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1.
J Med Chem ; 63(1): 66-87, 2020 01 09.
Article in English | MEDLINE | ID: mdl-31804826

ABSTRACT

UDP-3-O-((R)-3-hydroxymyristoyl)-N-glucosamine deacetylase (LpxC) is as an attractive target for the discovery and development of novel antibacterial drugs to address the critical medical need created by multidrug resistant Gram-negative bacteria. By using a scaffold hopping approach on a known family of methylsulfone hydroxamate LpxC inhibitors, several hit series eliciting potent antibacterial activities against Enterobacteriaceae and Pseudomonas aeruginosa were identified. Subsequent hit-to-lead optimization, using cocrystal structures of inhibitors bound to Pseudomonas aeruginosa LpxC as guides, resulted in the discovery of multiple chemical series based on (i) isoindolin-1-ones, (ii) 4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-ones, and (iii) 1,2-dihydro-3H-pyrrolo[1,2-c]imidazole-3-ones. Synthetic methods, antibacterial activities and relative binding affinities, as well as physicochemical properties that allowed compound prioritization are presented. Finally, in vivo properties of lead molecules which belong to the most promising pyrrolo-imidazolone series, such as 18d, are discussed.


Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Escherichia coli Infections/drug therapy , Gram-Negative Bacteria/drug effects , Hydroxamic Acids/therapeutic use , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Escherichia coli/drug effects , Female , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacokinetics , Klebsiella pneumoniae/drug effects , Mice, Inbred ICR , Microbial Sensitivity Tests , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/enzymology , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Pyrroles/therapeutic use
2.
J Med Chem ; 63(1): 88-102, 2020 01 09.
Article in English | MEDLINE | ID: mdl-31804829

ABSTRACT

LpxC inhibitors were optimized starting from lead compounds with limited efficacy and solubility and with the goal to provide new options for the treatment of serious infections caused by Gram-negative pathogens in hospital settings. To enable the development of an aqueous formulation for intravenous administration of the drug at high dose, improvements in both solubility and antibacterial activity in vivo were prioritized early on. This lead optimization program resulted in the discovery of compounds such as 13 and 30, which exhibited high solubility and potent efficacy against Gram-negative pathogens in animal infection models.


Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Escherichia coli Infections/drug therapy , Hydroxamic Acids/therapeutic use , Administration, Intravenous , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacokinetics , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Gram-Negative Bacteria/drug effects , Hepatocytes/metabolism , Hydroxamic Acids/administration & dosage , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacokinetics , Mice , Microbial Sensitivity Tests , Molecular Structure , Rats , Solubility
3.
J Med Chem ; 60(9): 3776-3794, 2017 05 11.
Article in English | MEDLINE | ID: mdl-28406300

ABSTRACT

There is an urgent unmet medical need for novel antibiotics that are effective against a broad range of bacterial species, especially multidrug resistant ones. Tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent activity against Gram-positive pathogens and no target-mediated cross-resistance with fluoroquinolones. We report our research efforts aimed at expanding the antibacterial spectrum of this class of molecules toward difficult-to-treat Gram-negative pathogens. Physicochemical properties (polarity and basicity) were considered to guide the design process. Dibasic tetrahydropyran-based compounds such as 6 and 21 are potent inhibitors of both DNA gyrase and topoisomerase IV, displaying antibacterial activities against Gram-positive and Gram-negative pathogens (Staphylococcus aureus, Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii). Compounds 6 and 21 are efficacious in clinically relevant murine infection models.


Subject(s)
Anti-Bacterial Agents/pharmacology , Gram-Negative Bacteria/drug effects , Pyrans/pharmacology , Topoisomerase Inhibitors/chemical synthesis , Topoisomerase Inhibitors/pharmacology , Animals , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/chemical synthesis , Guinea Pigs , Humans , Microbial Sensitivity Tests , Myocytes, Cardiac/drug effects , Pyrans/adverse effects , Pyrans/chemical synthesis , Topoisomerase Inhibitors/adverse effects
4.
J Med Chem ; 58(2): 927-42, 2015 Jan 22.
Article in English | MEDLINE | ID: mdl-25494934

ABSTRACT

Novel antibacterial drugs that are effective against infections caused by multidrug resistant pathogens are urgently needed. In a previous report, we have shown that tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. During the course of our optimization program, lead compound 5 was deprioritized due to adverse findings in cardiovascular safety studies. In the effort of mitigating these findings and optimizing further the pharmacological profile of this class of compounds, we have identified a subseries of tetrahydropyran-based molecules that are potent DNA gyrase and topoisomerase IV inhibitors and display excellent antibacterial activity against Gram positive pathogens, including clinically relevant resistant isolates. One representative of this class, compound 32d, elicited only weak inhibition of hERG K(+) channels and hNaV1.5 Na(+) channels, and no effects were observed on cardiovascular parameters in anesthetized guinea pigs. In vivo efficacy in animal infection models has been demonstrated against Staphylococcus aureus and Streptococcus pneumoniae strains.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Gram-Positive Bacteria/drug effects , Pyrans/chemical synthesis , Topoisomerase II Inhibitors/chemical synthesis , Animals , Anti-Bacterial Agents/pharmacology , Guinea Pigs , Hemodynamics/drug effects , Humans , Male , Mice , Microbial Sensitivity Tests , Pyrans/pharmacology , Rats , Rats, Wistar , Structure-Activity Relationship , Topoisomerase II Inhibitors/pharmacology
5.
J Med Chem ; 56(18): 7396-415, 2013 Sep 26.
Article in English | MEDLINE | ID: mdl-23968485

ABSTRACT

There is an urgent need for new antibacterial drugs that are effective against infections caused by multidrug-resistant pathogens. Novel nonfluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) have the potential to become such drugs because they display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. Bacterial topoisomerase inhibitors that are built on a tetrahydropyran ring linked to a bicyclic aromatic moiety through a syn-diol linker show potent anti-Gram-positive activity, covering isolates with clinically relevant resistance phenotypes. For instance, analog 49c was found to be a dual DNA gyrase-topoisomerase IV inhibitor, with broad antibacterial activity and low propensity for spontaneous resistance development, but suffered from high hERG K(+) channel block. On the other hand, analog 49e displayed lower hERG K(+) channel block while retaining potent in vitro antibacterial activity and acceptable frequency for resistance development. Furthermore, analog 49e showed moderate clearance in rat and promising in vivo efficacy against Staphylococcus aureus in a murine infection model.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , DNA Topoisomerases/metabolism , Drug Design , Gram-Positive Bacteria/drug effects , Pyrans/chemical synthesis , Pyrans/pharmacology , Animals , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacokinetics , Chemistry Techniques, Synthetic , DNA Gyrase/chemistry , DNA Gyrase/metabolism , DNA Topoisomerase IV/antagonists & inhibitors , DNA Topoisomerase IV/chemistry , DNA Topoisomerase IV/metabolism , DNA Topoisomerases/chemistry , Female , Gram-Positive Bacteria/enzymology , Humans , Inhibitory Concentration 50 , Mice , Molecular Docking Simulation , Protein Conformation , Pyrans/metabolism , Pyrans/pharmacokinetics , Rats , Structure-Activity Relationship , Topoisomerase II Inhibitors , Topoisomerase Inhibitors/chemical synthesis , Topoisomerase Inhibitors/metabolism , Topoisomerase Inhibitors/pharmacokinetics , Topoisomerase Inhibitors/pharmacology
6.
Bioorg Med Chem Lett ; 22(21): 6705-11, 2012 Nov 01.
Article in English | MEDLINE | ID: mdl-23006603

ABSTRACT

A series of 2-amino-[1,8]-naphthyridine-3-carboxamides (ANCs) with potent inhibition of bacterial NAD(+)-dependent DNA ligases (LigAs) evolved from a 2,4-diaminopteridine derivative discovered by HTS. The design was guided by several highly resolved X-ray structures of our inhibitors in complex with either Streptococcus pneumoniae or Escherichia coli LigA. The structure-activity-relationship based on the ANC scaffold is discussed. The in-depth characterization of 2-amino-6-bromo-7-(trifluoromethyl)-[1,8]-naphthyridine-3-carboxamide, which displayed promising in vitro (MIC Staphylococcus aureus 1 mg/L) and in vivo anti-staphylococcal activity, is presented.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , DNA Ligases/antagonists & inhibitors , Drug Design , Staphylococcus/drug effects , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/therapeutic use , Crystallography, X-Ray , DNA, Bacterial/antagonists & inhibitors , Inhibitory Concentration 50 , Mice , Microbial Sensitivity Tests , Molecular Structure , Rats , Staphylococcal Infections/drug therapy , Structure-Activity Relationship
7.
J Am Chem Soc ; 126(47): 15592-602, 2004 Dec 01.
Article in English | MEDLINE | ID: mdl-15563189

ABSTRACT

The ruthenium-catalyzed cycloisomerization of 1,6- and 1,7-enynes substituted in the terminal allylic position with a tert-butyldimethylsilyl ether group emerges as an effective reaction to form unprecedented five- or six-membered rings possessing a geometrically defined enol silane. Straightforward synthetic access to a variety of achiral 1,6- and 1,7-enynes, as well as chiral ones, is presented. Ruthenium catalysts effect efficiently such single-step cycloisomerization at room temperature in acetone under neutral conditions. The cycloisomerization functions with (E) or (Z) 1,2-disubstituted alkenes. Parameters influencing the enol silane geometry are discussed. The level of selectivity depends on the alkyne substitution, the geometry of the double bond, and the nature of the catalyst. Furthermore, examples of stereoinduction are shown and lead to highly substituted carbo- and heterocycles with excellent diastereocontrol.


Subject(s)
Alkenes/chemistry , Alkynes/chemistry , Allyl Compounds/chemistry , Ethers/chemistry , Hydrocarbons, Cyclic/chemical synthesis , Ruthenium/chemistry , Silanes/chemistry , Catalysis , Cyclization , Isomerism
8.
J Am Chem Soc ; 126(38): 11966-83, 2004 Sep 29.
Article in English | MEDLINE | ID: mdl-15382932

ABSTRACT

The Pd-catalyzed asymmetric allylic alkylation (AAA) of phenol allyl carbonates serves as an efficient strategy to construct the allylic C-O bond allowing access to chiral chromans in up to 98% ee. The effect of pH and the influence of olefin geometry, as well as substitution pattern on the ee and the absolute configuration of the chiral chromans were explored in detail. These observations suggest a mechanism involving the cyclization of the more reactive pi-allyl palladium diastereomeric intermediate as the enantiodiscriminating step (Curtin-Hammett conditions). This methodology led to the enantioselective synthesis of the vitamin E core, the first enantioselective total synthesis of (+)-clusifoliol and (-)-siccanin, and the synthesis of an advanced intermediate toward (+)-rhododaurichromanic acid A.


Subject(s)
Allyl Compounds/chemistry , Carbonates/chemistry , Chromans/chemical synthesis , Alkylation , Catalysis , Molecular Conformation , Palladium/chemistry , Phenols/chemistry , Stereoisomerism , Xanthenes/chemical synthesis
9.
J Am Chem Soc ; 126(39): 12565-79, 2004 Oct 06.
Article in English | MEDLINE | ID: mdl-15453789

ABSTRACT

(-)-Siccanin (1), a natural product possessing significant antifungal properties, was synthesized enantioselectively via a biomimetic route. This synthetic route features two sequential radical cyclizations: a Ti(III)-mediated radical cyclization of epoxyolefin 48 to construct the B-ring, and a Suarez reaction to establish the tetrahyrofuran ring. Chiral chroman moiety of siccanin was prepared based on our recent development of the Pd-catalyzed asymmetric allylic alkylation (AAA) of phenol trisubstituted allyl carbonates. Several other members of the siccanin family were also synthesized including siccanochromenes A (2), B (3), E (6), F (7), and the methyl ether of siccanochromene C (55). These studies may shed light on the biosynthesis of this novel family of compounds.


Subject(s)
Allyl Compounds/chemistry , Xanthenes/chemical synthesis , Alkylation , Antifungal Agents/chemical synthesis , Biomimetic Materials/chemistry , Catalysis , Cyclization , Helminthosporium/chemistry , Helminthosporium/metabolism , Models, Molecular , Palladium/chemistry , Stereoisomerism
11.
J Am Chem Soc ; 125(31): 9276-7, 2003 Aug 06.
Article in English | MEDLINE | ID: mdl-12889940

ABSTRACT

An examination of earlier reports of poor-to-modest results using Pd-catalyzed asymmetric allylic alkylations (AAA) to effect cyclization to form tetrasubstituted carbons reveals several novel factors that can influence this class of reactions. Thus, carboxylate has a major effect on such cyclizations wherein the ee increases from 14% ee favoring the S with no carboxylate to 84% ee favoring the R enantiomer in the presence of 1 equiv of carboxylate. Changing the double bond geometry from E to Z further increases the ee to 97%. Furthermore, the chiral catalyst that forms the R enantiomer with the E-alkene forms the S enantiomer with the Z alkene. In contrast to trisubstituted alkene substrates, disubstituted ones show a decrease in ee in going from the E to Z alkenes. The role of carboxylate appears to be a ligand to Pd during the catalytic cycle, a previously unsuspected phenomenon since such reactions are generally believed to involve pi-allylpalladium cationic complexes. The dependence upon alkene geometry helps define the nature of the chiral pocket which better accommodates a Z alkene compared to an E alkene. The results are compatible with the enantiodiscriminating step being ionization which occurs by coordination of the palladium to one of the two prochiral faces of the double bond. A synthesis of (+)-clusifoliol, a constituent of a folk medicine for treatment of malignant tumors, which also assigns the absolute configuration, illustrates the utility of the method.


Subject(s)
Allyl Compounds/chemistry , Chromans/chemical synthesis , Phenols/chemistry , Alkylation , Allyl Compounds/chemical synthesis
13.
Angew Chem Int Ed Engl ; 40(8): 1468-1471, 2001 Apr 17.
Article in English | MEDLINE | ID: mdl-29712378

ABSTRACT

Di- or trisubstituted alkenes of defined geometry, with terminal enamide groups, are formed in an atom-economic three-carbon chain extension of alkynes with allyl amides catalyzed by ruthenium (see, for example, Equation (1); Boc=tert-butoxycarbonyl, TMS=trimethylsilyl).

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