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Lectures 2, 3 Medicinal Chemistry 1 PC 509 Prof. Dr/ Ghaneya Sayed Hassan [email protected] 1 Antibiotics • Definition of antibiotics: Chemical compounds produced by a living m.o. and capable of inhibiting life process of other m.o. • If kill m.o. Bactericidal, if just inhibit its growth Bacteriostatic. • There are compounds with anti-bacterial activity but not antibiotic [as sulfonamides] because they are fully synthetic compounds named anti-bacterial drugs. Classification of antibiotics: (1) According to M.O.A: inhibit cell wall, act on protein synthesis… (2) According to spectrum of activity: Broad spectrum, narrow spectrum. (3) Chemical classification: -lactams & non--lactam 2antibiotics. Antibiotics Definition: Microbial metabolites, semi-synthetics or synthetic analogues which inhibit [in small doses] growth & survival of m.o. without serious toxicity on the host. Classified into: B-lactam Antibiotics Penicillins. Cephalosporins. Novel -lactam antibiotics. 3 Non B-lactam Antibiotics Tetracyclines. Aminoglycosides. Macrolides. Miscellaneous [Chloramphenicol] -lactam antibiotics -lactam ring [4-membered cyclic amide]: is the main part of penicillin and cephalosporin structures. -lactam ring = Azetidinone NH O N -lactam ring 4 O N O -lactam ring 4 Fundamental structural requirements for classical -lactam antibiotics: (1) Highly strained fused -lactam structure. (2) Free carboxylic group. (3) One or more substituted amino side chain. (4) Optimal activity in -lactam requires a side chain with a hydrogen-bonding group & some structural features that chemical reactivity of -lactam ring. B-lactam ring O Classes of -lactam antibiotics: (1) Penicillin. (2) Cephalosporin. (3) Novel -lactam antibiotics. 5 R C HN O 6 5 N 7 4 1 CH3 S 2 CH3 3 COOH M.O.A. of -lactam antibiotics: [Inhibitors of cell wall synthesis] NAG NAM L-Ala L-Ala D-Glu D-Glu L-Lys Gly Gly Gly Gly L-Lys Gly D-Ala D-Ala D-Ala D-Ala NAG L-Ala D-Glu D-Glu D-Ala Gly Gly Gly Gly Gly Gly Gly L-Lys Gly Gly carboxy peptidase B-lactams Sugar Backbone NAG NAM L-Ala L-Lys Gly Sugar Backbone Transpeptidase D-Ala NAM NAG NAM Gly Gly Gly Gly Gly D-Ala Cross - Linking 6 https://www.youtube.com/watch?v=qBdYnRhdWcQ M.O.A. of -lactam antibiotics: [Inhibitors of cell wall synthesis] β-lactam antibiotics cause: (1) irreversible inhibition of transpeptidase enzyme by acylation of OH of serine amino acid residue on it no cross-linkage rigidity leakage of important components and entrance of water swelling and rupture of cell [Bactericidal effect] in the growth phase. (2) -lactams also inhibit D-alanine carboxypeptidase [responsible for cleavage of D-ala.] 7 The β-lactam is able, because of a structural resemblance to the Dalanyl-D-alanine segment, to compete with the catalytic process and form a transient pencilloyl-enzyme complex 8 [I] Penicillins Structure: Highly unstable Bicylic system: β-lactam ring [Azetidinone] + Thiazolidine ring B-lactam ring O R C HN O 6 5 N 7 4 Their structure biosynthesized by m.o. from the two amino acids: cysteine & valine forming 6Amino Penicillanic Acid [6-APA]. 3 S CH3 CH3 N O Thiazolidine ring COOH H2N Cysteine 9 1 CH3 S 2 CH3 COOH Valine R for Rectus ,Latin for right,)S (for Sinister, Latin for left) Stereochemistry: • With three chiral carbons: theoretical 8 isomers. • The only active is C3 [S] , C5 [R] & C6 [R]. O R O 4-thia-1-azabicyclo [3.2.0] heptanes. 6 N 7 1 O S 10 N O R S C HN C HN O CH3 CH3 N COOH Penicillanic acid derivatives: CH3 CH3 N O S COOH COOH O 2 * CH3 CH3 CH3 3 Penam derivatives: [without any substitutions] * N O R CH3 S * Nomenclature: 4 5 S C HN COOH Penicillin derivatives: Physicochemical properties: 1- White or yellowish-white crystalline powders [sometimes Pen.G = Crystalline Pen.] 2- Strongly dextrorotatory. 3- Relatively strong acidic [with pka around 2.65] due to COOH group. 4- If compound with basic side chain present as Zwitter ions. 5- Most penicillins used Na or K salts water soluble salts. 6- Fused -lactam ring highly reactive [due to strained amide bond] extremely susceptible to nucleophilic attack & electrophilic attacks. 7- They are inactivated by hydrolysis [especially in presence of heavy metal salts, acids & bases] 8- They are also hydrolyzed by enzymatic action acylase [amidase] & -lactamase. O R O N H O S N CH3 CH3 COOH - R alklaine medium [OH ] B-lactamase enzyme S N H O CH3 HN OH CH3 COOH Penicilloic acid 11 Penicillin analogues = Semisynthetic penicillins 6-APA is now produced by hydrolysing penicillin G or penicillin V with an enzyme (penicillin acylase) or by fermentation 12 Semi-synthetic Penicillins: • Natural penicillins isolated from cultures of Penicillium chrysogenum & Penicillium notatum fungi. • To overcome drawbacks of natural penicillins [Pen.G]: (1) Add precursors as phenoxy acetic acid to fermentation medium Penicillin V. (2) Isolation of 6-Amino Penicillanic Acid [6-APA] in Beecham Research Lab.[1957] preparation of no. of semi-synthetic compounds. This is done by reaction of 6-APA with: [1] Acid chloride [R-CO-Cl] / organic solvent / (Et)3N as proton acceptor. [2] Acid anhydride [(R-CO)2O]. [3] Carboxylic acid [R-COOH] + DCC [N,N-dicyclohexyl carbodiimide] at R.T. N 13 C N SAR: amide is essential Stereochemistry of bicyclic system relative to acylamino is important is essential S isn't essential O R C HN H H S N O CH3 CH3 COOH free COOH is essential strained B-lactam is essential Bicylic system is important --------> other cycle confers strain on B-lactam ring & so, increase its activity [ also increase its instability] Substituents above the plane of the steroid are described as beta and are shown as a solid line ( or ); those below the plane are described as alpha and are shown by a broken line ( or ---) 14 Penicillin G [Benzyl Penicillin] O H2C S C HN CH3 N O CH3 COOH Properties: • The PROTOTYPE [parent compound] [lead compound]. • Discovered by chance. • Active ≠ G+ve bacilli [Staph., gonorrhoea] & G-ve cocci. • Non-toxic [selective]. Serious limitations: (1) Short duration of action rapidly excreted from kidney [need injection /4 hrs] (2) Ineffective orally stomach acidity-sensitive & poorly absorbed from GIT. (3) Bacterial resistance by Penicillinase [-lactamase]. (4) Narrow spectrum of activity [active mainly ≠ G+ve with 15 activity ≠ G-ve]. [i] Acid resistant penicillins Penicillin G is acid-sensitive due to: (1) Small angle & torsional strains [highly strained -lactam ring relieve strain by opening in acidic medium] (2) Carbonyl group in -lactam ring is highly sensitive to Nu attack [not behave as normal tertiary amide which is resistant to Nu attack]. (3) Acyl group in the side chain attack -lactam ring. Ph H2C C .. HN O S N O CH3 CH3 COOH H + Ph H2C C N S O N O CH3 CH3 COOH unstable intermediate To overcome acid sensitivity: • The first two factors can't be treated since •-lactam is the essential moiety which •can't be replaced; the only factor •we can overcome is the third [acyl chain]. 16 Ph H2C C N S O HN O Inactive CH3 CH3 COOH This is done by tendency of acyl carbonyl group to act as a nucleophilie by attachment of e-withdrawing group to it. Penicillin V [Phenoxy methyl penicillin] O O H2C S C HN CH3 N O CH3 COOH Phenethicillin [Phenoxy ethyl penicillin] O O HC CH3 C HN O CH3 CH3 N Taken orally but less active than penicllin G 17 S COOH [ii] -lactamase-Resistant penicillins Action of -lactamase: [as action of alkaline medium] Ph CH2 C NH O S N O CH3 Ph CH2 B-lactamase CH3 C HN HO COOH S O O HN Penicilloic acid [inactive] CH3 CH3 COOH To overcome this problem: Modify structure of -lactam antibiotic: By placing a BULKY GROUP on the side chain shielding and steric hindrance. Methicillin: -lactamase resistant but acid sensitive [NOT taken orally] OMe O S C HN 18 OMe N O CH3 CH3 COOH 2,6-dimethoxy phenyl penicillin With 1/5 activity of Pen.G & inactive ≠ G-ve [Disadvantages] Oxacillin Cloxacillin 5-methy-3-phenyl isoxazol-4-yl penicillin O N Me O O O CH3 S C HN 3-(o-chloro phenyl)-5-methyl isoxazol-4-yl penicillin CH3 N COOH S C HN Cl N O Me O CH3 CH3 N COOH Flucloxacillin 3-(2-chloro-6-fluro phenyl)-5methyl isoxazol-4-yl penicillin F S C HN Cl N 19 O O Me O N CH3 CH3 COOH Isoxazole ring with two roles: 1.Bulky group -lactamase resistant. 2.e-withdrawing group acid stable. [iii] Narrow spectrum Penicillin G with poor activity ≠ G –ve due to: (1) Permeability barrier: G –ve bacteria with a coat on cell wall composed of fats, sugars & proteins. (2) level of transpeptidase produced. (3) Mutation of transpeptidase enzyme: producing form not antagonized by penicillin. (4) Presence & transfer of β-lactamase enzyme. We notice that: (1) Hydrophilic group on side chain: activity ≠ G-ve & with little change on activity ≠ G+ve bacteria. (2) G-ve activity if the hydrophilic group [NH2, OH, COOH] is attached to C to Carbonyl. 20 [i] Class I Broad spectrum penicillins: Taken orally [hydrophilic group is amino] Amoxicillin Ampicillin O O HC S C HN NH2 Phenyl glycine moeity CH3 N O CH3 HO HC NH2 S C HN CH3 N O CH3 COOH COOH Ampicillin: is the 2nd most used penicillin in medicinal practice. Amoxicillin: is analogue to ampicillin with phenolic group and better absorption. Proprieties: (1) Active against G+ve & G-ve bacteria, but sensitive to –lactamase. (2) Acid resistant due to amino group (can be used orally). (3) Non toxic. 21 Side effects of Ampicillin: Ampicillin is poorly absorbed from GIT disruption of gut flora diarrhea. This is due to bipolar nature [Zwitter ionic form] presence of free amino & free carboxylic group. This is alleviated by using Prodrugs in which one of its polar group is masked [this group removed by metabolism releasing free drug]. When we make esters of ampicillin to improve its oral bioavailability: It’s supposed to be cleaved by esterase enzyme to give free ampicillin. But pencillin nucleus is very bulky that prevent approach of esterase enzyme. So, we make Double ester in which carboxyl group is attached to C3-monoesters of gemdiols [has 2nd OH group esterified by simple carboxylic acid] That’s why we can’t make simple methyl ester as a prodrug for ampicillin. 22 O Pivampicillin S HC C HN NH2 O N CH3 CH3 O COO CH2 CH3 O C C CH3 CH3 Pivalic acid (2,2-Dimethylpropanoic acid) O O Talampicillin HC C HN NH2 Bacampicillin NH2 CH3 O N COO O O HC CH3 S S C HN CH3 N O CH3 COO O CH CH3 23 O C O C2H5 ► All of them are acyloxymethyl esters susceptible to non-specific esterase which act on 2nd ester group that is further away from penicillin nucleus. ► The products formed from hydrolysis are unstable & decomposed spontaneously to reveal free carboxylic acid & formaldehyde. O HC C HN NH2 H+ CH3 S CH3 N COO O O CH2 O C CH3 C CH3 Esterase O HC HN H3C 24 C S N CH3 CH3 CH3 N O COOH COO CH2 + CH3 Hetacillin Pen Pen H OH COOH Ampicillin CH2=O Prodrug for ampicllin by blocking other polar group [amino group]. It’s formed by condensation of ampicillin with acetone. Semi-synthesis of Ampicillin: O NH2 CH O COOH + Cl Phenyl glycine C O CH2 O C O CH2 O NH S O N C OH Pd / H2 NH 25 CH3 - CO2 S N O COOH CH2 Cl S C CH3 CH3 COOH O Et Ethyl chloro formate [activating group] CH3 O CH3 NH COOH C O CH2 CH 6-APA O C O O O COOH CH O CH CH3 O NH O O N CH O C Benzyl oxy carbonyl chloride [protecting group] H2N NH NH NH2 Ampicillin CH NH O S N O CH3 CH3 COOH Et [i] Class II Broad spectrum penicillins: Hydrophilic group is COOH. Carbenicillin O O HC C COOH Carfecillin N H O S CH3 CH3 N COOH Active ≠ wide range of G-ve > ampicillin. More penicillinase resistant. Active ≠ Pseudomonas aeruginosa. 26 HC C COO N H O S CH3 CH3 N COOH Prodrug for Carbenicillin with improved absorption [higher lipophilicity] We use aryl ester not alkyl ester aryl esters are more liable to hydrolysis due to e-withdrawing and inductive effect of aryl ring. [iv] To prolong duration of action [Latent penicillins] Done by: (1) Penicillin salts that are sparingly soluble in water. (2) Penicillin amides. (3) Penicillin esters. (4) Substitution in the amino side chain. We making suspension of M.Wt amino salts free penicillin is released as compound dissolve & dissociate. [used as I.M. injection] Penicillin G procaine [1:1] O Ph H2C S C HN CH3 CH3 N O COO- O H2N 27 C O CH2 CH2 NH CH2 CH3 CH2 CH3 Penicillin G benzathine 1:2 O Ph H2C S C HN N O H3C CH3 CH3 CH2 CH2 H3C COO- NH2 CH2 CH2 NH2 OOC Long Acting Penicillin Injection حقن بنسلين طويل المفعول Penicillin G Benzathine and Penicillin G Procaine. A potent formulation penicillin G that effectively kills susceptible disease-causing bacteria . 28 O S NH C N O CH2 Ph Novel -lactam Antibiotics (-lactamase inhibitors) -lactamase inhibitors used in combination with -lactamase sensitive penicillins for infections caused by -lactamase-producing bacterial strains (e.g. Clavulanic acid, Sulbactam and Thienamycin). Clavulanic acid 4 No 6-acyl amino side chain 6 7 O 5 OH O Z-configuraion 3 N 1 2 H COOH oxapenam [B-lactam+oxazolidine] ►1st natural -lactam without sulfur ► Isolated from Streptomyces clavuligerus in 1976. ► With weak anti-bacterial activity but Potent irreversible inhibitor of most -lactamases. 29 SAR: (1) -lactam ring. (2) Double bond with Z configuration. (3) No substitution at C6. (4) Positions 2 & 5 R stereochemistry. (5) Carboxylic group. M.O.A: (1) Irreversible inhibitor [Suicide substrate] for -lactamase. (2) The drug fits active site of -lactamase opening of -lactam ring by serine residue on the enzyme [as in penicillins]. (3) Acyl enzyme intermediate react further with another enzymic nucleophilic group [amino group] irreversible inhibition. (4) This mechanism is carried out in presence of proton donor/acceptor as histidine. 30 Amoxicillin and clavulanic acid (Augmentin®) Combination with Amoxicillin and Clavulanic acid 1- Decrease dose of amoxicillin 2- Increase spectrum of activity. Clavulanic acid has weak anti-bacterial activity but Potent irreversible inhibitor of most -lactamases. Sulbactam O O S CH3 CH3 N O COOH Semisynthetic ß-lactamase inhibitors e.g. sulbactam (penicillanic acid sulphone) (2S,5R)-3,3-Dimethyl-7-oxo-4-thia-1-bicyclo[3.2.0]heptane-2-carboxylic 31 acid –4,4-dioxide Synthesis of Sulbactam H H Br S H2N N CH3 CH3 O (1) NaNO2 (2) Br2 S Br N O O OH O H CH3 KMnO4 CH3 OH 6-APA Br Br HO O S CH3 N O O HO O S CH3 10% Pd / C CH3 N O O OH Tazobactam -1,2,3-Methyl-7-oxo-3-(1H-3-)(2S,3S,5R) triazol-1-ylmethyl)-4-thia-1-azabicyclo [3.2.0]heptane-2-carboxylic acid 4,4-dioxide 32 CH3 OH Sulbactam Sultamicillin Saltum®, Unasyn® Sultamicillin is an oral form of the antibiotic combination )codrug or mutual prodrug ( ampicillin/sulbactam . It contains esterified ampicillin and sulbactam Sultamicillin increased the absorption and decreased the chances of diarrhoea and dysentery . 33 Thienamycin [Anti-bacterial + -lactamase inhibitor] Opposite to penicillins carbapenam OH H H3C H H N O S CH2 CH2 NH2 endocyclin double bond COOH ► Isolated from Streptomyces cattleya. ► Potent with extra-ordinary broad range of activity ≠ G+ve & G-ve including Pseudomonas. ► With toxicity & -lactamase resistance. ► With poor metabolic & chemical stability. 34 Cephalosporins 35 First one discovered is Cephalosporin C [1948] from fungus obtained from sewer water on island of Sardinia [by chance as penicillin G] H2N Dihydrothiazine ring instead of thiazolidine ring in penicillins O CH (CH2)3 C HN HOOC S O N CH2 O high polar side chain 4. 5. 36 C CH3 COOH Advantages [over Penicillin G] 1. 2. 3. O Non-toxic ↓ risk of allergy. More stable in acidic medium [less ring strain] Higher penicillinase resistance. Good activity ≠ G-ve & G+ve. Disadvantages 1. 2. 3. Difficult to isolate & purify [with highly polar side chain] Lower potency [less strained ring] ↓ absorbed orally. Nomenclature: IUPAC name: 5-Thia-1-azabicyclo[4.2.0] octane Cepham: 1 7 6 8 N 5 O 1 S 7 2 8 3 Cepham 37 3 4 7-Amino Cephalosporanic acid [7-ACA] S O O O COOH Use Cephem & refer to substitution at C3,4,7 H2N S O 2 Cephem Cephalosporanic acid: N S N 5 O 4 6 C N CH3 O O C CH3 COOH Use cephalosporanic acid & refer to substitution at C7 Synthesis of 7-ACA: 7-ACA prepared from cephalosporin C by chemical hydrolysis. This is not an easy task. After all, a secondary amide has to be hydrolyzed in the presence of a highly reactive B-lactam ring. Normal hydrolytic procedures are not suitable and so a special method had to be worked out O R'-O Cl HN N S R N OAc O COO PCl5 Me H 2O N COO Me imino chloride OAc R Cl O COOH 7-ACA 38 Si Me Me R'-OH Acylation S R N OAc O COO Me imino ether O S N OAc O Protected Cephalosporin C H2 N R Me Si N S range of cephalosporins Si Me Me Me Classes of Cephalosporins 1) Based on route of administration: I- Oral cephalosporins. II- Parentral cephalosporins. 3-Acetoxy methyl side chain: By metabolism → alcoholic group → Lactone formation [loss activity + poor absorption]. O O HN R S HN O N CH2 O O C CH3 S R esterase N COOH COOH O [active] spontaneous lactonization [acidic] HN R S N O O 39 CH2 O [inactive] O OH 2) Based on Generation system: [I] 1st Generation Cephalosporins - Introduced in clinical use in 1960 - 1970. - With narrow spectrum of activity. - ß-lactamase resistant [but not to G-ve bacteria]. - With short half life & poor ability to penetrate cerebrospinal fluid. O H2C Cephalothin C HN S S O N CH2 O O C CH3 COOH Cephalexin [Ceporex®] Cefadroxil [Duricef®] Cephradine [Velocef®] O HC C HN HO NH2 N CH3 O COOH O O S HC C HN NH2 S N CH3 O COOH 40 Good for absorption Usually bad for activity HC C HN NH2 S N CH3 O COOH [II] 2nd Generation Cephalosporins • Introduced since 1970 till the present. • Spectrum as 1st generation, but more active ≠ G-ve. • More resistant to ß-lactamase. • Half lives similar to 1st generation, but penetrate better into cerebrospinal fluid. O HC Cefuroxime C HN NH2 (parentral agent) N COOH Cefaclor O S HN O N O NH2 O HO 41 Cl O OCH3 N S O O oral agent Cefonicid Cephamandole O O HC C HN OH HC S N N CH2 S O COOH N N N CH3 C HN OH S N N CH2 S O COOH N N N CH2 SO3H OH on -carbon succeed in SO3H lipophilicity NO CSF cephalosporins NOT in penetration. penicillins 42 [III] 3rd Generation Cephalosorins • Introduced in 1980s, most of them are semi-synthetic derivatives of cephalosporin C. • With good stability ≠ ß-lactamase & with broader spectrum. • Some of them active ≠ Pseudomonas. • Taken I.M. or I.V. • very expensive. • Subdivided according to structure of side chain into: 1- Cephalosporins with amino thiazolyl oximino moiety. 2- Cephalosporins with different acyl residues. 43 1) Cephalosporins with amino thiazolyl oximino moiety Cefotaxime [Cefotax®] Cefmenoxime OMe OMe H2N N N O C C HN H2N S S N N N O C C HN S S S N O COOH N H3C O N CH2 O N O C CH3 COOH N Oxime ether group → increase B-lactamase resistance. Paranetrally [W?] 2) Cephalosporins with different acyl residues N Opened chain C Cefivitril O C HN S S N N CH2 O 44 COOH S N H3C N N OCH3 N Cefotaxime C S C HN N Claforan® H2N O O H S N HO O O CH3 O • Cefotaxime was the first third-generation cephalosporin to be introduced. • It possesses excellent broad-spectrum activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria. • Many β–lactamase-producing bacterial strains are sensitive to cefotaxime. 45 The fourth-generation cephalosporins • The fourth-generation cephalosporins show some slight further advantages. • They have similar antibacterial activity with the third generation , but more stable to -lactamase. • There is a quaternary ammonium group at position 3 • Fourth-generation cephalosporins are zwitterions that can penetrate the outer membrane of gram-negative bacteria. • They also have a greater resistance to beta-lactamases than the third46 generation cephalosporins 2007 Cefpirome Cefepime The fifth-generation cephalosporins Fifth-generation cephalosporins are effective against MRSA (methicillin-resistant Staphyloccus aureus) and enterococci. Ceftolozane Ceftolozane is a new option for treatment of Complicated Intra-abdominal Infections (cIAI), and Complicated Urinary Tract Infections (cUTI( Zerbaxa®(ceftolozane/tazobactam( 47 February 01, 2015 [IV] Cephamycins (= 7-methoxy cephalosporins) ► Parent is Cephamycin C → isolated from Streptomyces clavuligerus [the 1st ß-lactam isolated from bacterial source]. ► By modification of side chain → Cefoxitin [Broader spectrum than most cephalosporins due to high resistance ≠ ß-lactamase]. ► ↑ ß-lactamase resistance is due to steric hinderance of extra methoxy group. ► Cephamycins possess methoxy group at the 7-alpha position ► Cephalosprins and Cephamycins are cephem derivatives O H2 C HOOC H C O (CH2)3 C NH NH2 OMe Cephamycin C HOOC 48 O Cephalosporin C C Cephalothin CH2 S N O O COOH O C NH2 COOH CH (CH2)3 O CH2 O N O C HN S N S O H2N C HN S O CH2 O C CH3 COOH Cefoxitin O S H2C C HN OMe S O N CH2 O COOH O C NH2 CH3