Sıra | DOSYA ADI | Format | Bağlantı |
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01. | Orhnwall Organizer Infections Antimicrobial | ppt | Sunumu İndir |
Transkript
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-Lactams cidal against MtbMonika KonaklievaAmerican University
Synthesis and Characterization of Biologically Active Molecules
• Drug Resistance and Challenges for Drug Discovery• Synthesis and Biological Evaluation of Novel Monocyclic -Lactams against:• Mycobacterium tuberculosis• Staphyloccocus aureusOverview
To Fight Resistant Microbes, FDA to Ban 2 Poutry DrugsThe removal would mark the first time the government has pulledany drug to combat infections that have grown resistant to antibiotics, a rising problem that public health officials have been warning for years could return the world to the days before penicillin and other infection-killers.Washington Post, October 27, 2000Poultry Antibiotics Pose Human Threat…This is the first time FDA has approved banning any antibioticbecause of bacterial resistance. It is also the first time FDA hasproposed withdrawing approval for an antibiotic used in the livestockindustry.C & E News, November 6, 2000
Global Map showing Emergence of a Number of Antimicrobial- Resistance OrganismsJAMA, 275, pp.300-304, 1996
TB kills approximately one person every 20 seconds — nearly 4,700 people every day, or 1.7 million in 2009 alone, according to the latest estimates from the World Health Organization World Health Organization (WHO). TB is second only to HIV as the leading infectious killer of adults worldwide. It is among the three greatest causes of death of women aged 15-44 and is the leading infectious cause of death among people with HIV/AIDS.The Statistics for Mycobacterium tuberculosis (Mtb)
The Effects of Mycobacterium tuberculosis (Mtb)
The WHO estimates that two billion people — one third of the world's population — are infected with Mycobacterium tuberculosis (Mtb), the bacillus that causes the disease. Mtb's unique cell wall, which has a waxy coating primarily composed of mycolic acids, allows the bacillus to lie dormant for many years. The body's immune system may restrain the disease, but it does not destroy it. While some people with this latent infection will never develop active TB, five to 10 percent of carriers will become sick in their lifetime.TB is Global
Drug Resistant TB is a Growing, Deadly ThreatExtensively Drug Resistant TB (XDR-TB) is emerging as an ominous global health threat. The World Health Organization (WHO) and the United States Centers for Disease Control and Prevention (CDC) have now identified XDR-TB cases in all regions of the world, and global health authorities have launched an intensive response to escalating global TB resistance. XDR-TB treatment is extremely complicated, with some strains virtually untreatable with current medicines.
Superbugs Increasing Rapidly - Cost US $5 Billion a YearWASHINGTON (Reuters) - Virtually all strains of the common staph bacterium are now resistant to penicillin, other bugs are rapidly developing drug-resistant forms, and the costs are skyrocketing, disease experts said Thursday. \This is a global public health problem.'' Dr. James Hughes, Assistant Surgeon General and Director of the National Center for Infectious Diseases at the Centers for Disease Control and Prevention (CDC).
Early Ideas on Controlling Infectious Disease
A Closeup Shot of Mycobacterium tuberculosis
Pre WW II Poster advertising Penicillin against TB
Alexander Fleming Introduces the World to Penicillin
Fleming’s Culture of Penicillium Notatum
1928: Alexander Fleming discovers that a broth of Penicillium notatum kills staphylococci, and names the active substance penicillin (0.5 mg/L)The Penicillins: The First Class of -Lactam Antibiotics
1928: Alexander Fleming discovers that a broth of Penicillium notatum kills staphylococci, and names the active substance penicillin (0.5 mg/L) 1945: Dorothy Hodgkin and Barbara Rogers-Low determine the molecular structure of penicillin G by X-ray crystallographyThe Penicillins: The First Class of -Lactam Antibiotics
1928: Alexander Fleming discovers that a broth of Penicillium notatum kills staphylococci, and names the active substance penicillin (0.5 mg/L) 1945: Dorothy Hodgkin and Barbara Rogers-Low determine the molecular structure of penicillin G by X-ray crystallographyThe Penicillins: The First Class of -Lactam AntibioticsNO
1928: Alexander Fleming discovers that a broth of Penicillium notatum kills staphylococci, and names the active substance penicillin (0.5 mg/L) 1945: Dorothy Hodgkin and Barbara Rogers-Low determine the molecular structure of penicillin G by X-ray crystallographyThe Penicillins: The First Class of -Lactam AntibioticsNOa \beta-lactam\CC NCOis
1928: Alexander Fleming discovers that a broth of Penicillium notatum kills staphylococci, and names the active substance penicillin (0.5 mg/L) 1945: Dorothy Hodgkin and Barbara Rogers-Low determine the molecular structure of penicillin G by X-ray crystallographypenicillin G (USA)The Penicillins: The First Class of -Lactam AntibioticsNSOCO2HHNO
1928: Alexander Fleming discovers that a broth of Penicillium notatum kills staphylococci, and names the active substance penicillin (0.5 mg/L) 1945: Dorothy Hodgkin and Barbara Rogers-Low determine the molecular structure of penicillin G by X-ray crystallographypenicillin G (USA)The Penicillins: The First Class of -Lactam AntibioticsNSOCO2HHNO penicillin F(Great Britain)OHNCO2HOSN
NORRCONHNO SO3RRCONHCO2HOHNORCONH SCO2HNOSCO2HROHNORCONHNOCO2HXOHSCO2HXCommon Classes of -Lactam AntibioticsNOOCO2HOH nocardicins monobactams-penicillins penemscephalosporins carbapenemsclavulanic acids
Chemical Structure of the Bacterial Cell WallONHAcOOHOMeOHNMeONHHOOOHNNHONH2MeHNO MeOHOONHAcHOHOONHAcOOOHOMeOHNMeONHHOOOHNNHONH2MeHNO MeOHOONHAcOHOHOONHAcOOHOMeOHNMeONHHOOOHNNHONH2MeHNO MeOHOONHAcOHOHOO
ONHAcOOHOMeOHNMeONHHOOOHNNHONH2MeHNO MeOHOONHAcHOHOONHAcOOOHOMeOHNMeONHHOOOHNNHONH2MeHNO MeOHOONHAcOHOHOONHAcOOHOMeOHNMeONHHOOOHNNHONH2MeHNO MeOHOONHAcOHOHOOONHAcOOHOMeOHNMeONHHOOOHNNHONH2MeNHO MeOHOONHAcHOHOONHAcOOOHOMeOHNMeONHHOOOHNNHONH2MeNHO MeOHOONHAcOHOHOONHAcOOHOMeOHNMeONHHOOOHNNHONH2MeNHO MeOHOONHAcOHOHOO
ONHAcOOHOMeOHNMeONHHOOOHNNHONH2MeHNO MeOHOONHAcHOHOONHAcOOOHOMeOHNMeONHHOOOHNNHONH2MeHNO MeOHOONHAcOHOHOONHAcOOHOMeOHNMeONHHOOOHNNHONH2MeHNO MeOHOONHAcOHOHOOONHAcOOHOMeOHNMeONHHOOOHNNHONH2MeNHO MeOHOONHAcHOHOONHAcOOOHOMeOHNMeONHHOOOHNNHONH2MeNHO MeOHOONHAcOHOHOONHAcOOHOMeOHNMeONHHOOOHNNHONH2MeNHO MeOHOONHAcOHOHOOenzymatictranspeptidation
ONHAcOOHOMeOHNMeONHHOOOHNNHONH2MeHNO MeOHOONHAcHOHOONHAcOOOHOMeOHNMeONHHOOOHNNHONH2MeONHONHAcOHOHOONHAcOOHOMeOHNMeONHHOOOHNNHONH2MeHNO MeOHOONHAcOHOHOOONHAcOOHOMeOHNMeONHHOOOHNNHONH2MeNHO MeOHOONHAcHOHOONHAcOOOHOMeOHNMeONHHOOOHNONHAcOHOHOONHAcOOHOMeOHNMeONHHOOOHNNHONH2MeNHO MeOHOONHAcOHOHOOHNO MeNHO MeHOOH2NMeOHO
How is the Cell Wall Built?NNOCH3HHWallORWall
From the Coupling of Two Separate PiecesNNOCH3CH3OCHHOWall-ORH2NWall
Mechanism of Enzymatic TranspeptidationNNOCH3CH3OCHHOOH+serWall-ORH2NWall
Mechanism of Enzymatic TranspeptidationNNOCH3CH3OCHHOOH+serWall-The enzyme uses a serine nucleophileto cleave thealanine-alanineamide bondORH2NWall
Mechanism of Enzymatic TranspeptidationN H2NOCH3CH3OCHOO+serWall-ORH2NWall
Mechanism of Enzymatic TranspeptidationNH2NOCH3CH3OCHOO+serWall-ORH2NWall
Mechanism of Enzymatic TranspeptidationNH2NOCH3CH3OCHOO+serWall-ORH2NWall
Mechanism of Enzymatic TranspeptidationN OCH3HO+serWall ORH2NWallSecond strand of wall now enters active site
Mechanism of Enzymatic TranspeptidationN OCH3HO+serWall ORH2NWall
Mechanism of Enzymatic TranspeptidationN OCH3HO+serWall ORH2NWall
Mechanism of Enzymatic TranspeptidationNOCH3HOH+serWallORNWallH
Mechanism of Enzymatic TranspeptidationNOCH3HOH+serWallORNWallH
Mechanism of Enzymatic TranspeptidationNOCH3HOH+serWallORNWallH
Mechanism of Enzymatic TranspeptidationNOCH3HOH+ser WallORNWallH
Penicillin's Mechanism of ActionSNCORHN HOO-
Penicillin's Mechanism of ActionSNCORHN HOO-OH+ser
Penicillin's Mechanism of ActionSNCORHN HOO-OH+ser
Penicillin's Mechanism of ActionSNCORHN HOO-OH+ser
Penicillin's Mechanism of ActionSNCORHN HOO-OH+ser
Penicillin's Mechanism of ActionSNCORHN HOO-O+serH
Penicillin's Mechanism of ActionSNCORHN HOO-O+serHdeath of bacterium
What is a drug-resistant infection?
What is a drug-resistant infection?An infection that can not be easily treated with conventional antibiotics
What is a drug-resistant infection?An infection that can not be easily treated with conventional antibioticsReasons:Natural resistance to new drugs
What is a drug-resistant infection?An infection that can not be easily treated with conventional antibioticsReasons:Natural resistance to new drugsMan-made resistance to old drugs
What Causes Drug Resistance?Bacterial resistance to -lactam drugs is due to the production of beta-lactamases
What Causes Drug Resistance?Bacterial resistance to -lactam drugs is due to the production of beta-lactamasesTo be effective, the drug must find a way to avoid being destroyed by these \warrior\ proteins
-Lactamase: A Protein That Destroys Penicillin
Drug Resistance in the '90'sAntibiotic resistance known since the 1940's
Drug Resistance in the '90'sAntibiotic resistance known since the 1940'sRate of resistant bacterial infections accelerated during the 1980's
Drug Resistance in the '90'sAntibiotic resistance known since the 1940'sRate of resistant bacterial infections accelerated during the 1980's Effectiveness of most drugs has been significantly compromised
Drug Resistance in the '90'sAntibiotic resistance known since the 1940'sRate of resistant bacterial infections accelerated during the 1980's Effectiveness of most drugs has been significantly compromisedNeed new antibiotics to combat drug resistance
THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 282, NO. 42, pp. 30414–30422, October 19, 2007Drug Resistance in 2000’sL, D-Transpeptidases as a “Plan B” Pathway of bacteria
• Drug Resistance and Challenges for Drug Discovery• Synthesis and Biological Evaluation of Novel Monocyclic -LactamsOutline
NORRCONHNO SO3HRRCONHCO2HOHNORCONH SCO2HNOCO2HXOHNORCONHNOSCO2HROHSCO2HXCommon Classes of -Lactam AntibioticsNOOCO2HOH nocardicins monobactamspenicillins carbapenemscephalosporins penemsclavulanic acids
NORRCONHNO SO3HRRCONHCO2HOHNORCONH SCO2HNOCO2HXOHNORCONHNOSCO2HROHSCO2HXCommon Classes of -Lactam AntibioticsNOOCO2HOH nocardicins monobactamspenicillins carbapenemscephalosporins penemsclavulanic acids
NORRCONHNO SO3HRRCONHCO2HOHNORCONH SCO2HNOCO2HXOHNORCONHNOSCO2HROHSCO2HXCommon Classes of -Lactam AntibioticsNOOCO2HOH nocardicins monobactamspenicillins carbapenemscephalosporins penemsclavulanic acids
NOSNOSCO2HRA Penem A Penem-like lactam Design of penem-like -Lactams
Synthesis of non-transpeptidase -LactamsNO HOAcY= Y' = H, Y\ = F, CF3, NO2, CO2H, Y = Y\ = H, Y' = F, CF3, NO2, CO2HY = Y' = Y\ = FNHOYSY'\YY SHY' Y\ Z = PhCH2NCOZNZOYSY'\YNZOY(O)nSY'\Y n = 0, 1 or 2Synthesis of N-substituted C4 arylthio--lactams.
Y = Y' = FNHOYSY'\Y Z=PhCH2NCO,CH3CH2NCO,Ph(NO2)NCO,Ph(F)CH2NCO, Ph(OCH3)CH2NCOZNZOYSY'\YSynthesis of differently substituted at the lactam Nitrogen -Lactams
R1b # R2 M.cat.a MIC/MBC g/ml Mtb w/out and with/clav. g/ml # R2 M.cat. MIC/MBC g/ml Mtb w/out and with/clav. g/ml 2 H >200 25/25 30 12.5/12.5 6.25/6.25 3 H 200 25 31 25/50 3.125/3.125 4 H >200 100/25 32 25/100 NT 5 H >200 >100/25 33 25/25 6.25/6.25 6 H 1.5/3.1 3.125/3.125 34 1.625/1.625 100/12.5 7 H 50/50 50/25 35 12.5/25 6.25/6.25 8 H 1.5/1.5 >100 36 3.1/6.25 >100 9 12.5/50 NT yet 37 12.5/25 NT yet 10 12.5/25 Nt yet 38 6.25/6.25 Nt yet 11 6.25/6.25 Nt yet 39 3.13/6.25 Nt yet 12 H 6.25/12.5 25/25 40 3.125/25 25/25 S CHNOSFCHNOSFCHNOS F CHNOS FFCHNOS FFCHNOS FFFF FCHNOSClFCHNOS FClCHNOSClClCHNOS NO2 CHNO 13 H 1.5/1.5 ≥100 41 25/25 125 14 H 200 6.25/12.5 42 3.125/6.25 25/6.25 15 H 100/100 12.5/6.25 43 1.625/12.5 12.5/6.25 16 H 12.5/100 >100 44 6.25/6.25 6.25/25 17 H 100/>200 250/>250 45 200/200 125-250 18 H 100/>200 >100 46 200/200 100 19 H 200/>200 100 47 200/200 125 20 H 100/>200 250 48 100/200 50 21 H 200/200 250 49 200/>200 250 22 H 25/100 6.25/12.5 50 50/100 6.25/6.25 23 H 100/100 >100 51 NE >100 24 H 100/>200 >250 52 200/>200 >100 SF3CCHNOSCF3 CHNOS CF3 CHNOSCF3CF3CHNOSH3COCHNOSOCH3 CHNOS OCH3CHNOSOCH3H3COCHNOS OCH3OCH3CHNOSS CHNOSHS CHNOSCHNONon-transpeptidase binding arylthioether beta-lactams active against Mycobacterium tuberculosis and Moraxella catarrhalis. Konaklieva, M. et.al., Bioorg. And Med. Chem. 2015, 23, 632-647Synthesis of non-transpeptidase -Lactams
NHSOFFNSOFFCHNHCOH3CO C NHCH3CO C NHCCH3NSOFFCHNHCOH3C+NSOFFCHNHCOCH3NSOFFCHNHCOCH3+Et3N22 2324 255Synthesis of chiral -Lactams
Purification of chiral -Lactams
One of the pure diastereoisomers with determined, by X-ray analysis, absolute configuration: C2S, C16S
S. No. Compound name7H9 (ug/ml)GAST Fe (ug/ml)Day 14 Day 181 RK1 >100 0.19-0.392 RK2 100 <0.193 RK5 25 <0.194 RK6 12.5 <0.195 KL04 50-100 0.396 KL08 25 0.39-0.787 JF3 100 0.788 CM01 25 0.789 CM02 25 0.7810 DL37 25-50 0.7811 DL06 100 1.512 DL46 50 0.7813 DL47 25 NG14 RK-FITC 100 NG15B-lactam ring-SO-phenyl-mCF3*25 NG16 INH 0.07 NGNotes:1. Highest concentration tested was 100ug/ml for all test compounds except INH which was 10ug/ml.2. At Day14 growth in GAST-Fe was still too low (due to higher dilution of cells than usual: 1:500 as opposed to 1:250) to effectively discern MIC hence day 18 values are reported.Minimal inhibitory concentrations in different media
A BC D EIntracellular killing of Mtb
Structure Moraxella Clinical strains MIC/MBC ug Moraxella Clinical strains MIC/MBC μM Mtb H37Rv Without/ With clavulanic acid μg/mL Mtb H37Rv Without/ With clavulanic acid μM NHOS >200 >1000 139 >250 NOSOHN 12.5/12.5 40/40 6.25/6.25 20.03/20.03 NHOS NO2 1.25-3.125/12.5 7.24-13.93/55.74 25/25 >100/>100 NOSONHCH2NO2 3.125/100 8.74/69.95 25-50/25 70/70 NOSONHCH2F 25/50 75.67/150 6.25/6.25 18.93/18.93 NOSOHNF 25/50 75.6/150 3.125/3.125 9.47/9.47 NOSONHCH2FF 12.5/25 35.88/70 6.25/6.25 17.96/17.96
AcknowledgementsCollaborationsClifton Barry, III (TRS, NIH)Helena Boshoff (TRS, NIH)Kriti Arora (TRS, NIH)Balbina Plotkin, Ph.D. (MWU)SynthesisTim BeckDina LloydRostislav KuskovskyJeanette MinahJuliana FritzVictor SchultzSteven Moss Susan SchultzKlare LazorCarly MontaneroMoira EssonDepartment of ChemistryAmerican University
The Lawn in front of Beeghly building, Chemistry Department, AUSummer 2010
Synthesis and Characterization of Biologically Active Molecules
The Effects of Staphylococcus Aureus
A Closeup Shot of Staphylococcus Aureus
An Electron Micrograph of Staphylococcus Aureus
An Electron Micrograph of Staphylococcus AureusCell wallCytoplasm
NORRCONHNO SO3HRRCONHCO2HOHNORCONH SCO2HNOCO2HXOHNORCONHNOSCO2HROHSCO2HXCommon Classes of -Lactam AntibioticsNOOCO2HOH nocardicins monobactamspenicillins carbapenemscephalosporins penemsclavulanic acids
NORRCONHNO SO3HRRCONHCO2HOHNORCONH SCO2HNOCO2HXOHNORCONHNOSCO2HROHSCO2HXCommon Classes of -Lactam AntibioticsNOOCO2HOH nocardicins monobactamspenicillins carbapenemscephalosporins penemsclavulanic acids
NORRCONHNO SO3HRRCONHCO2HOHNORCONH SCO2HNOCO2HXOHNORCONHNOSCO2HROHSCO2HXCommon Classes of -Lactam AntibioticsNOOCO2HOH nocardicins monobactamspenicillins carbapenemscephalosporins penemsclavulanic acids
N-Thiolated -LactamsNSO R
N-Thiolated -LactamsNSO Rorganothio groupon the nitrogen
N-Thiolated -LactamsNSO3HO monobactams (active)R'CONH RNS-CH2CO2HO thiamazins (inactive)R'CONH R
N-Thiolated -LactamsNSO3HO monobactams (active)Nature 1981, 289, 590Nature 1981, 291, 489R'CONH RNS-CH2CO2HO thiamazins (inactive)S.R. Woulfe and M.J. Miller Tetrahedron Letters 1984, 25, 3293R'CONH R
N-Thiolated -LactamsNSO3HOmonobactams (active)R'CONH RNS-CH2CO2HOthiamazins (inactive)R'CONH RNS-CH3ON-thiomethylated lactams (active)MeO R
Literature on N-Thiomethyl -LactamsNHOLDA, HMPACH3OOCH3TBSONSCH3OCH3OOCH3TBSOCH3SO2SCH3
Literature on N-Thiomethyl -LactamsNHOShah and Cama Heterocycles 1987, 25, 221LDA, HMPADeveloped as a nitrogen protecting group, stable to acid and base, but which can be easily removed with thiolateCH3OOCH3TBSONSCH3OCH3OOCH3TBSOCH3SO2SCH3
Synthesis of N-Thiomethylated -LactamsNOCH3OPhOCH3NOCH3OPhOCH3Cl+ Et3NCH2Cl2
Synthesis of N-Thiomethylated -LactamsNOCH3OPhNOCH3OPhOCH3NOCH3OPhOCH3Cl+ Et3NCH2Cl2ceric ammonium nitrateaqueous CH3CNH
Synthesis of N-Thiomethylated -LactamsN SOCH3OCH3PhNOCH3OPhNOCH3OPhOCH3NOCH3OPhOCH3Cl+ Et3NCH2Cl2ceric ammonium nitrateaqueous CH3CN1) BuLi2) CH3SO2SCH3H
N-Thiolated -LactamsNSORCH3R'Why are they biologically-active?
Modifying the Lactam NitrogenNO SMeMeOPh (active)
Modifying the Lactam Nitrogen Loss of Antimicrobial Activity!NO HMeOPhNO SMeMeOPh (inactive) (active)
Modifying the Lactam Nitrogen Loss of Antimicrobial Activity!NO HMeOPhNO ClMeOPhNO SMeMeOPh (inactive) (inactive) (active)
Modifying the Lactam Nitrogen Loss of Antimicrobial Activity!NO HMeOPhNO ClMeOPhNO Se-PhMeOPhNO SMeMeOPh (inactive) (inactive) (inactive) (active)
Modifying the Lactam Nitrogen Loss of Antimicrobial Activity!NO SMeOPhO ONO S-CH2PhMeOPhMeNO HMeOPhNO ClMeOPhNO Se-PhMeOPhNO SMeMeOPh (inactive) (inactive) (inactive) (inactive) (active) (weakly active)
Modifying the Lactam Nitrogen Loss of Antimicrobial Activity!NO SMeOPhO ONO S-CH2PhMeOPhNO S-PhMeOPhMeNO HMeOPhNO ClMeOPhNO Se-PhMeOPhNO SMeMeOPh (inactive) (inactive) (inactive) (inactive) (inactive) (active) (weakly active)
Modifying the Lactam Nitrogen Loss of Antimicrobial Activity!NO SMeOPhO ONO S-CH2PhMeOPhNO S-PhMeOPhNO SMeOPhNOSOMePhMeNO HMeOPhNO ClMeOPhNO Se-PhMeOPhNO SMeMeOPh (inactive) (inactive) (inactive) (inactive) (inactive) (inactive) (active) (weakly active)
Modifying the Lactam Nitrogen Loss of Antimicrobial Activity!NO SMeOPhO ONO S-CH2PhMeOPhNO S-PhMeOPhNO SMeOPhNOSOMePhMeNO HMeOPhNO ClMeOPhNO Se-PhMeOPhNO SMeMeOPh (inactive) (inactive) (inactive) (inactive) (inactive) (inactive) (active) (weakly active)
Effect of the C3 and C4 Ring SubstituentsNO SMeOPh (active)Me3 4NO SMe
Effect of the C3 and C4 Ring SubstituentsNO SNPhMeOONO SMeOPh (active) (inactive)Me3 4NO SMe
Effect of the C3 and C4 Ring SubstituentsNO SNPhMeOONO SPhCH2SPhMe NO S MeNO SMeOPh (active) (inactive) (inactive) (inactive)Me3 4NO SMe
Effect of the C3 and C4 Ring SubstituentsNO SNPhMeOONO SPhCH2SPhMe NO S Me NO S MeOAcNO SMeOPh (active) (inactive) (inactive) (inactive)Me3 4NO SMe
Effect of the C3 and C4 Ring SubstituentsNO SNPhMeOONO SPhCH2SPhMe NO SMe NO SMeOAcNO SMeOPh (active) (inactive) (inactive) (inactive)Me3 4NO SMe (broad-spectrum activity)
Effect of the C4 Ring SubstituentNO SMeMeOPh (active)
Effect of the C4 Ring SubstituentNO SMeMeOPh (active)NO SMeMeO (inactive)AcOPh
Effect of the C4 Ring SubstituentNO SMeMeOMeNO SMeMeOPh (active)NO SMeMeO (inactive)AcOPh (active)
Effect of the C4 Ring SubstituentNO SMeMeOMeNO SMeMeOPh (active)NO SMeMeONO SMeMeO (inactive)AcOPh (active) (inactive)
Effect of the C4 Ring SubstituentNO SMeMeOMeNO SMeMeOClNO SMeMeOPh (active)NO SMeMeONO SMeMeO (inactive)AcOPh (active) (inactive)
Effect of the C4 Ring SubstituentNO SMeMeOMeNO SMeMeOClNO SMeMeONO SMeMeOPh (active)ClNO SMeMeONO SMeMeO (inactive)AcOPh (active) (inactive)
Effect of the C4 Ring SubstituentNO SMeMeOMeNO SMeMeOClNO SMeMeONO SMeMeOPh (active)NO SMeMeOClClNO SMeMeONO SMeMeO (inactive)AcOPh (active) (inactive)
Effect of the C4 Ring SubstituentNO SMeMeOMeNO SMeMeOClNO SMeMeONO SMeMeOPh (active)NO SMeMeOClClNO SMeMeONO SMeMeO (inactive)AcOPh (active) (inactive) (active) (active) (active)
Effect of the C4 Ring SubstituentNO SMeMeOMeNO SMeMeOClNO SMeMeONO SMeMeOPh (active)NO SMeMeONO SMeMeOClClNO2NO SMeMeONO SMeMeO (inactive)AcOPh (active) (inactive) (active) (active) (active) (active)
Effect of the C4 Ring SubstituentNO SMeMeO SOONO SMeMeOMeNO SMeMeOClNO SMeMeONO SMeMeOPhNO SMeMeONO2 (active)NO SMeMeONO SMeMeONO SMeMeO NClClNO2NO SMeMeONO SMeMeO (inactive)AcOPhNO SMeMeO S (active) (inactive) (active) (active) (active) (active) (active) (active) (inactive) (inactive)Turos, Edward; Long, Timothy E.; Konaklieva, Monika I.; Coates, Cristina; Shim, Jeung-Yeop; Dickey, Sonja; Lim, Daniel V.; Cannons, Andrew. N-Thiolated -Lactams: novel antibacterial agents for methicillin-Resistant Staphylococcus aureus. Bioorganic & Medicinal Chemistry Letters (2002), 12(16), 2229-2231
Three Potential Modes of Nucleophilic AttackNO S MeMeO RNu-
Three Potential Modes of Nucleophilic AttackNO S MeNSMeO RMeNuOat carbonyl -MeO RNu-
Three Potential Modes of Nucleophilic AttackNO S MeNSMeO RMeNuONOMeO RNO SMeO Rat carbonyl+ Nu-SMeat sulfurat methyl---MeO RNu-+ Nu-Me
Results and ConclusionsA structurally new class of -lactam antibacterials has been found
Results and ConclusionsA structurally new class of -lactam antibacterials has been foundThe S-Me group on the lactam nitrogen is essential for activity
Results and ConclusionsA structurally new class of -lactam antibacterials has been foundThe S-Me group on the lactam nitrogen is essential for activityThe R3 and R4 ring substituents alter the activity (broad-spectrum versus narrow-spectrum) and strain specificity
Results and ConclusionsA structurally new class of -lactam antibacterials has been foundThe S-Me group on the lactam nitrogen is essential for activityThe R3 and R4 ring substituents alter the activity (broad-spectrum versus narrow-spectrum) and strain specificity The -lactams are selective for Staphylococcus, including MRSA, and human cancer cell lines (leukemia, breast, neck)
Results and ConclusionsA structurally new class of -lactam antibacterials has been foundThe S-Me group on the lactam nitrogen is essential for activityThe R3 and R4 ring substituents alter the activity (broad-spectrum versus narrow-spectrum) and strain specificity The -lactams are selective for Staphylococcus, including MRSA, and human cancer cell lines (leukemia, breast, neck)The lactams show no appreciable toxicity in normal human cell lines
Results and ConclusionsA structurally new class of -lactam antibacterials has been foundThe S-Me group on the lactam nitrogen is essential for activityThe R3 and R4 ring substituents alter the activity (broad-spectrum versus narrow-spectrum) and strain specificity The -lactams are selective for Staphylococcus, including MRSA, and human cancer cell lines (leukemia, breast, neck)The lactams show no appreciable toxicity in normal human cell linesThe chemical and biological mechanisms of action appear to differ from that of all previously known classes of antibiotics
220th ACS National Meeting, Washington DC, August 20- 24, 2000
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