WO2024196830A1 - Fabk inhibitor compositions - Google Patents

Fabk inhibitor compositions Download PDF

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WO2024196830A1
WO2024196830A1 PCT/US2024/020337 US2024020337W WO2024196830A1 WO 2024196830 A1 WO2024196830 A1 WO 2024196830A1 US 2024020337 W US2024020337 W US 2024020337W WO 2024196830 A1 WO2024196830 A1 WO 2024196830A1
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compound
composition
scaffold
cln
brn
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Kirk HEVENER
Dianqing SUN
Julian G. Hurdle
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University of Hawaii at Manoa
Texas A&M University System
University of Tennessee Research Foundation
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University of Hawaii at Manoa
Texas A&M University System
University of Tennessee Research Foundation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D419/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/36—Sulfur atom
    • C07D473/38—Sulfur atom attached in position 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • embodiments of the invention are directed to FabK inhibitors and their use in the treatment of infections caused by microbes such as C. difficile, F. nucleatum and P. gingivalis.
  • BACKGROUND Clostridioides difficile infection (CDI) is a leading cause of healthcare-associated diarrhea that is often associated with the use of broad-spectrum antibacterial agents.
  • C. difficile caused approximately 223,900 cases in hospitalized patients and 12,800 deaths in 2017 in the United States.
  • metronidazole and vancomycin Prior to the approval of fidaxomicin in 2011, metronidazole and vancomycin were the two main antibiotic treatments for CDI.
  • metronidazole is not recommended as a first-line CDI medication in the 2021 IDSA/SHEA and ESCMID CDI guidelines, with fidaxomicin recommended as the first-line treatment and vancomycin as its alternate.
  • Fidaxomicin is a narrow-spectrum anti-C. difficile agent with limited activity against other gut bacteria compared to vancomycin, which has a broader spectrum of activity.
  • resistance to fidaxomicin has emerged and alternative CDI antimicrobials are needed for recurrent CDI to complement current non-antimicrobial treatments for recurrent CDI, i.e., fecal microbiota transplantation (FMT) and adjunctive treatment with bezlotoxumab, a monoclonal antibody.
  • FMT fecal microbiota transplantation
  • FAS-II The bacterial type II fatty acid synthesis pathway (FAS-II) comprises a series of individual enzymatic steps to synthesize critical lipids required for bacterial membranes. Lipophilic substrates of the FAS-II enzymes are shuttled between the enzyme steps by an acyl-linked carrier protein (ACP). Several FAS-II steps are conducted by species-specific isozymes that may be exploited as narrow-spectrum antibacterial targets.
  • the rate-limiting enoyl-ACP reductase step responsible for the reduction of a double bond, has four known major isozymes – FabI, FabL, FabV, and FabK.
  • the FabK isozyme is structurally and mechanistically distinct from the other enoyl-ACP reductase isozymes and presents an opportunity for the design of agents targeting organisms that solely express this enzyme.
  • C. difficile is one such organism.
  • C. difficile FabK (CdFabK) is essential for growth even in the presence of host fatty acids.
  • Other pathogens carrying the FabK enzyme also include Fusobacterium species (for example, F. nucleatum), Porphyromonas species (for example, P.
  • F. nucleatum is implicated in multiple diseases including periodontal disease, pre-term births, inflammatory bowel disease, and colorectal (CRC) and breast cancers. In periodontal disease, F. nucleatum assists periodontal pathogens such as Porphyromonas gingivalis by promoting their integration into the oral microbiota community. In the context of CRC, genomic analysis of patient biopsies has shown a frequent association of F. nucleatum with tumor tissues, as opposed to normal tissues. F.
  • nucleatum expresses virulence factors that contribute to the development of a pro- tumorigenic environment, which includes suppression of the immune system, promotion of chemoresistance, and induction of inflammation. Similar to C. difficile, F. nucleatum and P. gingivalis depend on the FAS-II pathway to synthesize ⁇ -Hydroxyacyl-ACPs, which are essential precursors for the lipid component of lipopolysaccharide outer membranes. Therefore, targeting FabK, which is a required enzyme in the FAS-II pathway, provides an avenue for the development of narrow-spectrum antimicrobials, while minimizing collateral damage of the normal microbiota in the human body.
  • the pathogens discussed above are either associated with, or present risk factors for, a range of diseases, ranging from diseases of the oral cavity (gum diseases- for example, periodontal disease and gingivitis-; cariogenic diseases- for example, dental caries; halitosis); 2 Attorney Docket 13260-P301WO gastrointestinal and systemic diseases (for example, colorectal cancer, cardiovascular disease, atherosclerosis, cerebral aneurysm, inflammatory bowel disease, appendicitis, Lemierre’s syndrome, rheumatoid arthritis, and pre-term births, and Alzheimer's).
  • FabK could have broad applicability in treating microbial infections.
  • an embodiment of the invention is directed to a composition comprising an inhibitor of FabK activity.
  • the claimed inhibitor is a compound having a structure selected from the group consisting of an imidazole scaffold, a thiazole scaffold, a pyridine-thiazole scaffold, a benzothiazole scaffold, a benzimidazole scaffold, a benzoxazole scaffold and combinations thereof.
  • the inhibitor is a unsubsituted or substituted phenylimidazole compound BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG.1 shows potential structural modifications of phenylimidazole analogs.
  • FIG.2 shows the synthesis of compounds 5a-5i; a) 10, K2CO3, DMF, 80 °C, 1.5 h, 25–91%; b) CDI, DCM, rt; c) MeONa, MeOH, rt, o/n, then NH 4 Cl, rt, o/n, 86%; d) 15, K 2 CO 3 , 80 °C, o/n, 37%; e) HCl, H2O, 100 °C, 91%; f) Et3N, DCM, rt, 80 min, 30–99%.
  • FIG.3 shows the synthesis of compounds 6a–6l; a) CDI, DCM, rt, o/n; b) 16, Et 3 N, DCM, rt, o/n, 13–98% over two steps.
  • FIG.4 shows the synthesis of compounds 8a-8c; a) CDI, DCM, rt, o/n; b) Et 3 N, DCM, rt, o/n, 53–72%.
  • FIG.5 shows the general structure of a compound having a thiazole scaffold.
  • FIG.6 shows the general structure of a compound having a benzothiazole/ benzimidazole/ benzoxazole scaffold.
  • FIG.7 is a listing of representative compounds of the claimed invention.
  • an embodiment of the claimed invention is directed to a composition comprising an antimicrobial agent.
  • the antimicrobial agent comprises an inhibitor of FabK enzyme.
  • the antimicrobial agent is a compound having a scaffold selected from the group consisting of an imidazole scaffold, a thiazole scaffold, a pyridine- thiazole scaffold, a benzothiazole scaffold, a benzimidazole scaffold, a benzoxazole scaffold and combinations thereof.
  • the antimicrobial agent is a phenylimidazole compound. In some embodiments, the phenylimidazole compound contains substitutions.
  • the anti-C. difficile agent is a phenylimidazole compound having a substitution to the pyridine head group.
  • the phenylimidazole compound has a modification to the pyridine head group.
  • the head group is modified by the addition of halogen substitutions.
  • the phenylimidazole compound comprises modifications to the planar central aromatic region.
  • the thiazole of the central aromatic region is substituted with quinoline and/or benzothiazole.
  • the urea is replaced by a thiourea.
  • the phenylimidazole compound comprises modifications to the aromatic tail group ring system involving substitution of the phenylimidazole group with varying aromatic bicyclic systems.
  • Embodiments of the invention are directed to the use of the claimed compounds as inhibitors of microbial infections in which the microbes contain FabK. In certain embodiments that claimed compounds are used as the sole inhibitor of FabK. In other embodiments, the claimed compounds are used in conjunction with other antimicrobial agents. In certain embodiments, the claimed compounds may be used to treat inflammatory diseases in which the progenitor is a microbial pathogen carrying FabK enzyme.
  • the claimed compounds may be formulated for administration in compositions that are either dispersed in formulation or attached, for example, to polymeric materials designed to be embedded in a human or animal subject.
  • the compounds may be delivered via different routes of administration, including topical, oral administration, inhalation, trans or sub-dermal, and rectal.
  • compositions comprising one or more of the claimed compounds may be used to modulate or alter the composition of the human microbiome (microbiota) to produce beneficial health effects, for example to increase microbial community associated with producing secondary bile that protects against infection, or modulate microbiome metabolism in a way to produce other metabolites that are beneficial to human health.
  • FIG.1 shows the potential structural modifications of phenylimidazole analogs that form a part of the claimed invention.
  • the reference labels 5b-i, 6a-l, 7a, 7b and 8a-c refer to representative compounds that were synthesized and/or used as starting compounds to synthesize the claimed compounds.
  • FIG.2 shows a schematic for the synthesis of compounds 5a-5i.
  • the reference labels 5a-i, 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 9a-l, 11a-l, 12a-l, 13, 14 and 16 refer to representative compounds that were synthesized and/or used as starting compounds to synthesize the claimed compounds.
  • FIG.3 shows a schematic for the synthesis of compounds 6a–6l.
  • the reference labels 17a-l, 18a-l, 6a-l, 6a, 6b, 6c, 6d, 6e, 6f, 6g, 6h, 6i, 6j, 6k and 6l refer to representative compounds that were synthesized and/or used as starting compounds to synthesize the claimed compounds.
  • FIG.4 shows a schematic for the synthesis of compounds 8a-8c.
  • the reference labels 11a, 12a, 23, 24, 25, 8a, 8b and 8c refer to representative compounds that were synthesized and/or used as starting compounds to synthesize the claimed compounds.
  • FIG.5 shows a structure of a compound having a thiazole scaffold.
  • the ring compounds are selected from benzene, pyridine, pyrimidine, benzothiazole, benzimidazole or quinoline.
  • R1 and R2 is a halogen, methoxy, trifluoro-methyl, cyano or trifluoro-methoxy functional group.
  • FIG.6 shows a structure of a compound having a benzothiazole/ benzimidazole/ benzoxazole scaffold.
  • the ring compounds are selected from benzene, pyridine, pyrimidine, benzothiazole or benzimidazole.
  • R1 and R2 is a halogen, trifluoromethyl, methyl, methoxy, mesylate, methoxy, methyl-carbonyl, ethoxy, or sulfonamide functional group.
  • FIG.7 is a non-limiting list of inhibitor compounds of the claimed invention.
  • an inhibitor compound has the formula and structure of C19H16N6OS2 (Compound A); C 19 H 15 BrN 6 OS 2 (Compound B); C 16 H 14 N 4 OS 2 (Compound C); C19H15FN6OS2 (Compound D); C20H18N6O2S2 (Compound E); C20H15F3N6OS2 (Compound F); C20H15F3N6O2S2 (Compound G); C20H15N7OS2 (Compound H); C19H16N6O2S2 (Compound I); C 21 H 18 N 6 O 4 S 2 (Compound J); C 19 H 17 N 6 O 5 PS 2 (Compound K); C30H34N8O3S2 (Compound L); C23H20N6O6S2 (Compound M); C25H22N6O8S2 (Compound N); C 17 H 14 N 6 OS 3 (Compound O); C 19 H 15 BrN 6 S 3 (Compound P); (C 20 H 15 Br 2 N 5 OS 2
  • Certain embodiments are directed to pharmaceutical compositions comprising one or more of inhibitor compounds.
  • the inhibitor compounds of the claimed invention were tested at a concentration of 10 ⁇ M to determine percentage inhibition of the CdFabK activity. This information was used to identify potent compounds for IC 50 determinations (>50% inhibition) and MIC testing against C. difficile R20291.
  • Pyridine Head Group Modifications (5a-i) Table 1 shows the biochemical and microbiological activity of the compounds synthesized with pyridine head group modifications, along with other relevant activity data. To determine the importance of the 2-pyridine moiety for inhibitory activity, the pyrimidine counterpart 5b was synthesized and tested.
  • Compound 5b showed comparable activity to 5a, with an IC50 of 1.02 ⁇ M (vs.1.23 ⁇ M) and an MIC of 1.56-3.12 ⁇ g/mL (vs.1.56 ⁇ g/mL).
  • the IC 50 of compound 5d with a p-bromophenyl group substituted for the 8 Attorney Docket 13260-P301WO pyridine group, was 2-fold greater than that of 5a (0.53 vs 1.23 ⁇ M).
  • 5b displayed partial inhibition to ⁇ 65 percent, which influenced the calculated IC 50 .
  • Several of the compounds in this series showed a pattern of partial inhibition due to low aqueous solubility when tested at higher concentrations.
  • EWG electron-withdrawing groups
  • IC50 4.53 ⁇ M
  • MIC anti-C. difficile activity
  • the low Hill slope of this compound suggests a non-ideal inhibitory behavior, possibly due to poor solubility or aggregation.
  • Phenylimidazole Tail Group Modifications (8a–c) In the modification of the phenylimidazole tail group, compounds 8a–c were synthesized to explore tail group substitutions of phenyl-triazole (8a), benzimidazole (8b), and quinazolinone (8c) as shown in Table 3. These compounds were designed to retain the recognized hydrogen bond donor and acceptor groups of the phenylimidazole discussed above, while exploring differing bicyclic ring systems and steric bulk. As shown in Table 3, overall these compounds showed low inhibitory activity against CdFabK (IC50 > 10 ⁇ M) and no anti-C. difficile activity with MICs of > 50 ⁇ g/mL.
  • a lysis buffer consisting of Buffer A (50 mM HEPES pH 8.0, 300 mM NH 4 Cl, 18% glycerol, 100 ⁇ M FMN, 10 mM imidazole, and 1 mM DTT), 0.5 mg/mL lysozyme, 0.5% Triton-X 100, 25 mM sucrose, 10 ⁇ g/mL DNase, and protease inhibitor.
  • Buffer A 50 mM HEPES pH 8.0, 300 mM NH 4 Cl, 18% glycerol, 100 ⁇ M FMN, 10 mM imidazole, and 1 mM DTT
  • 0.5 mg/mL lysozyme 0.5%
  • Triton-X 100, 25 mM sucrose, 10 ⁇ g/mL DNase, and protease inhibitor.
  • the protein was further purified by gel filtration on a SuperDex 200 PG column (GE Healthcare) with a buffer containing, 50 mM Hepes pH 8.0, 300 mM NH 4 Cl, 18% glycerol, 100 ⁇ M FMN, and 3 mM DTT. After purification, the protein was concentrated using a centrifugal filter (Amicon Ultra -15).
  • the CdFabK enzyme assays were conducted at 25 °C using assay buffer (100 mM HEPES pH 8.0, 500 mM NH4Cl, 10% glycerol) in 384-well microplates at a final volume of 100 ⁇ L (30 ⁇ L of buffer, 10 ⁇ L inhibitor, 5 ⁇ L of crotonyl-CoA substrate, 5 ⁇ L of protein, and 50 ⁇ L NADH).
  • the final concentrations of enzyme, NADH cofactor, and crotonyl-CoA substrate were 15 nM, 125 ⁇ M, and 325 ⁇ M, respectively.
  • Test compounds were serially diluted using DMSO prior to assay.
  • the initial concentration of the test compounds and the dilution factor were determined by initial single concentration assays at 10 ⁇ M and 100 ⁇ M to give an appropriate concentration range with data points above and below the inflection for best curve fits.
  • a working dilution of the protein was prepared using the assay buffer with 2.5 mg/ml ⁇ -globulins (used for a crowding effect to stabilize the CdFabK dimer at low concentrations). The compound and enzyme were incubated for 10 minutes, after which crotonyl-CoA substrate was added.
  • the reaction is started by the addition of the NADH cofactor and continuously monitored for NADH conversion to NAD + by fluorescence intensity (ex 340, em 460) in a Biotek Synergy H1 microplate reader for 10 min total 15 Attorney Docket 13260-P301WO duration with reads every 20 seconds.
  • eleven concentrations were tested, in duplicate, along with a DMSO control.
  • IC 50 determination Slopes obtained from the steady-state period of the continuous assays (linear range) were calculated and used with control data to determine percent inhibition at each concentration. Percent inhibitions (duplicate) and compound concentrations were used to calculate IC 50 values for each compound by four-parameter non-linear regression (Hill equation) fit with GraphPad Prism 9.0.
  • MIC determination MICs were performed by the broth microdilution method, as previously described, using C. difficile strain R20291, in brain heart infusion broth (BHI, from BD Diagnostics). Compound stock solutions were prepared to 10 mg/mL in DMSO (Alfa Aesar). BHI was deoxygenated overnight in a PLAS Labs 857-OTA anaerobic chamber. Strain R20291 was grown anaerobically overnight in BHI broth in a Don Whitley A35 anaerobic at 37 °C.

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Abstract

Embodiments of the invention are directed to inhibitors of FabK activity. Embodiments of the inventions are directed to compounds having a structure selected from the group consisting of an imidazole scaffold, a thiazole scaffold, a pyridine-thiazole scaffold, a benzothiazole scaffold, a benzimidazole scaffold, a benzoxazole scaffold and combinations thereof.

Description

Attorney Docket 13260-P301WO   FABK INHIBITOR COMPOSITIONS CROSS-REFERENCE TO RELATED APPLICATION(S)
Figure imgf000003_0001
Patent Application No. 63/490,897 filed March 17, 2023, the entire specification of which is fully incorporated by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under federal grant number W81XWH-20-1-0296 awarded by the Department of Defense and federal grant number R21AI126755 awarded by the National Institutes of Health. The government has certain rights in the invention. TECHNICAL FIELD The invention relates generally to FabK (Fatty Acid Synthesis Protein Enoyl-ACP Reductase II) inhibitor compositions having antimicrobial activity. Specifically, embodiments of the invention are directed to FabK inhibitors and their use in the treatment of infections caused by microbes such as C. difficile, F. nucleatum and P. gingivalis. BACKGROUND Clostridioides difficile infection (CDI) is a leading cause of healthcare-associated diarrhea that is often associated with the use of broad-spectrum antibacterial agents. According to the CDC, C. difficile caused approximately 223,900 cases in hospitalized patients and 12,800 deaths in 2017 in the United States. Prior to the approval of fidaxomicin in 2011, metronidazole and vancomycin were the two main antibiotic treatments for CDI. However, metronidazole is not recommended as a first-line CDI medication in the 2021 IDSA/SHEA and ESCMID CDI guidelines, with fidaxomicin recommended as the first-line treatment and vancomycin as its alternate. Fidaxomicin is a narrow-spectrum anti-C. difficile agent with limited activity against other gut bacteria compared to vancomycin, which has a broader spectrum of activity. However, resistance to fidaxomicin has emerged and alternative CDI antimicrobials are needed for recurrent CDI to complement current non-antimicrobial treatments for recurrent CDI, i.e., fecal microbiota transplantation (FMT) and adjunctive treatment with bezlotoxumab, a monoclonal antibody. Therefore, inhibitors of enoyl-acyl 1   Attorney Docket 13260-P301WO   carrier protein (enoyl-ACP) reductase FabK, which is involved in de novo fatty acid synthesis, may present good options. The bacterial type II fatty acid synthesis pathway (FAS-II) comprises a series of individual enzymatic steps to synthesize critical lipids required for bacterial membranes. Lipophilic substrates of the FAS-II enzymes are shuttled between the enzyme steps by an acyl-linked carrier protein (ACP). Several FAS-II steps are conducted by species-specific isozymes that may be exploited as narrow-spectrum antibacterial targets. The rate-limiting enoyl-ACP reductase step, responsible for the reduction of a double bond, has four known major isozymes – FabI, FabL, FabV, and FabK. The FabK isozyme is structurally and mechanistically distinct from the other enoyl-ACP reductase isozymes and presents an opportunity for the design of agents targeting organisms that solely express this enzyme. C. difficile is one such organism. C. difficile FabK (CdFabK) is essential for growth even in the presence of host fatty acids. Other pathogens carrying the FabK enzyme also include Fusobacterium species (for example, F. nucleatum), Porphyromonas species (for example, P. gingivalis) and Streptococcus species (for example, S. mutans). F. nucleatum is implicated in multiple diseases including periodontal disease, pre-term births, inflammatory bowel disease, and colorectal (CRC) and breast cancers. In periodontal disease, F. nucleatum assists periodontal pathogens such as Porphyromonas gingivalis by promoting their integration into the oral microbiota community. In the context of CRC, genomic analysis of patient biopsies has shown a frequent association of F. nucleatum with tumor tissues, as opposed to normal tissues. F. nucleatum expresses virulence factors that contribute to the development of a pro- tumorigenic environment, which includes suppression of the immune system, promotion of chemoresistance, and induction of inflammation. Similar to C. difficile, F. nucleatum and P. gingivalis depend on the FAS-II pathway to synthesize β-Hydroxyacyl-ACPs, which are essential precursors for the lipid component of lipopolysaccharide outer membranes. Therefore, targeting FabK, which is a required enzyme in the FAS-II pathway, provides an avenue for the development of narrow-spectrum antimicrobials, while minimizing collateral damage of the normal microbiota in the human body. The pathogens discussed above are either associated with, or present risk factors for, a range of diseases, ranging from diseases of the oral cavity (gum diseases- for example, periodontal disease and gingivitis-; cariogenic diseases- for example, dental caries; halitosis); 2   Attorney Docket 13260-P301WO   gastrointestinal and systemic diseases (for example, colorectal cancer, cardiovascular disease, atherosclerosis, cerebral aneurysm, inflammatory bowel disease, appendicitis, Lemierre’s syndrome, rheumatoid arthritis, and pre-term births, and Alzheimer's). As such, inhibitors of FabK could have broad applicability in treating microbial infections. SUMMARY OF THE INVENTION An embodiment of the invention is directed to a composition comprising an inhibitor of FabK activity. In certain embodiments, the claimed inhibitor is a compound having a structure selected from the group consisting of an imidazole scaffold, a thiazole scaffold, a pyridine-thiazole scaffold, a benzothiazole scaffold, a benzimidazole scaffold, a benzoxazole scaffold and combinations thereof. In certain embodiments, the inhibitor is a unsubsituted or substituted phenylimidazole compound BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 shows potential structural modifications of phenylimidazole analogs. FIG.2 shows the synthesis of compounds 5a-5i; a) 10, K2CO3, DMF, 80 ℃, 1.5 h, 25–91%; b) CDI, DCM, rt; c) MeONa, MeOH, rt, o/n, then NH4Cl, rt, o/n, 86%; d) 15, K2CO3, 80 ℃, o/n, 37%; e) HCl, H2O, 100 ℃, 91%; f) Et3N, DCM, rt, 80 min, 30–99%. FIG.3 shows the synthesis of compounds 6a–6l; a) CDI, DCM, rt, o/n; b) 16, Et3N, DCM, rt, o/n, 13–98% over two steps. FIG.4 shows the synthesis of compounds 8a-8c; a) CDI, DCM, rt, o/n; b) Et3N, DCM, rt, o/n, 53–72%. FIG.5 shows the general structure of a compound having a thiazole scaffold. FIG.6 shows the general structure of a compound having a benzothiazole/ benzimidazole/ benzoxazole scaffold. FIG.7 is a listing of representative compounds of the claimed invention. 3   Attorney Docket 13260-P301WO   DETAILED DESCRIPTION An embodiment of the claimed invention is directed to a composition comprising an antimicrobial agent. In certain embodiments, the antimicrobial agent comprises an inhibitor of FabK enzyme. In other embodiments, the antimicrobial agent is a compound having a scaffold selected from the group consisting of an imidazole scaffold, a thiazole scaffold, a pyridine- thiazole scaffold, a benzothiazole scaffold, a benzimidazole scaffold, a benzoxazole scaffold and combinations thereof. In certain embodiments, the antimicrobial agent is a phenylimidazole compound. In some embodiments, the phenylimidazole compound contains substitutions. In certain embodiments, the anti-C. difficile agent is a phenylimidazole compound having a substitution to the pyridine head group. In other embodiments, the phenylimidazole compound has a modification to the pyridine head group. In certain embodiments, the head group is modified by the addition of halogen substitutions. In certain embodiments, the phenylimidazole compound comprises modifications to the planar central aromatic region. In certain embodiments, the thiazole of the central aromatic region is substituted with quinoline and/or benzothiazole. In other embodiments, the urea is replaced by a thiourea. In certain embodiments, the phenylimidazole compound comprises modifications to the aromatic tail group ring system involving substitution of the phenylimidazole group with varying aromatic bicyclic systems. Embodiments of the invention are directed to the use of the claimed compounds as inhibitors of microbial infections in which the microbes contain FabK. In certain embodiments that claimed compounds are used as the sole inhibitor of FabK. In other embodiments, the claimed compounds are used in conjunction with other antimicrobial agents. In certain embodiments, the claimed compounds may be used to treat inflammatory diseases in which the progenitor is a microbial pathogen carrying FabK enzyme. 4   Attorney Docket 13260-P301WO   In certain embodiments, the claimed compounds may be formulated for administration in compositions that are either dispersed in formulation or attached, for example, to polymeric materials designed to be embedded in a human or animal subject. The compounds may be delivered via different routes of administration, including topical, oral administration, inhalation, trans or sub-dermal, and rectal. In certain embodiments, compositions comprising one or more of the claimed compounds may be used to modulate or alter the composition of the human microbiome (microbiota) to produce beneficial health effects, for example to increase microbial community associated with producing secondary bile that protects against infection, or modulate microbiome metabolism in a way to produce other metabolites that are beneficial to human health. FIG.1 shows the potential structural modifications of phenylimidazole analogs that form a part of the claimed invention. The reference labels 5b-i, 6a-l, 7a, 7b and 8a-c refer to representative compounds that were synthesized and/or used as starting compounds to synthesize the claimed compounds. FIG.2 shows a schematic for the synthesis of compounds 5a-5i. The reference labels 5a-i, 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 9a-l, 11a-l, 12a-l, 13, 14 and 16 refer to representative compounds that were synthesized and/or used as starting compounds to synthesize the claimed compounds. FIG.3 shows a schematic for the synthesis of compounds 6a–6l. The reference labels 17a-l, 18a-l, 6a-l, 6a, 6b, 6c, 6d, 6e, 6f, 6g, 6h, 6i, 6j, 6k and 6l refer to representative compounds that were synthesized and/or used as starting compounds to synthesize the claimed compounds. FIG.4 shows a schematic for the synthesis of compounds 8a-8c. The reference labels 11a, 12a, 23, 24, 25, 8a, 8b and 8c refer to representative compounds that were synthesized and/or used as starting compounds to synthesize the claimed compounds. FIG.5 shows a structure of a compound having a thiazole scaffold. The ring compounds are selected from benzene, pyridine, pyrimidine, benzothiazole, benzimidazole or quinoline. R1 and R2 is a halogen, methoxy, trifluoro-methyl, cyano or trifluoro-methoxy functional group. 5   Attorney Docket 13260-P301WO   FIG.6 shows a structure of a compound having a benzothiazole/ benzimidazole/ benzoxazole scaffold. The ring compounds are selected from benzene, pyridine, pyrimidine, benzothiazole or benzimidazole. R1 and R2 is a halogen, trifluoromethyl, methyl, methoxy, mesylate, methoxy, methyl-carbonyl, ethoxy, or sulfonamide functional group. FIG.7 is a non-limiting list of inhibitor compounds of the claimed invention. In certain embodiments, an inhibitor compound has the formula and structure of C19H16N6OS2 (Compound A); C19H15BrN6OS2 (Compound B); C16H14N4OS2 (Compound C); C19H15FN6OS2 (Compound D); C20H18N6O2S2 (Compound E); C20H15F3N6OS2 (Compound F); C20H15F3N6O2S2 (Compound G); C20H15N7OS2 (Compound H); C19H16N6O2S2 (Compound I); C21H18N6O4S2 (Compound J); C19H17N6O5PS2 (Compound K); C30H34N8O3S2 (Compound L); C23H20N6O6S2 (Compound M); C25H22N6O8S2 (Compound N); C17H14N6OS3 (Compound O); C19H15BrN6S3 (Compound P); (C20H15Br2N5OS2 (Compound Q); C21H15BrN6OS3 (Compound R); C17H14N6OS2 (Compound S); C18H15N7OS2 (Compound T); C18H14N6O2S2 (Compound U); C18H14BrN7OS2 (Compound V); C23H17BrN6OS2 (Compound W); C19H14BrClN6OS2 (Compound X); C20H14BrF3N6OS2 (Compound Y); C20H14BrF3N6OS2 (Compound Z); C20H16BrN5OS2 (Compound AA); C21H18BrN5O2S2 (Compound AB); C20H15BrClN5OS2 (Compound AC); C18H14N4O3S2 (Compound AD); C16H12N4OS2 (Compound AE); C15H14N4O3S2 (Compound AF); C17H16N4O4S2 (Compound AG); C18H18N4O3S2 (Compound AH); C17H16N2O5S3 (Compound AI); C20H13ClN2O5S2 (Compound AJ); C17H13N3O3S (Compound AK); C14H10N6OS2 (Compound AL); C18H13N3O5S2 (Compound AM); C18H16N2O5S2 (Compound AN); C20H23N5O3S (Compound AO); C18H18N4O4S2 (Compound AP); C16H13ClN2O3S3 (Compound AQ); C17H14N4O3S3 (Compound AR); C18H16N6O3S (Compound AS); C19H15ClN4O2S (Compound AT); C17H12ClN3O2S3 (Compound AU); C16H14N4O4S2 (Compound AV); C18H20N4O3S2 (Compound AW); C14H14N4O2S3 (Compound AX); C16H14N4O4S2 (Compound AY); C21H16N4O5S2 (Compound AZ); C18H13N3O4S2 (Compound BA); C13H12N4O3S3 (Compound BB); C22H19N3O4S2 (Compound BC); C17H14N4O3S2 (Compound BD); C17H16N2O3S2 (Compound BE); C17H16N2O3S3 (Compound BF); C20H15ClN4O4S3 (Compound BG); C16H12N4OS2 (Compound BH); C16H12N4O3S3 (Compound BI); C17H14N6O3S3 (Compound BJ); C18H16N6O4S2 (Compound BK); C17H13BrN6O3S2 (Compound BL); C17H13ClN6O3S2 (Compound BM); C17H14N6O3S2 (Compound BN); C18H15N5O3S2 (Compound BO); C18H15N5O3S2 (Compound BP); C18H14BrN5OS (Compound BQ); C18H13BrFN5OS (Compound BR); C18H13Br2N5OS 6   Attorney Docket 13260-P301WO   (Compound BS); C19H13BrF3N5OS (Compound BT); C18H12BrF2N5OS (Compound BU); C18H14N4O2S (Compound BV); C19H16BrN5O3S2 (Compound BW); C18H13BrClN5OS (Compound BX); C20H18BrN5O2S (Compound BY); C18H23BrN4OS (Compound BZ); C19H13BrF3N5O2S (Compound CA); C19H13BrF3N5OS (Compound CB); C19H13BrF3N5OS (Compound CC); C19H13BrF3N5OS (Compound CD); C14H10F3N3O3S3 (Compound CE); C17H13N3O4S3 (Compound CF); C17H13N3O3S4 (Compound CG); C18H19N5O2S2 (Compound CH); C19H15N5O2S2 (Compound CI); C21H15ClN4O2S2 (Compound CJ); C14H12N4O2S2 (Compound CK); C19H16N4OS2 (Compound CL); C18H16N6OS2 (Compound CM); C19H13ClN4O2S2 (Compound CN); C17H12N6O2S2 (Compound CO); C17H12N6O2S2 (Compound CP); C18H14N4OS2 (Compound CQ); C19H13ClN4O2S2 (Compound CR); C17H12N4O3S2 (Compound CS); C19H14ClN5O2S2 (Compound CT); C20H16N4O3S2 (Compound CU); C18H19N3O3S2 (Compound CV); C18H18N2O5S2 (Compound CW); C20H21ClN4O2S (Compound CX); C18H16F3N3O3S (Compound CY); C18H19N3O5S2 (Compound CZ; C20H21FN4O2S (Compound DA); C20H22N4O2S (Compound DB); C18H14ClN5OS2 (Compound DC); C20H15F3N4OS2 (Compound DD); C20H18N4O3S2 (Compound DE); C20H17FN4O2S2 (Compound DF); C20H15ClN4O2S2 (Compound DG); C20H17ClN4O2S2 (Compound DH); C21H17F3N4O2S2 (Compound DI); C20H16ClN5O2S2 (Compound DJ); C20H18N4O2S2 (Compound DK); C20H15F3N4O2S2 (Compound DL); C19H15N3OS2 (Compound DM); C20H17N3OS2 (Compound DN); C20H17N3OS2 (Compound DO); C21H19N3O2S2 (Compound DP); C20H17N3OS2 (Compound DQ); C20H17N3O2S2 (Compound DR); C22H21N3OS2 (Compound DS); C21H19N3OS2 (Compound DT); C22H16F3N3O2S (Compound DU); C22H16F3N3OS (Compound DV); C19H18F3N3O3S (Compound DW); C22H19N3O4S2 (Compound DX); C22H19N3O3S2 (Compound DY); C19H16N4O3S3 (Compound DZ); C21H18ClN5O3S2 (Compound EA); C20H16ClN5O2S2 (Compound EB); C19H14ClN5O2S2 (Compound EC); C20H16ClN5O2S2 (Compound ED); C19H21N3O5S2 (Compound EE); C19H18F3N3O4S (Compound EF); C18H16F3N3O4S (Compound EG); C22H16F3N3OS (Compound EH); C22H16F3N3O2S (Compound EI); C23H18F3N3O2S (Compound EJ); C22H19N3O4S2 (Compound EK); C17H18N4O3S2 (Compound EL); C12H10N4OS2 (Compound EM); C19H13FN4O2S2 (Compound EN); C18H20N4O5S3 (Compound EO); C13H12N4O3S3 (Compound EP); C19H20N4O5S3 (Compound EQ); C17H14F3N3O4S2 (Compound ER); C16H14ClN3O3S2 (Compound ES); C14H14N4O3S3 (Compound ET); C19H17N5O3S2 (Compound EU); C16H14BrN3O3S2 (Compound EV); C18H15N3O3S2 (Compound EW); C19H21N5O4S3 (Compound EX); C20H16N4O4S3 (Compound EY); C19H16N4O3S3 (Compound EZ); C18H16N4O3S2 (Compound FA); 7   Attorney Docket 13260-P301WO   C20H23N3O3S2 (Compound FB); C18H14FN3O3S2 (Compound FC); C17H13N5O4S4 (Compound FD); C17H15FN4O4S3 (Compound FE); C21H15F3N4O5S3 (Compound FF); C18H15N5OS (Compound FG); C18H16N4O3S2 (Compound FH); C21H18N4O5S3 (Compound FI); C21H15F3N4O4S3 (Compound FJ); C20H18N4O3S2 (Compound FK); C17H14N6O3S3 (Compound FL); C21H18N4O4S3 (Compound FM); C19H16N4O3S3 (Compound FN); C20H14Cl2N4O4S3 (Compound FO); C14H13N3O3S3 (Compound FP); C17H15N5O3S2 (Compound FQ); C18H16N4O3S2 (Compound FR); C18H15N3O3S3 (Compound FS); C20H15ClN4O4S3 (Compound FT); C19H16BrN5O3S2 (Compound FU); C19H16N4O3S2 (Compound FV); C22H19N3O3S2 (Compound FW); C19H21N3O5S2 (Compound FX); C19H16N4OS2 (Compound FY); C20H17ClN4O2S2 (Compound FZ); C20H18N4O2S2 (Compound GA); C19H15ClN4OS2 (Compound GB); C18H14ClN5OS2 (Compound GC); C18H13ClN4OS2 (Compound GD); C19H15ClN4OS2 (Compound GE); C19H16N4OS2 (Compound GF); C18H14N4OS (Compound GH); C18H13BrN4OS (Compound GI); C19H16N4O2S (Compound GJ); C17H19N5O3S (Compound GK); C12H11N5OS (Compound GL); C19H17N5OS (Compound GM); C18H16N6O (Compound GN); C19H19F3N4O3 (Compound GO); C18H17F3N4O3 (Compound GP); C18H14ClN5OS (Compound GQ); C19H18F3N3O4 (Compound GR); C18H16F3N3O4 (Compound GS); C17H18N4O4S (Compound GT); C12H10N4O2S (Compound GU); C18H15N5O2 (Compound GV); C16H12N4O2S (Compound GW); or C14H16ClN3O4S2 (Compound GX). Certain embodiments are directed to pharmaceutical compositions comprising one or more of inhibitor compounds. The inhibitor compounds of the claimed invention were tested at a concentration of 10 μM to determine percentage inhibition of the CdFabK activity. This information was used to identify potent compounds for IC50 determinations (>50% inhibition) and MIC testing against C. difficile R20291. Pyridine Head Group Modifications (5a-i) Table 1 shows the biochemical and microbiological activity of the compounds synthesized with pyridine head group modifications, along with other relevant activity data. To determine the importance of the 2-pyridine moiety for inhibitory activity, the pyrimidine counterpart 5b was synthesized and tested. Compound 5b showed comparable activity to 5a, with an IC50 of 1.02 μM (vs.1.23 μM) and an MIC of 1.56-3.12 μg/mL (vs.1.56 μg/mL). Interestingly, the IC50 of compound 5d, with a p-bromophenyl group substituted for the 8   Attorney Docket 13260-P301WO   pyridine group, was 2-fold greater than that of 5a (0.53 vs 1.23 μM). Notably, 5b displayed partial inhibition to ~65 percent, which influenced the calculated IC50. Several of the compounds in this series showed a pattern of partial inhibition due to low aqueous solubility when tested at higher concentrations. Compounds bearing electron-withdrawing groups (EWG) at the 5-position of the pyridine ring were also tested. Compounds 5e and 5f showed similar inhibition patterns as 5d with IC50’s of 0.85 μM and 0.77 μM, respectively. These compounds also showed partial inhibition, although not at the same extent as 5d. With respect to their anti-C. difficile activity, compounds 5e and 5f were one-fold less active with MIC’s of 3.12 μg/mL. Notably, 5g with a 3-CF3 substitution showed significantly improved FabK inhibition (IC50 0.24 μM) and anti-C. difficile activity equipotent to 5a with MIC of 1.56 μg/mL. Larger bicyclic substitutions of the pyridine group, quinoline 5h and benzothiazole 5i, were largely inactive against C. difficile (MIC’s >50 μg/mL), although they possessed sub-micromolar IC50’s of 0.75 μM and 0.42 μM, respectively. It is unclear how the bulkier ring substitutions diminished antibacterial activity but decreased cellular uptake and/or efflux pump are potential reasons. All compounds tested in this series, except 5g and 5i, showed good curve fit statistics (R2 = 0.95 – 0.97) and Hill slope values near unity, indicating ideal stoichiometric inhibitor behavior (one inhibitor to one active site). The Hill slopes significantly less than unity of 5g and 5i indicate non-ideal behavior and may be indicative of solubility or compound aggregation issues. Table 1 CdFabK Inhibition and Antibacterial Activity of Pyridine-Headed Modifications R20291 Compound R-group
Figure imgf000011_0001
slope R2 MIC (%) (μg/mL) 5a 85.5 1.23 93 1.07 0.95 1.56 5b
Figure imgf000011_0002
78.1 1.02 92 0.82 0.97 1.56-3.12 5c
Figure imgf000011_0003
0.90 91 0.95 0.93 1.56-3.12 5d
Figure imgf000011_0004
0.95 25 5e
Figure imgf000011_0005
0.98 3.12
Figure imgf000011_0006
9   Attorney Docket 13260-P301WO   5f 69.7 0.77 89 1.06 0.97 3.12 85.5 0.24 100 0.66 0.98 1.56 68.7 0.75 77 1.16 0.95 >50 - 0.42 76 0.69 0.98 >50 0.39-0.78
Figure imgf000012_0001
Cerulenin 3.12 Benzothiazole Derivatives (6a–l) and Central Planar Group Modifications (7a–b) Compounds that replaced the 2-pyridine thioether head group with a benzothiazole ring system were tested. This substitution affected both the head group and central planar regions. Table 2 shows the biochemical and microbiological activity of the compounds in this series. Except for 6k, the curve fit statistics and Hill slopes calculated were within the acceptable range for a competitive enzyme inhibitor. Compound 6a, with an unsubstituted benzothiazole system, had a calculated IC50 of 1.88 μM, but was inactive against C. difficile in MIC testing. Improvements in activity were seen by the addition of electron withdrawing functional groups, including halogen substitutions, CF3, and methyl sulfone. Compound 6d, bearing a 6-CF3 substitution showed excellent CdFabK inhibition (IC50 = 0.10 μM), but an MIC of 6.25 μg/mL. Slight partial inhibition was observed for this compound. Compound 6f, bearing a stronger EWG methyl sulfone, showed slightly less enzyme inhibition (IC50 = 0.45 μM), however it was inactive against C. difficile (MIC > 100 μg/mL) presumably due to decreased cellular penetration. Compounds 6g, 6h, and 6i (6-Br, 6-Cl, and 6-F, respectively) showed CdFabK inhibition with IC50’s ranging from 0.11 to 0.34 μM. Interestingly, 6h showed the most potent anti-C. difficile activity with an MIC of 6.25 μg/mL. In contrast, compound 6j, possessing a 4,6-difluoro substitution, showed significantly less enzyme inhibition (IC50 = 4.53 μM) and anti-C. difficile activity (MIC = 12.5 μg/mL). To further explore the SAR of this series, the effect of electron donating groups on biochemical and microbiological activity was investigated. Compound 6k, bearing a 6-ethoxy group, showed promising CdFabK inhibition (IC50 = 0.17 μM) with anti- C. difficile activity of MIC = 12.5 μg/mL. The low Hill slope of this compound suggests a non-ideal inhibitory behavior, possibly due to poor solubility or aggregation. Compound 6l, 10   Attorney Docket 13260-P301WO   bearing a trifluoromethoxy group, showed excellent activity in the nanomolar range (IC50 = 0.09 μM) with moderate anti-C. difficile activity (MIC 12.5-25 μg/mL). Modifications of the urea moiety in the central planar region of 5a were explored by substitution of the urea with a thiourea, giving 7a. Compound 7a showed CdFabK inhibitory activity that was comparable to 5a (IC50 = 1.77 μM), but significantly improved anti-C. difficile activity with an MIC of 0.39 μg/mL, which is comparable to vancomycin. However, the thiourea functionality is a well-known toxicophore, necessitating caution in future investigations of this scaffold. In contrast, removal of the central planar system in compound 7b abolished enzymatic and cellular inhibition (IC50 > 100 μM, MIC > 50 μg/mL), confirming that a planar group is essential. Table 2 CdFabK Inhibition and Antibacterial Activity of 6a–l with substituted Benzothiazole Rings Hill R20291 Compound R group
Figure imgf000013_0001
slop R2 MIC e (μg/mL) 6a 78.3 1.88 95 0.94 0.98 >50
Figure imgf000013_0002
6b >10 - - - 1.56 6c >10 - - - 3.12 6d 0.10a 89 1.07 0.99 6.25 6e 2.81 71 1.01 0.98 12.5 6f 0.45 95 0.97 0.98 >100 6g 0.34 99 1.02 0.94 50 6h 0.11 96 0.86 0.99 6.25 6i 0.23 98 0.85 0.96 NDb 6j 4.53 79 1.18 0.97 12.5 6k 0.17 91 0.67 0.97 12.5
Figure imgf000013_0003
11   Attorney Docket 13260-P301WO   6l 86.3 0.09 91 0.84 0.95 12.5-25 Vancomycin 0.39-0.78 Cerulenin 3.12 a The protein concentration used in these assays was 4 nM. b Not determined. Phenylimidazole Tail Group Modifications (8a–c) In the modification of the phenylimidazole tail group, compounds 8a–c were synthesized to explore tail group substitutions of phenyl-triazole (8a), benzimidazole (8b), and quinazolinone (8c) as shown in Table 3. These compounds were designed to retain the recognized hydrogen bond donor and acceptor groups of the phenylimidazole discussed above, while exploring differing bicyclic ring systems and steric bulk. As shown in Table 3, overall these compounds showed low inhibitory activity against CdFabK (IC50 > 10 μM) and no anti-C. difficile activity with MICs of > 50 μg/mL. This suggests that the tail region of this inhibitor series is significantly less tolerant to substitution compared to the head and central regions. Table 3 CdFabK Inhibition and Antibacterial Activity of 8a–c with Various Tail Groups
Figure imgf000014_0001
Compound Solubility 12   Attorney Docket 13260-P301WO To investigate the experimental solubility, select compounds from the 5a-i and 6a-l series were tested using a turbidimetric assay previously reported and results are shown in Table 4. The most soluble compound, 6j, with an estimated precipitation point of 125 μM, showed low inhibition activity against CdFabK (IC50 = 4.53 μM) and pyrimidine analog 5b had a precipitation point of 83.9 μM. The nature of the endogenous FabK substrate (fatty acids) and the observed lipophilic regions of the CdFabK active site suggest that lipophilic interactions are a key driver for binding affinity. The biochemical activity and solubility assay data shown here imply that a careful balance of lipophilic and hydrophilic character is required for a compound to possess potent CdFabK inhibition. For example, the most potent analogs evaluated here, compounds 5g, 6d, 6f, and 6i, have estimated precipitation points in the range of 44.5 μM to 65.3 μM. This suggests that the optimal solubility, that correlates to optimal activity, can be predicted by a compound precipitation point of approximately 55 μM. Compound 6h was an unusual outlier in these studies as it showed a decrease in absorbance above the precipitation point of 76.9 μM, indicating the compound’s solubility was improving at higher concentrations. It is noted that the low Hill slope of 6h may imply aggregation or micelle formation is occurring with this compound. Table 4 Solubility Assay Data of Select Compound Set Estimated Entry Compound precipitation point R2
Figure imgf000015_0001
Attorney Docket 13260-P301WO   Estimated Entry Compound precipitation point R2 (μM)
Figure imgf000016_0001
The following experiments are intended to further elaborate and expand on the detailed description and are in no way intended to limit the scope of the invention, nor should they be construed as limiting the scope of the invention. General Methods Solvents and Reagents Commercial reagents were purchased from Sigma-Aldrich or Fisher Scientific and used without additional purification. Dichloromethane (DCM), dimethylformamide (DMF), and tetrahydrofuran (THF) were purchased in a Sure/Seal bottle (≥ 99.8%, anhydrous) and additionally sparged with N2 prior to use. Reaction Setup, Monitoring, and Product Purification Reactions were carried out in oven-dried glassware under a positive pressure of N2 in anhydrous solvents using standard Schlenk techniques. Reactions run at room temperature (22−23 °C) and heating temperature (80−100 °C) controlled by an IKA temperature modulator. Reaction progress was monitored using an analytical high-performance liquid chromatography (HPLC) employing a Shimadzu LC-20A series HPLC system. Compounds were purified by flash column chromatography on silica gel using a Biotage Isolera One system on prefilled, Biotage SNAP Ultra columns and Biotage SNAP NH columns using ACS grade solvents. Organic solutions were concentrated under reduced pressure on a Heidolph temperature-controlled rotary evaporator equipped with a Brinkmann Lauda WK 1200 Circulation Chiller. 14   Attorney Docket 13260-P301WO   Biological Assays Enzyme expression & purification The CdFabK enzyme was expressed following known protocols. After harvesting the cells, they were suspended in a lysis buffer consisting of Buffer A (50 mM HEPES pH 8.0, 300 mM NH4Cl, 18% glycerol, 100 µM FMN, 10 mM imidazole, and 1 mM DTT), 0.5 mg/mL lysozyme, 0.5% Triton-X 100, 25 mM sucrose, 10 µg/mL DNase, and protease inhibitor. Cells were then lysed in a pulse sonifier with 8 seconds of ultrasonic pulse and 24 seconds of interval with a total pulse time of 8 min, and then the lysates were centrifuged at 18000 RPM for 15 minutes using a JA-20 rotor in a Beckman Coulter Centrifuge. The supernatant was passed through 0.22 µM filters. Protein purification was done by affinity chromatography in a His-Trap HP column (Cytiva Life Sciences) and eluted with an elution buffer (50 mM HEPES pH 8.0, 300 mM NH4Cl, 18% glycerol, 100 µM FMN, 500 mM imidazole and 1 mM DTT). The protein was further purified by gel filtration on a SuperDex 200 PG column (GE Healthcare) with a buffer containing, 50 mM Hepes pH 8.0, 300 mM NH4Cl, 18% glycerol, 100 µM FMN, and 3 mM DTT. After purification, the protein was concentrated using a centrifugal filter (Amicon Ultra -15). General assay method The CdFabK enzyme assays were conducted at 25 ℃ using assay buffer (100 mM HEPES pH 8.0, 500 mM NH4Cl, 10% glycerol) in 384-well microplates at a final volume of 100 µL (30 µL of buffer, 10 µL inhibitor, 5 µL of crotonyl-CoA substrate, 5 µL of protein, and 50 µL NADH). The final concentrations of enzyme, NADH cofactor, and crotonyl-CoA substrate were 15 nM, 125 µM, and 325 µM, respectively. Test compounds were serially diluted using DMSO prior to assay. The initial concentration of the test compounds and the dilution factor were determined by initial single concentration assays at 10 µM and 100 µM to give an appropriate concentration range with data points above and below the inflection for best curve fits. A working dilution of the protein was prepared using the assay buffer with 2.5 mg/ml γ-globulins (used for a crowding effect to stabilize the CdFabK dimer at low concentrations). The compound and enzyme were incubated for 10 minutes, after which crotonyl-CoA substrate was added. The reaction is started by the addition of the NADH cofactor and continuously monitored for NADH conversion to NAD+ by fluorescence intensity (ex 340, em 460) in a Biotek Synergy H1 microplate reader for 10 min total 15   Attorney Docket 13260-P301WO   duration with reads every 20 seconds. For each test compound, eleven concentrations were tested, in duplicate, along with a DMSO control. IC50 determination Slopes obtained from the steady-state period of the continuous assays (linear range) were calculated and used with control data to determine percent inhibition at each concentration. Percent inhibitions (duplicate) and compound concentrations were used to calculate IC50 values for each compound by four-parameter non-linear regression (Hill equation) fit with GraphPad Prism 9.0. For a better estimate of the goodness of fit, Sy.x (Standard deviation of the Residual) was calculated with GraphPad Prism 9.0. Solubility assays Solubility of the compounds was measured using standard turbidimetric protocols.1 mL of the CdFabK assay buffer was placed in a cuvette. From a 10 mM DMSO stock, 1 µL of test compound was added to the buffer every minute, and absorbance was measured at 620 nm. A total of 14 concentrations were tested. The precipitation point was calculated using a segmental linear regression fit to the absorbance at Y-axis and the concentration at the X-axis. The intersection of the two-line is the inflection point and is the estimated concentration where the compound begins to precipitate. MIC determination MICs were performed by the broth microdilution method, as previously described, using C. difficile strain R20291, in brain heart infusion broth (BHI, from BD Diagnostics). Compound stock solutions were prepared to 10 mg/mL in DMSO (Alfa Aesar). BHI was deoxygenated overnight in a PLAS Labs 857-OTA anaerobic chamber. Strain R20291 was grown anaerobically overnight in BHI broth in a Don Whitley A35 anaerobic at 37 °C. Compounds were serially two-fold diluted (100-0.1 µg/mL) and incubated anaerobically for 1 h before being inoculated with 100 µL of bacteria prepared as a 1:100 dilution of the overnight culture. After 24 h of anaerobic incubation at 37 °C, MICs were recorded as the lowest concentration of compound that inhibited visible growth. MICs reported were performed in biological duplicates and values are shown as a range, where found. 16   Attorney Docket 13260-P301WO   Although various embodiments of the present disclosure have been illustrated in the accompanying Drawings and described in the foregoing Detailed Description, it will be understood that the present disclosure is not limited to the embodiments disclosed herein, but is capable of numerous rearrangements, modifications, and substitutions without departing from the spirit of the disclosure as set forth herein. The term “substantially” is defined as largely but not necessarily wholly what is specified, as understood by a person of ordinary skill in the art. In any disclosed embodiment, the terms “substantially”, “approximately”, “generally”, and “about” may be substituted with “within [a percentage] of” what is specified, where the percentage includes 0.1, 1, 5, and 10 percent. The foregoing outlines features of several embodiments so that those skilled in the art may better understand the aspects of the disclosure. Those skilled in the art should appreciate that they may readily use the disclosure as a basis for designing or modifying other processes and structures for carrying out the same purposes and/or achieving the same advantages of the embodiments introduced herein. Those skilled in the art should also realize that such equivalent constructions do not depart from the spirit and scope of the disclosure, and that they may make various changes, substitutions, and alterations herein without departing from the spirit and scope of the disclosure. The scope of the invention should be determined only by the language of the claims that follow. The term “comprising” within the claims is intended to mean “including at least” such that the recited listing of elements in a claim are an open group. The terms “a”, “an”, and other singular terms are intended to include the plural forms thereof unless specifically excluded. Conditional language used herein, such as, among others, “can”, “might”, “may”, “e.g.”, and the like, unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to convey that certain embodiments include, while other embodiments do not include, certain features, elements and/or states. Thus, such conditional language is not generally intended to imply that features, elements and/or states are in any way required for one or more embodiments or that one or more embodiments necessarily include logic for deciding, with or without author input or prompting, whether these features, elements and/or states are included or are to be performed in any particular embodiment. 17   Attorney Docket 13260-P301WO   While the above detailed description has shown, described, and pointed out novel features as applied to various embodiments, it will be understood that various omissions, substitutions, and changes in the form and details of the devices or algorithms illustrated can be made without departing from the spirit of the disclosure. As will be recognized, the processes described herein can be embodied within a form that does not provide all of the features and benefits set forth herein, as some features can be used or practiced separately from others. The scope of protection is defined by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope. Although various embodiments of the method and apparatus of the present invention have been illustrated in the accompanying Drawings and described in the foregoing Detailed Description, it will be understood that the invention is not limited to the embodiments disclosed, but is capable of numerous rearrangements, modifications and substitutions without departing from the spirit of the invention as set forth herein. 18  

Claims

Attorney Docket 13260-P301WO   CLAIMS What is claimed is: 1. A composition comprising an inhibitor of FabK activity. 2. The composition of claim 1, wherein the inhibitor is a compound having a structure selected from the group consisting of an imidazole scaffold, a thiazole scaffold, a pyridine- thiazole scaffold, a benzothiazole scaffold, a benzimidazole scaffold, a benzoxazole scaffold and combinations thereof. 3. The composition of claim 1, wherein the inhibitor is a phenylimidazole compound. 4. The composition of claim 3, wherein the phenylimidazole compound has a substitution to the pyridine head group. 5. The composition of claim 3, wherein the phenylimidazole compound has a modification to the pyridine head group. 6. The composition of claim 3, wherein the head group of the phenylimidazole compound is modified by the addition of one or more halogen groups. 7. The composition of claim 3 wherein, the phenylimidazole compound comprises modifications to the planar central aromatic region. 8. The composition of claim 7, wherein a thiazole of the central aromatic region is substituted with quinoline and/or benzothiazole. 9. The composition of claim 7, wherein the urea is replaced with a thiourea. 10. The composition of claim 3, wherein the phenylimidazole compound comprises modifications to the aromatic tail group ring. 11. The composition of claim 10, wherein the modifications to the aromatic tail group involves substitution of the phenylimidazole group with aromatic bicyclic groups. 12. A compound having the structure: 19   Attorney Docket 13260-P301WO  
Figure imgf000022_0001
R1 and R2 are a halogen, -OCH3, -CF3, -CN or -OCF3. 13. A compound having the structure:
Figure imgf000022_0002
wherein: X is S, N or O; R1 is -CF3, -CH3, -SO2CH3, halogen, -OCH3, -OCOCH3, -OC2H5 or -SO2N(CH3)2; Z, when present, is NH, NHCO or NHCONH; Y is S or N; and R2 is a halogen, -OCH3, -CF3, -CN or -OCF3. 14. A compound having the structure: 20   Attorney Docket 13260-P301WO  
Figure imgf000023_0001
D is a benzene, pyridine, pyrimidine, benzothiazole, or quinoline; and R1 and R2 are a halogen, -OCH3, -CF3, -CN or -OCF3. 15. A compound selected from the group consisting of: C19H16N6OS2 (Compound A); C19H15BrN6OS2 (Compound B); C16H14N4OS2 (Compound C); C19H15FN6OS2 (Compound D); C20H18N6O2S2 (Compound E); C20H15F3N6OS2 (Compound F); C20H15F3N6O2S2 (Compound G); C20H15N7OS2 (Compound H); C19H16N6O2S2 (Compound I); C21H18N6O4S2 (Compound J); C19H17N6O5PS2 (Compound K); C30H34N8O3S2 (Compound L); C23H20N6O6S2 (Compound M); C25H22N6O8S2 (Compound N); C17H14N6OS3 (Compound O); C19H15BrN6S3 (Compound P); (C20H15Br2N5OS2 (Compound Q); C21H15BrN6OS3 (Compound R); C17H14N6OS2 (Compound S); C18H15N7OS2 (Compound T); C18H14N6O2S2 (Compound U); C18H14BrN7OS2 (Compound V); C23H17BrN6OS2 (Compound W); C19H14BrClN6OS2 (Compound X); C20H14BrF3N6OS2 (Compound Y); C20H14BrF3N6OS2 (Compound Z); C20H16BrN5OS2 (Compound AA); C21H18BrN5O2S2 (Compound AB); C20H15BrClN5OS2 (Compound AC); C18H14N4O3S2 (Compound AD); C16H12N4OS2 (Compound AE); C15H14N4O3S2 (Compound AF); C17H16N4O4S2 (Compound AG); C18H18N4O3S2 (Compound AH); C17H16N2O5S3 (Compound AI); C20H13ClN2O5S2 (Compound AJ); C17H13N3O3S (Compound AK); C14H10N6OS2 (Compound AL); C18H13N3O5S2 (Compound AM); C18H16N2O5S2 (Compound AN); C20H23N5O3S (Compound AO); C18H18N4O4S2 (Compound AP); C16H13ClN2O3S3 (Compound AQ); C17H14N4O3S3 (Compound AR); C18H16N6O3S (Compound AS); C19H15ClN4O2S (Compound AT); C17H12ClN3O2S3 (Compound AU); C16H14N4O4S2 (Compound AV); C18H20N4O3S2 (Compound AW); C14H14N4O2S3 (Compound AX); C16H14N4O4S2 (Compound AY); C21H16N4O5S2 21   Attorney Docket 13260-P301WO   (Compound AZ); C18H13N3O4S2 (Compound BA); C13H12N4O3S3 (Compound BB); C22H19N3O4S2 (Compound BC); C17H14N4O3S2 (Compound BD); C17H16N2O3S2 (Compound BE); C17H16N2O3S3 (Compound BF); C20H15ClN4O4S3 (Compound BG); C16H12N4OS2 (Compound BH); C16H12N4O3S3 (Compound BI); C17H14N6O3S3 (Compound BJ); C18H16N6O4S2 (Compound BK); C17H13BrN6O3S2 (Compound BL); C17H13ClN6O3S2 (Compound BM); C17H14N6O3S2 (Compound BN); C18H15N5O3S2 (Compound BO); C18H15N5O3S2 (Compound BP); C18H14BrN5OS (Compound BQ); C18H13BrFN5OS (Compound BR); C18H13Br2N5OS (Compound BS); C19H13BrF3N5OS (Compound BT); C18H12BrF2N5OS (Compound BU); C18H14N4O2S (Compound BV); C19H16BrN5O3S2 (Compound BW); C18H13BrClN5OS (Compound BX); C20H18BrN5O2S (Compound BY); C18H23BrN4OS (Compound BZ); C19H13BrF3N5O2S (Compound CA); C19H13BrF3N5OS (Compound CB); C19H13BrF3N5OS (Compound CC); C19H13BrF3N5OS (Compound CD); C14H10F3N3O3S3 (Compound CE); C17H13N3O4S3 (Compound CF); C17H13N3O3S4 (Compound CG); C18H19N5O2S2 (Compound CH); C19H15N5O2S2 (Compound CI); C21H15ClN4O2S2 (Compound CJ); C14H12N4O2S2 (Compound CK); C19H16N4OS2 (Compound CL); C18H16N6OS2 (Compound CM); C19H13ClN4O2S2 (Compound CN); C17H12N6O2S2 (Compound CO); C17H12N6O2S2 (Compound CP); C18H14N4OS2 (Compound CQ); C19H13ClN4O2S2 (Compound CR); C17H12N4O3S2 (Compound CS); C19H14ClN5O2S2 (Compound CT); C20H16N4O3S2 (Compound CU); C18H19N3O3S2 (Compound CV); C18H18N2O5S2 (Compound CW); C20H21ClN4O2S (Compound CX); C18H16F3N3O3S (Compound CY); C18H19N3O5S2 (Compound CZ; C20H21FN4O2S (Compound DA); C20H22N4O2S (Compound DB); C18H14ClN5OS2 (Compound DC); C20H15F3N4OS2 (Compound DD); C20H18N4O3S2 (Compound DE); C20H17FN4O2S2 (Compound DF); C20H15ClN4O2S2 (Compound DG); C20H17ClN4O2S2 (Compound DH); C21H17F3N4O2S2 (Compound DI); C20H16ClN5O2S2 (Compound DJ); C20H18N4O2S2 (Compound DK); C20H15F3N4O2S2 (Compound DL); C19H15N3OS2 (Compound DM); C20H17N3OS2 (Compound DN); C20H17N3OS2 (Compound DO); C21H19N3O2S2 (Compound DP); C20H17N3OS2 (Compound DQ); C20H17N3O2S2 (Compound DR); C22H21N3OS2 (Compound DS); C21H19N3OS2 (Compound DT); C22H16F3N3O2S (Compound DU); C22H16F3N3OS (Compound DV); C19H18F3N3O3S (Compound DW); C22H19N3O4S2 (Compound DX); C22H19N3O3S2 (Compound DY); C19H16N4O3S3 (Compound DZ); C21H18ClN5O3S2 (Compound EA); C20H16ClN5O2S2 (Compound EB); C19H14ClN5O2S2 (Compound EC); C20H16ClN5O2S2 (Compound ED); C19H21N3O5S2 (Compound EE); C19H18F3N3O4S (Compound EF); C18H16F3N3O4S (Compound EG); C22H16F3N3OS (Compound EH); 22   Attorney Docket 13260-P301WO   C22H16F3N3O2S (Compound EI); C23H18F3N3O2S (Compound EJ); C22H19N3O4S2 (Compound EK); C17H18N4O3S2 (Compound EL); C12H10N4OS2 (Compound EM); C19H13FN4O2S2 (Compound EN); C18H20N4O5S3 (Compound EO); C13H12N4O3S3 (Compound EP); C19H20N4O5S3 (Compound EQ); C17H14F3N3O4S2 (Compound ER); C16H14ClN3O3S2 (Compound ES); C14H14N4O3S3 (Compound ET); C19H17N5O3S2 (Compound EU); C16H14BrN3O3S2 (Compound EV); C18H15N3O3S2 (Compound EW); C19H21N5O4S3 (Compound EX); C20H16N4O4S3 (Compound EY); C19H16N4O3S3 (Compound EZ); C18H16N4O3S2 (Compound FA); C20H23N3O3S2 (Compound FB); C18H14FN3O3S2 (Compound FC); C17H13N5O4S4 (Compound FD); C17H15FN4O4S3 (Compound FE); C21H15F3N4O5S3 (Compound FF); C18H15N5OS (Compound FG); C18H16N4O3S2 (Compound FH); C21H18N4O5S3 (Compound FI); C21H15F3N4O4S3 (Compound FJ); C20H18N4O3S2 (Compound FK); C17H14N6O3S3 (Compound FL); C21H18N4O4S3 (Compound FM); C19H16N4O3S3 (Compound FN); C20H14Cl2N4O4S3 (Compound FO); C14H13N3O3S3 (Compound FP); C17H15N5O3S2 (Compound FQ); C18H16N4O3S2 (Compound FR); C18H15N3O3S3 (Compound FS); C20H15ClN4O4S3 (Compound FT); C19H16BrN5O3S2 (Compound FU); C19H16N4O3S2 (Compound FV); C22H19N3O3S2 (Compound FW); C19H21N3O5S2 (Compound FX); C19H16N4OS2 (Compound FY); C20H17ClN4O2S2 (Compound FZ); C20H18N4O2S2 (Compound GA); C19H15ClN4OS2 (Compound GB); C18H14ClN5OS2 (Compound GC); C18H13ClN4OS2 (Compound GD); C19H15ClN4OS2 (Compound GE); C19H16N4OS2 (Compound GF); C18H14N4OS (Compound GH); C18H13BrN4OS (Compound GI); C19H16N4O2S (Compound GJ); C17H19N5O3S (Compound GK); C12H11N5OS (Compound GL); C19H17N5OS (Compound GM); C18H16N6O (Compound GN); C19H19F3N4O3 (Compound GO); C18H17F3N4O3 (Compound GP); C18H14ClN5OS (Compound GQ); C19H18F3N3O4 (Compound GR); C18H16F3N3O4 (Compound GS); C17H18N4O4S (Compound GT); C12H10N4O2S (Compound GU); C18H15N5O2 (Compound GV); C16H12N4O2S (Compound GW); and C14H16ClN3O4S2 (Compound GX). 16. A pharmaceutical composition comprising one or compounds of claim 15. 23  
PCT/US2024/020337 2023-03-17 2024-03-17 Fabk inhibitor compositions Ceased WO2024196830A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040053814A1 (en) * 2000-10-06 2004-03-18 Martin Brandt Methods of agonizing and antagonizing FabK
WO2007086584A1 (en) * 2006-01-30 2007-08-02 Meiji Seika Kaisha, Ltd. NOVEL INHIBITOR OF FabK AND FabI/K

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040053814A1 (en) * 2000-10-06 2004-03-18 Martin Brandt Methods of agonizing and antagonizing FabK
WO2007086584A1 (en) * 2006-01-30 2007-08-02 Meiji Seika Kaisha, Ltd. NOVEL INHIBITOR OF FabK AND FabI/K

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE PubChem 13 January 2016 (2016-01-13), ANONYMOUS: "SID 280658235 ", XP093218604, Database accession no. 280658235 *
DATABASE PubChem 22 December 2010 (2010-12-22), ANONYMOUS: "CHEMBL237639", XP093218608, Database accession no. SID 103541742 *
DATABASE PubChem 7 December 2019 (2019-12-07), ANONYMOUS: "SID 399608265 ", XP093218605, Database accession no. 399608265 *
DATABASE PubChem Substance 17 February 2021 (2021-02-17), "CHEMBL244804", XP093260928, Database accession no. CHEMBL244804 *

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