AM8191 showed parenteral and oral efficacy (ED 50 ) at less than 2.5 mg/kg doses in a S. aureus murine infection model. A cocrystal structure of AM8191 bound to S. aureus DNA-gyrase showed binding interactions similar to that reported for GSK299423, displaying a key contact of Asp83 with the basic amine at position-7 of the linker.
We report the first total synthesis of the complex C-aryl glycoside isokidamycin, the epimer of the naturally-occurring pluramycin antibiotic kidamycin. The synthesis features a highly efficientDiels-Alder reaction between a substituted naphthyne and a glycosylatedfuran to form the anthracene core bearing a pendant angolosamine C-glycoside. The regiochemical outcome of the Diels-Alder reaction was controlled by employing a disposable silicon-tether to link the reactive napthyne and the glycosyl furan, rendering the cycloaddition intramolecular. The benzopyranone moietyof the aromatic nucleus was appended by cyclization of a functionalized vinylogous amide onto an advanced anthrol intermediate. The vancosamine amino glycoside was introduced by an O→C-glycoside rearrangement that produced the β-anomer. Subsequent refunctionalizations then led to isokidamycin.
The synthesis of isokidamycin, which represents the first total synthesis of a bis-C-aryl glycoside natural product in the pluramycin family, has been completed. The synthesis features the use of a silicon tether as a disposable regiocontrol element in an intramolecular Diels-Alder reaction between a substituted naphthyne and a glycosyl furan and a subsequent O → C-glycoside rearrangement.Kidamycin (1) is a member of the pluramycin class of C-aryl glycoside antibiotics that was isolated from Streptomyces phaeoverticillatus and displays a broad range of antibacterial, antifungal and anticancer properties.i Like other pluramycins, 1 binds to DNA, leading to single strand cleavage.ii Kidamycin possesses an angular anthrapyranone tetracyclic core that is adorned with a β-angolosaminyl C-glycoside substituent at C(8) and an α-N,Ndimethylvancosaminyl C-glycoside group at C(10).iii Kidamycin (1) is both light and acid sensitive and is easily transformed into isokidamycin (2) upon treatment with acid.iiia , iv No doubt owing to their complex structures and labile functionality, none of the bis-Carylglycoside antibiotics of the pluramycin family have succumbed to total synthesis. Indeed, few have even dared to embark on such a challenging enterprise.v Several years ago we reported a unified strategy for preparing the four major classes of Caryl glycoside antibiotics.vi The approach relies on the ring-opening of glycosyl-substituted oxabicycles that are produced by the Diels-Alder reactions of substituted arynes with glycosyl furans. A significant feature of this novel entry to C-aryl glycosides is that it couples the introduction of the C-aryl glycoside moiety with the annelation of a new aromatic ring, thereby leading to a rapid increase in complexity. We subsequently applied this method to the syntheses of several C-aryl glycoside natural products.vii However, we wished to extend this methodology to the synthesis of a more complex member of the pluramycin family. We now report our efforts in this area that resulted in the total synthesis of isokidamycin (2), the first bis-C-arylglycoside antibiotic to be prepared by total synthesis.The essential elements of our approach to kidamycin are outlined in Figure 1. Given the known propensity for the N,N-dimethylvancosamine moiety at C(10) of 1 to suffer epimerization at the anomeric center to give 2, we favored the late stage introduction of this residue from the advanced intermediate 3 using the O→C-glycoside rearrangement that had been pioneered by Suzuki and had been shown to be applicable to the preparation of some α-C-aryl glycosides.viii We envisioned that anthrol 3 would be accessible from 4 by cleavage of the disposable silicon tether, ring-opening of the oxabicycle, and annelation of the NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript substituted pyranone ring. Intermediate 4 would then be formed by the pivotal intramolecular naphthyne-furan cycloaddition that would be initiated by reductive dehalogenation of 5, which would be assem...
Silicon tethers were employed to control the regiochemistry of Diels-Alder reactions between substituted benzynes and glycosyl furans as a key step in the syntheses of unsymmetrical representatives of three major groups of C-aryl glycosides. The cycloaddition precursors were readily prepared by O-alkylation of substituted phenols with various sugar-substituted furylsilane derivatives. Selective deprotonation on the benzene ring of these ethers led to a benzyne that underwent an intramolecular Diels-Alder reaction to give bridged cycloadducts. Fluoride-induced removal of the silicon tether and acid-catalyzed ring opening of the oxabicycloheptadiene subunit yielded the desired C-aryl glycosides as single isomers.
dOxabicyclooctane-linked novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of recently described antibacterial agents with broad-spectrum activity. NBTIs dually inhibit the clinically validated bacterial targets DNA gyrase and topoisomerase IV and have been shown to bind distinctly from known classes of antibacterial agents directed against these targets. Herein we report the molecular, cellular, and in vivo characterization of AM-8722 as a representative N-alkylated-1,5-naphthyridone left-hand-side-substituted NBTI. Consistent with its mode of action, macromolecular labeling studies revealed a specific effect of AM-8722 to dose dependently inhibit bacterial DNA synthesis. AM-8722 displayed greater intrinsic enzymatic potency than levofloxacin versus both DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli and displayed selectivity against human topoisomerase II. AM-8722 was rapidly bactericidal and exhibited whole-cell activity versus a range of Gram-negative and Gram-positive organisms, with no whole-cell potency shift due to the presence of DNA or human serum. Frequency-of-resistance studies demonstrated an acceptable rate of resistance emergence in vitro at concentrations 16-to 32-fold the MIC. AM-8722 displayed acceptable pharmacokinetic properties and was shown to be efficacious in mouse models of bacterial septicemia. Overall, AM-8722 is a selective and potent NBTI that displays broad-spectrum antimicrobial activity in vitro and in vivo.
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