Inhibitors of bacterial enoyl acyl carrier protein reductase (FabI): 2,9-disubstituted 1,2,3,4-tetrahydropyrido[3,4-b]indoles as potential antibacterial agents

Seefeld, Mark A.; Miller, William H.; Newlander, Kenneth A.; Burgess, Walter J.; Payne, D. J.; Rittenhouse, Stephen; Moore, Terrance; DeWolf, Walter E.; Keller, Paul M.; Qiu, Xiayang; Janson, Cheryl A.; Vaidya, Kalindi; Fosberry, Andrew; Smyth, Martin G.; Jaworski, Deborah D.; Slater-Radosti, Courtney; Huffman, William F.

doi:10.1016/s0960-894x(01)00405-x

Cited by 63 publications

(39 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In one case, screening of over 300,000 compounds in the GlaxoSmith Kline compound collection led to the identification of a benzodiazepine derivative [38]. Chemical optimization studies and structure activity relationship studies led to the identification of four related chemical series of inhibitorsaminopyridines [39], imidazoles [34], indoles [35], naphthyridines [38]. Further optimization of the indole naphthyridinone class resulted in quite potent compounds with IC 50 's as low as 0.02 µM and MICs <0.001 µg/ml [40].…”

Section: Results Of Screening and Optimizationmentioning

confidence: 99%

“…Detection may be by spectrophotometric measurement of the decrease in absorbency at 340 nm [31,34,35] or by measurement of the decrease in fluorescence beyond 460 nm [36]. These assays are based on the following reaction: crotonoyl-CoA + NADH à butyryl-CoA + NAD + .…”

Section: Endpoint and Kinetic Assaysmentioning

confidence: 99%

“…Screens typically involve addition of all components including test compounds (at 10-20 µg/ml, or 20-40 µM), followed by initiation of the reaction by the addition of crotonyl-CoA substrate [36]. Several screens have included triclosan as a positive control in a portion of the wells of each test microtiter dish [34,35]. Quality control parameters of FabI screens have not been published widely, but one group indicated a signal:background ratio of 3-4 and a Z' factor [37] of 0.69 [36].…”

Section: Endpoint and Kinetic Assaysmentioning

confidence: 99%

See 2 more Smart Citations

Identification of Inhibitors of Bacterial Enoyl-Acyl Carrier Protein Reductase

Moir¹

2005

CDTID

View full text Add to dashboard Cite

The FabI-related enoyl-ACP reductase enzymes of bacteria meet many of the criteria for antibacterial targets. These enzymes are essential for the growth of several pathogenic species, have no significant mammalian homologs, catalyze a rate-limiting step in a vital macromolecular biosynthetic pathway, and are already the targets of antibacterials used in the clinic (isoniazid) and in consumer products (triclosan). The suitability of FabI as an antibiotic target is diminished somewhat by the discovery that many pathogens carry an alternate unrelated enoyl-ACP reductase (FabK) or both reductases. However, a key human pathogen, Staphylococcus aureus and its increasingly common drug-resistant derivative MRSA are sensitive to FabI inhibitors. Screening for inhibitors of this target has resulted in the identification of five chemical classes of potent inhibitors. In addition, analogs of triclosan with increased potency and with pro-drug features have been engineered. At least one of these classes of inhibitors has been optimized and tested in animals for pharmacokinetic properties and efficacy. Further development of one or more of these classes and further screening are expected to generate new FabI inhibitors for application in the clinic against drug-resistant S. aureus.

show abstract

Section: Results Of Screening and Optimizationmentioning

confidence: 99%

Section: Endpoint and Kinetic Assaysmentioning

confidence: 99%

Section: Endpoint and Kinetic Assaysmentioning

confidence: 99%

See 1 more Smart Citation

Identification of Inhibitors of Bacterial Enoyl-Acyl Carrier Protein Reductase

Moir¹

2005

CDTID

View full text Add to dashboard Cite

show abstract

“…Compounds based on 2,9-disubstituted 1,2,3,4-tetrahydropyrido [3,4-b]indole have been synthesized and their inhibitory activity against S. aureus and E. coli enoyl reductase assessed in vitro [200]. The compounds showing submicromolar IC50 against enoyl reductase activity were tested for in vitro antibacterial activity with MIC values ranging from 0.5 to 4.0 µg mL -1 against S. aureus.…”

Section: Other Potential Inhibitorsmentioning

confidence: 99%

Drugs that Inhibit Mycolic Acid Biosynthesis in Mycobacterium tuberculosis - An Update

Basso¹,

Santos²

2005

MCRO

View full text Add to dashboard Cite

Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis, and infects approximately 32 % of the world's human population. It is estimated that 8.2 million new TB cases occurred worldwide in the year 2000, with approximately 1.8 million deaths in the same year, and more than 95 % of those were in developing countries. The interruption of centuries of decline in case rates of TB occurred, in most cases, in the late 1980s and involved the USA and some European countries due to increased poverty in urban settings and the immigration from TB high-burden countries. Thus, no sustainable control of TB epidemics can be reached in any country without properly addressing the global epidemic. The reemergence of TB as a potential public health threat, the high susceptibility of human immunodeficiency virus-infected persons to the disease, and the proliferation of multi-drug-resistant (MDR) strains have created much scientific interest in developing new antimycobacterial agents to both treat M. tuberculosis strains resistant to existing drugs, and shorten the duration of short-course treatment to improve patient compliance. Bacterial cell-wall biosynthesis is a proven target for new antibacterial drugs. Mycolic acids, which are key components of the mycobacterial cell wall, are α-alkyl, β-hydroxy fatty acids, with a species-dependent saturated "short" arm of 20-26 carbon atoms and a "long" meromycolic acid arm of 50-60 carbon atoms. The latter arm is functionalized at regular intervals by cyclopropyl, α-methyl ketone, or α-methyl methylethers groups, and, as shown more recently, by unsaturations. The mycolic acid biosynthetic pathway has been proposed to involve five distinct stages: (i) synthesis of C20 to C26 straightchain saturated fatty acids to provide the α-alkyl branch; (ii) synthesis of the meromycolic acid chain to provide the main carbon backbone, (iii) modification of this backbone to introduce other functional groups; (iv) the final Claisen-type condensation step followed by reduction; and (v) various mycolyltransferase processes to cellular lipids. The drugs shown to inhibit mycolic acid biosynthesis are isoniazid, ethionamide, isoxyl, thiolactomycin, and triclosan. Pyrazinamide was thought to inhibit fatty acid synthase type I, thereby reducing the synthesis of precursor of mycolic acids. However, current experimental evidence indicates that it has no defined target of action. The main focus of our contribution is on new data describing the mode of action of antitubercular drugs that inhibit mycolic acid biosynthesis, and description of inhibitors of fatty acid synthase type II enzymes as potential lead compounds that may allow the development of new antitubercular agents.

show abstract

“…Gamma-carboline derivatives are widely used in medical and pharmaceutical chemistry due to their antihistamine [1], antidopamine [2] and antiserotonin activity [3]. For example, the Russian antihistamine drug Dimebon also exhibits a pronounced therapeutic effect against a number of neurodegenerative and neurological diseases [4][5][6].…”

mentioning

confidence: 99%

CsF-Catalyzed alkylation of gamma-carbolines with fluorine-containing 3-vinylpyridines

2014

View full text Add to dashboard Cite

CsF-Catalyzed alkylation of gamma-carbolines with 3-vinyl-5-fluoropyridine and 3-vinyl-6-trifluoromethylpyridine led to the formation of 5-[2-(5-fluoropyrid-2-yl)ethyl]-2,3,4-tetrahydro-1Н-pyrido[4,3-b]-indoles and 5-[2-(6-trifluoromethylpyrid-2-yl)ethyl]-2,3,4-tetrahydro-1Н-pyrido[4,3-b]indoles.Gamma-carboline derivatives are widely used in medical and pharmaceutical chemistry due to their antihistamine [1], antidopamine [2] and antiserotonin activity [3]. For example, the Russian antihistamine drug Dimebon also exhibits a pronounced therapeutic effect against a number of neurodegenerative and neurological diseases [4][5][6]. Studies in the field of purposeful search for new neuroprotectors among gamma-carbolines derivatives are promising for designing effective agents for the treatment of various neuropathies [7][8][9].In this work we developed an approach towards synthesis of fluorinated analogs of Dimebon containing 5-fluoro-and (6-trifluoromethypyridin-3-yl)ethylsubstituted indole fragment. This method was based on a catalyzed alkylation of gamma-carbolines with 3-vinyl-5-fluoropyridine and 3-vinyl-6-trifluoromethylpyridine.Generally, the main known methods for alkylating gamma-carbolines with vinylpyridines by Michael addition include the use of equimolar amounts of strong bases, for example methoxide or sodium hydride as promoters in DMSO or DMSO-60%-aqueous KOH system [10][11][12].In the case of 3-vinyl-5-fluoropyridine and 3-vinyl-6-trifluoromethylpyridine the use of these promoters is not acceptable, since under the reaction conditions (150°C, DMSO) a nucleophilic substitution of the fluorine atom in 3-vinyl-5-fluoropyridine and a destruction of the C-F bond in 3-vinyl-6-trifluoromethylpyridine occur. In this connection, we studied the possibility of using cesium fluoride, which is a source of strong base, fluoride ion [13], as a catalyst for gamma-carbolines alkylation.It was found that reactions of equimolar amounts of gamma-carbolines I and fluorine-containing 3-vinylpyridines II or III under heating in DMSO at 160°C in the presence of catalytic amounts of CsF afforded substituted 5-[2-(5-fluoropyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1Н-pyrido[4,3-b]indoles IV or 5-[2-(6-trifluoromethylpyridin-3-yl)ethyl]-2-ethyl-2, 3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles V in yields of 75-80%. In the case of 3-vinyl-5-fluoropyridine II or less reactive 3-vinyl-6-trifluoromethylpyridine the reaction time was 6 or 12 h, respectively (Scheme 1).The synthesized compounds IVa, IVb, Va, and Vb were colorless crystalline substances whose composition and structure were proved by elemental analysis and 1 H, 19 F NMR spectroscopy. In the 1 H NMR spectra of compounds IV and V there were triplet signals of the ethylene spacer linking gammacarboline and pyridine moieties (3.01-3.05 and 4.16-4.21 ppm). The signals of fluorine atom of the pyridine ring of IV appeared at -47.46 and -48.22 ppm. The signals of CF 3 -group of the pyridine ring of V were observed at 9.59 and 10.01 ppm.

show abstract

Inhibitors of bacterial enoyl acyl carrier protein reductase (FabI): 2,9-disubstituted 1,2,3,4-tetrahydropyrido[3,4-b]indoles as potential antibacterial agents

Cited by 63 publications

References 13 publications

Identification of Inhibitors of Bacterial Enoyl-Acyl Carrier Protein Reductase

Identification of Inhibitors of Bacterial Enoyl-Acyl Carrier Protein Reductase

Drugs that Inhibit Mycolic Acid Biosynthesis in Mycobacterium tuberculosis - An Update

CsF-Catalyzed alkylation of gamma-carbolines with fluorine-containing 3-vinylpyridines

Contact Info

Product

Resources

About