1,4-Disubstituted imidazoles are potential antibacterial agents functioning as inhibitors of enoyl acyl carrier protein reductase (FabI)

Heerding, Dirk A.; Chan, George; DeWolf, Walter E.; Fosberry, Andrew; Janson, Cheryl A.; Jaworski, Deborah D.; McManus, Edward C.; Miller, William H.; Moore, Terrance; Payne, D. J.; Qiu, Xiayang; Rittenhouse, Stephen; Slater-Radosti, Courtney; Smith, Ward W.; Takata, Dennis T.; Vaidya, Kalindi; Yuan, Catherine C.K.; Huffman, William F.

doi:10.1016/s0960-894x(01)00404-8

Cited by 122 publications

(63 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The most salient features that had emerged from the atomic structures of ENR-NAD(H) complexed with triclosan and with other inhibitors like diazoborines, imidazoles, and aminopyridines were: 1) p-p stacking interaction between one of the aromatic rings of the inhibitors with the nicotinamide ring of the cofactor NADH and 2) a Hydrogen bond between the active site residue-Tyr277 and the inhibitor (15,(38)(39)(40). Our previous work to identify new scaffolds of inhibitors against PfENR, based on the above key features of interactions of the inhibitor with active-site residues and NADH led to the discovery of a new class of inhibitors.…”

Section: Resultsmentioning

confidence: 99%

SAR and pharmacophore models for the rhodanine inhibitors of Plasmodium falciparum enoyl‐acyl carrier protein reductase

et al. 2010

View full text Add to dashboard Cite

SummarySignificance of type II fatty acid synthase pathway in the life cycle of malarial parasite has long been established. Enoyl acyl carrier protein (ACP) reductase of Plasmodium falciparum (PfENR) is the rate determining enzyme of its elongation module. Hence, PfENR has been a target for the development of antimalarials as well as vaccines. Towards this endeavour, we had recently identified rhodanine class of compounds as inhibitors of PfENR. Here, we report a number of new inhibitors belonging to this class. These inhibitors have been divided into two broad subclasses: rhodanine-furans and rhodanine-phenyls. The inhibitory activity of all compounds was determined against purified PfENR. IC 50 of these compounds were found to be in nanomolar to low-micromolar range. The structure-activity relationship of both the classes has been explored in detail for the first time. Separate 3D pharmacophore models for this enzyme have been generated for both rhodanine furans and phenyls. The pharmacophore model for rhodanine furan has a Hydrogen bond donor, two Hydrogen bond acceptors, two metal ligators, three hydrophobic, and two aromatic ring features, whereas the pharmacophore model for the phenyl subclass has two hydrogen bond donors, two hydrogen bond acceptor, a metal ligator, two hydrophobic, and two aromatic ring features. These models could be used for in silico screening of compound libraries for PfENR inhibitors.

show abstract

Section: Resultsmentioning

confidence: 99%

SAR and pharmacophore models for the rhodanine inhibitors of Plasmodium falciparum enoyl‐acyl carrier protein reductase

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Several synthetic FabI inhibitors, including 1,4-disubstituted imidazoles, 10) aminopyridines, 11) naphthyridinones, 12,13) and thiopyridines 14) have been reported in previous studies. Cephalochromin, 15) vinaxanthone, 16) epigallocatechin gallate (EGCG), 17) and flavonoids 18) have all been identified as natural FabI inhibitors.…”

Section: Resultsmentioning

confidence: 97%

“…Disposition of the two hydroxyl and prenyl groups was deduced from the two proton singlet at 6.78 (2H, s, H-2′,6′). The above spectral data were compared with those in the literature, 10,11) and compounds 1 and 2 were identified as chalcomoracin and moracin C, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, inhibitors of S. aureus FabI may prove to be interesting lead compounds for the development of effective antibacterial drugs. Several synthetic [10][11][12][13][14] and natural [15][16][17][18] FabI inhibitors have been reported, but since some compounds showed toxicity and their structures are not so diverse for further study, Fab I inhibitors with new scaffold and low toxicity are desired. Since S. aureus is the most common pathogen and especially multidrugs-resistant S. aureus such as methicillin-resistant S. aureus (MRSA) is becoming increasingly prevalent in community-acquired infections, 19) new antibacterial with new mode of action like S. aureus FabI inhibitors is urgently needed.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Chalcomoracin and Moracin C, New Inhibitors of <i>Staphylococcus aureus</i> Enoyl-Acyl Carrier Protein Reductase from <i>Morus alba</i>

Kim

Sohn

Kim

2012

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Bacterial enoyl-acyl carrier protein (ACP) reductase has been confirmed as a novel target for antibacterial drug development. In the screening of inhibitors of Staphylococcus aureus enoyl-ACP reductase (FabI), we found that a methanol extract of leaves of Morus alba L. potently inhibited S. aureus FabI as well as growth of S. aureus. The active principles were identified as chalcomoracin and moracin C by MS and NMR analysis. Chalcomoracin and moracin C inhibited S. aureus FabI with IC 50 of 5.5 and 83.8 µM, respectively. They also prevented the growth of S. aureus with minimum inhibitory concentration (MIC) of 4 and 32 µg/ mL, respectively. Consistent with their inhibition against FabI and bacterial growth, they prevented [ 14 C]-acetate incorporation into fatty acid in S. aureus while didn't affect protein synthesis. In this study, we reported that chalcomoracin and moracin C, potent antibacterial compounds from Morus alba, inhibited FabI and fatty acid synthesis.

show abstract

“…While most bacteria possess the enoyl-ACP reductase FabI, Streptococcus pneumoniae has an alternative enoyl-ACP reductase, FabK, which displays no significant sequence homology to FabI (3). Although novel FabI inhibitors have been reported by several groups (6,8,11,14), there are very few reports of FabK inhibitors except for a small number of compounds with weak inhibitory activity (11,13). Prior to this study there was no clear evidence that a FabK inhibitor would prevent the growth of S. pneumoniae.…”

mentioning

confidence: 99%

AG205, a Novel Agent Directed against FabK of Streptococcus pneumoniae

Takahata

Iida

Osaki

et al. 2006

Antimicrob Agents Chemother

View full text Add to dashboard Cite

AG205 was identified from high-throughput screening as a potent inhibitor of FabK, the enoyl-ACP reductase in Streptococcus pneumoniae. Specific inhibition of lipid biosynthesis in a macromolecular biosynthesis assay and identification of an Ala141Ser substitution in FabK from spontaneous AG205-resistant mutants indicated that AG205 exerts antibacterial activity against S. pneumoniae through the specific inhibition of FabK.

show abstract

1,4-Disubstituted imidazoles are potential antibacterial agents functioning as inhibitors of enoyl acyl carrier protein reductase (FabI)

Cited by 122 publications

References 19 publications

SAR and pharmacophore models for the rhodanine inhibitors of Plasmodium falciparum enoyl‐acyl carrier protein reductase

SAR and pharmacophore models for the rhodanine inhibitors of Plasmodium falciparum enoyl‐acyl carrier protein reductase

Chalcomoracin and Moracin C, New Inhibitors of <i>Staphylococcus aureus</i> Enoyl-Acyl Carrier Protein Reductase from <i>Morus alba</i>

AG205, a Novel Agent Directed against FabK of Streptococcus pneumoniae

Contact Info

Product

Resources

About