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Azetidin = -lactamin
S N O
O N
O
CARBAPENEM: imipenem
N O
S N
MONOBACTAM:
NH O
Drugs that inhibit the cross-linking of the peptidoglycan chains The final step in the formation of the cell wall is the completion of the cross-links. This converts the water-soluble and therefore mobile peptidoglycans into the insoluble stationary cell wall. Investigations using Staphylcoccus aureus indicated that the cross-linking is brought about by a multistep displacement of the terminal alanine of the peptide attached to one peptidoglycan chain and its replacement by the terminal glycine of the peptide attached to a second peptidoglycan chain (Fig. 7.26). This reaction is catalysed by transpeptidases.
C CHE E KHANG
Vi khuan e khang lactamin theo cac c che sau: e khang enzym: VK sn xut -lactamase e khang khong enzym: - thay oi tnh tham thau cua mang te bao - bien mat hoac bien oi cac PBP - Efflux pumps Vd: multidrug resistance (MDR) pumps
- Sx penicillinases
- Thay i PBP: PBP 2a tm thy trong MRSA (Methicillinresistant Staphylococcus aureus)
(A) Stereo view of the active site of PBP 2a of S. aureus depicted as a solvent-accessible surface (green). The side chains of the active-site serine and lysine are shown as capped sticks and colored by atom types (carbon in gray, oxygen in red, and nitrogen in blue). The backbone of the loop that caps the active site is shown as an orange wire. (B) Stereo view of the active site from the same perspective shown in panel A, except the loop is now shown as a solvent-accessible surface for both the backbone and the side chain functionalities. The presence of the loop blocks the active-site access for molecules the size of typical lactam antibiotics.
The development of new lactam antibiotics that inhibit PBP 2a is significant progress and offers a glimmer of hope for the future treatment of MRSA infections, including those caused by vancomycin-resistant and -intermediate strains.
R1
H O 5 3 COOH H 2 4
NH O 7 O
H 6 N
H S
5 4 3 R2
1
COOH
Penicillin
R NH O N O
monobactam
cephalosporin
R1 R2 SO3H
NHOM PENICILLIN
R HN O H H S
H2N
H S
6 7
O N
6
3
5
O
5
N
3
COOH H 2
COOH H 2
Penicillin
Danh phap IUPAC
6-aminopenicillinic acid
Amid- 6 cua acid (2S, 5R, 6R-amino-6-dimethyl-3,3-oxo-7-thia-4-aza1-bicyclo [3.2.0]-heptan carboxylic). Danh phap thong dung Penicillin nh la nhng amid cua acid 6-amino penicillanic (6- APA).
IEU CHE
H H CH2 CO HN N O H S CH3 CH3 COO R'
H2 O O C C NH H H N O H
S COO
60mg/L
20 g/L
IEU CHE
Ban tong hp
R HN O H H S
4
A- condition
H2 N
H S
6 7
O N
5 3
COOH H 2
6 7
O N
5 3
COOH H 2
B-condition
Penicillin
A-condition = Aclylase B-condition = 1. Me2SiCl2
2. n-Bu-OH, -40oC 3. H2O, 0oC
R1 H2N H H S
6-aminopenicillinic acid
4
R'COCl, Et3N
O
HN
H S
6 7
O N
5 3
1
6 7
O N
5 3
COOH H 2
COOH H 2
6-aminopenicillinic acid
Penicillin
S CH3
HO (I) +
O Cl NH2
.HCl N,N-dimethylanilin HO O
O N HN NH 2
S CH3
O (II) H2 O, pH 1,3-1,5 HO O HN NH 2 N
Amoxcicillin
R HN O H H S
6 7
N
5 3
COOH H 2
Cac penicillin di dang muoi hoac dang acid la nhng bot trang khong mui khi tinh khiet. Pho UV
Benzylpenicillin K (BP 2007) Absorbance (2.2.25)
Penicillin
Dissolve 94.0 mg in water R and dilute to 50.0 ml with the same solvent. Measure the absorbance of the solution at 325 nm, 280 nm and at the maximum at 264 nm, diluting the solution, if necessary, for the measurement at 264 nm. The absorbances at 325 nm and 280 nm do not exceed 0.10 and that at the maximum at 264 nm is 0.80 to 0.88, calculated on the basis of the undiluted (1.88 g/l) solution. Verify the resolution of the apparatus (2.2.25); the ratio of the absorbances is at least 1.7.
Specific optical rotation (2.2.7) Dissolve 0.500 g in carbon dioxide-free water R and dilute to 25.0 ml with the same solvent. The specific optical rotation is + 270 to + 300, calculated with reference to the dried substance.
R HN O H H S
6 7
O N
5 3
COOH H 2
Tnh acid
Tao muoi natri va kali (bn) Tan trong nc, pha tiem
Penicillin
R HN O H H S
6 7
O N
5 3
COOH H 2
Penicillin
Procain benzylpenicillin
Benzathin benzylpenicillin
R HN O H H S
6 7
O N
5 3
COOH H 2
Penicillin
Tao thanh nhng este, tien chat cua PNC co kha nang phong thch tr lai cac khang sinh nay in vivo.
O R= H2 N H H N O O N S O O CH3 CH3 COOR Me R= O O O Me Bacampicillin R= O Talampicillin CMe3 Pivampicillin
Esterase
Penicillin
O H
O O
OMe 3
Penicillin
O H
Penicillin
O
OH
CH 2O
R R
Tnh khong ben cua vong beta lactam (OH- hay penicillinase)
R penicillin OH O H H H N S O N CO2 H O H H S R HO C HN O COOH acid penicilloic
S N OH COOH
H ROCHN O +
HS H2 N
-Phn ng d ng
penilloaldehyd
D-penicillamin
- nh lng
C O
NH
O D
Tac nhan ai nhan alcol R'OH amin R'-NH-R'' hydroxylamin NH2OH R'O R'-N-R'' NH-OH
H R C N O O N
CH 3 CH 3
H R C N NH 2OH O O HN NH OH
CH 3 CH 3
COOH Cu2+
COOH
H R C N O O
CH 3
HN CH 3 NH CO O Cu O
(xanh ngoc)
S m vng -lactam c xc tc bi cc ion kim lai (Phc to thnh vi ion kim lai hat ha s tn cng i nhn)
2+
O N S
O Ac HN
O CH 3 CH 3 Ac
2+
O N
O HN
O X S
H H
H H
Tnh khong ben cua vong beta lactam (acid mnh, nng hoc HgCl2)
R O O H H NH H N CH2 O2 H R S O O H NH H HN CO2H S
R R O HO H H H N HN O CO2H O O O S R N
NH
HS N
CO2H
HS HN CO2H
acid penicilloic
H ROCHN O +
HS H 2N
COOH
penilloaldehyd
D-penicillamin
H2 O O C C NH H H N O H
S COO
Peni G
Peni V
H H C NH2 O H CO NH N COO Na H S
H H HO C NH2 O CO NH N H COO Na H S
Amoxicillin
Ampicillin
Kiem nghiem
H CH2 CO HN
Kiem nghiem
Kiem tinh khiet - hp thu UV - pH
H H HO C NH2 O CO NH N H COO Na H S
Amoxicillin
Ampicillin
Kiem nghiem
nh lng
Penicilin
phan huy
2. PHNG PHAP HPLC 3. PHNG PHAP VI SINH VAT (Xac nh hoat lc cua khang sinh)
PENICILLIN NHOM I
Penicillin thien nhien
H H CH2 CO HN N O H S CH3 CH3 COO R'
H2 O O C C NH H H N O H
S COO
Peni G
Peni V
Penicillin G (benzyl penicillin) Dang tac dung nhanh: Na/K benzyl penicillin Dang tac dung cham: procain PNC, benethamin PNC, benzathin PNC Penicillin V (phenoxy methyl penicillin)
PENICILLIN NHOM I
Ben trong moi trng acid, hap thu tot hn, hoat chat trong huyet thanh cao hn, T1/2 dai hn.
H CH CO N Z X O
H H S N H CH 3 CH2 COO
H O CH CO N Z O
H H S N H CH 3 CH2 COO
PENICILLIN NHOM I
Pho khang khuan Pho khang khuan hep, chu yeu tren gram (+):
Cau khuan gram (+): tu cau khong tiet
Xoan khuan: xoan khuan giang mai, leptospira Trc khuan gram (+): trc khuan gay benh bach
PENICILLIN NHOM II
CH3
C C
CO CH3
HN
Ph KK ca mt penicillin ph thuc vo: - Cu trc - Kh nng xuyn mng VK gram m -Tnh nhy cm vi betalactamse - i lc vi enzym mc tiu transpeptidase - Tc b bm ra ngai VK gram m M mm (trial and error) tm kim penicillin ph rng Mt lng ln cht tng ng c tng hp vi nhng thay i nhnh bn, vi nhng nhn xt SAR nh sau: - Nhm hydrophobic (peni G) tt trn gram + nhng khng tt trn gram _ - S gia tng trn gram m tm thy tt nht vi nhng nhm hydrophylic carbon alpha (iu ny c cho l tr gip nhng penicillin ny bng qua porin outer cell membrane ca VK gram m)
H CH2 CO HN N O H H S CH3 CH3 COO R'
H CH2 CO HN
The tren C cua chc carboxamid (PNC- G): amin, hydroxyl, carboxylic, sulfonilic M rong hoat pho sang vi khuan gram am
(yeu hn peni G tren gramdng, nhng co tac ong tren gram am)
Nhom III: gom co 2 phan nhom IIIA va III B: III-A: khong co nhom the tren amin (NH2): Ampicillin, Amoxicillin III-B: co nhom the tren amin (NH2): Azlocillin, Mezlocillin, Piperacillin
(2S,5R,6R)-6-[[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-3,3dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid,
Mot so vi khuan gay nhiem trung mac phai tai benh vien khong nhay cam vi nhom khang sinh nay: Enterobacter, Serratia, Proteus indol dng, Providencia, Bacillus pyocyanic.
Tac ong tren cac mam e khang vi ampicillin nh: Klebsiella, Enterobacter, Serratia, Pseudomonas Piperacilin phoi hp vi aminosid hoac vi chat c che betalactamase
H O C C HN SO3H O
H H S N COO Na
Sulbenicillin
Na
Carbenicillin
Carindacillin
Z=phenyl : Carfecillin
Na S
Ticarcillin
- Hoat tnh tren trc khuan mu xanh - ong van vi aminosid - Ticarcillin hoat tnh 2 lan manh hn carbenicillin.
Pho KK hep, tap trung chu yeu tren VK gram am. Rat nhay cam: Escherichia coli. Nhay cam: Yersinia, Salmonella, Shigella,
N CH NH azepan-1-ylmethanimine
Enterobacter, Citrobacter,
Klebsiella (khong san xuat hoac san xuat yeu penicillinase). Khong e khang cheo vi ampicillin
Pho khang khuan cua phoi hp B. clavuclanic amoxicillin Cai thien tren nhng mam nhay cam san xuat beta lactamase nh Neiserria gonorhoeae, Haemophilus, E. coli, Salmonella. A. clavuclanic ticarcillin Phoi hp nay gia tang tac ong tren Staphylococcus (95% Streptococcus nhay cam vi phoi hp acid clavuclanic ticarcillin so vi 49% neu ch s dung mot mnh ticarcillin).
Sulbactam
(2S,5R)-3,3-Dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide
H H O S OCH H 3 N CH 3 O H COOH
Sultamicillin
NH 2 H N N O O Sultamicillin S CH3 CH 3 O H3 C H 3C O O O S O N O
- c dung trong tai-mui-hong, ho hap, sinh duc, da tren nhng mam nhay cam
Tazobactam
H H O N N S OCH H 2 N N CH 3 O H COOH
Dan chat cua sulbactam ma mot nhom methyl mang nhom the triazolyl
Chat c che betalactamase khong thuan nghch pho rong S dung di dang phoi hp tazobactam - piperacillin
CARBAPENEM
HO H3 C N O Carbapenem N O S COOH NH2
Thienamycin (1977)
Thienamycin :
- trch t moi trng nuoi cay Streptomyces cattleya. - hoat tnh khang khuan rong - hoat tnh tren Pseudomonas - khang lai -lactamase
NH2
NH CH NH
H OH H Me N O S CO2
Double bond leading to high ring strain and increase in lactam reactivity
IMIPENEM
HO H3C N O S COOH HO H3C benzyl formimidat N O S COOH Imipenem NH NH
NH 2
Thienamycin (1977)
IMIPENEM
HO H 3C N O
Pho khang khuan
NH NH S COOH
Ben vng vi men beta lactamase, pho khang khuan rat rong, bao gom:
-Cau khuan gram dng: Staphylococcus nhay meticillin (Staphylococcus khang meticillin e khang vi imipenem), Strepococcus (ke ca nhom D), Pneumococcus, Enterococcus.
-Cau khuan gram am: Neisseria
IMIPENEM
HO H 3C N O
- IV cham.
NH NH S COOH
khi s dung thng
ket hp imipenem vi cilastin (chat c che enzym dehydropeptidase) e gii han s chuyen hoa nay.
cilastin
CH3
O
1 R N R2
HO S CO 2H Imipenem
NH HN N
ME1036. ME1036 (CP5609; developed by Meiji Seika, licensed by Forest) is a broad-spectrum carbapenem that binds with a high affinity to PBP 2a of MRSA (IC50 0.13 to 0.73 g/ml) and that exhibits potent in vitro inhibitory activity against MRSA . A series of 4-methyl carbapenems having structural similarity to ME1036 showed potent activities against MRSA and PRSP, as well as against the gram-negative organism ampicillin-resistant, -lactamase-negative Haemophilus influenzae
HO S CO 2H Imipenem
NH HN N
PZ-601 (Razupenem). PZ-601 (formerly known as SMP601; licensed from Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan) is a new carbapenem currently being developed by Protez Pharmaceuticals (now Novartis) that has demonstrated a high degree of potency against MRSA.