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Química Medicinal · Drug design

Antibióticos β-lactâmicos e fármacos de transferência de acila

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O que você vai aprender

  • Explain why the β-lactam carbonyl of penicillins is unusually reactive, using ring strain, lost amide resonance and the high-wavenumber C=O band.
  • Recognise penams, cephems, carbapenems and clavams and name the structural changes that relate them.
  • Draw acyl transfer from a β-lactam to a serine hydroxyl, and explain why penicillin-binding proteins stay blocked while β-lactamases hydrolyse the acyl-enzyme.
  • Explain how clavulanic acid and sulbactam protect amoxicillin and ampicillin from β-lactamases.
  • Relate penicillin side chains to acid stability, β-lactamase resistance and spectrum, and draw the acylation of 6-APA that makes semisynthetic penicillins.
  • Draw the acetyl transfer of aspirin to a serine hydroxyl, the hydrolysis of aspirin, the ester hydrolysis that activates enalapril, and the acid-driven rearrangement that activates omeprazole.

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A strained, poorly conjugated amide

Penicillins and cephalosporins carry a β-lactam: a four-membered cyclic amide. An ordinary amide is unreactive because the nitrogen lone pair is delocalised into the C=O π bond, which makes the carbonyl carbon a weak electrophile. In a β-lactam the ring angles are close to 90° instead of the ideal 120° at the sp² carbon and nitrogen, so the ring is strained and opening it releases that strain. In a penicillin the β-lactam is also fused to a five-membered thiazolidine ring, which forces the nitrogen to be pyramidal; its lone pair then overlaps poorly with the C=O π system, so the carbonyl behaves more like a ketone than an amide. Infrared spectra show the effect: an acyclic amide C=O absorbs near 1650 cm⁻¹, a monocyclic β-lactam near 1745 cm⁻¹ and the β-lactam of a penicillin near 1770–1780 cm⁻¹. Drawn: benzylpenicillin (penicillin G).

Penams, cephems, carbapenems and clavams

Penicillins are penams: the β-lactam is fused to a saturated five-membered ring containing sulfur, with gem-dimethyl groups and a carboxylic acid next to the nitrogen. Cephalosporins are cephems: the β-lactam is fused to a six-membered dihydrothiazine ring with a C=C bond conjugated to the carboxylic acid; many carry a leaving group, such as acetoxy, on the CH₂ attached to C3. Carbapenems such as imipenem keep the five-membered ring but replace sulfur by CH₂ and put a C=C bond into it; the two hydrogens on their β-lactam ring carbons are trans (cis in penicillins), so the 6-hydroxyethyl group lies on the same face as the ring-fusion hydrogen. Clavams such as clavulanic acid have oxygen in place of sulfur. All of them have a carboxylic acid (or carboxylate) on the carbon next to the β-lactam nitrogen; penicillins and cephalosporins carry an acylamino group and carbapenems a hydroxyethyl group on the carbon next to the β-lactam carbonyl, while clavulanic acid has none. Drawn left to right: cephalexin, imipenem and clavulanic acid.

Acylating the transpeptidase

Bacterial transpeptidases, also called penicillin-binding proteins (PBPs), cross-link the peptide chains of peptidoglycan. Their active-site serine attacks the D-Ala–D-Ala end of a peptide strand and forms an acyl-enzyme ester. A penicillin mimics that D-Ala–D-Ala end. The serine oxygen adds to the β-lactam carbonyl carbon, the tetrahedral intermediate collapses, and the ring C–N bond breaks while the nitrogen picks up a proton. The result is a penicilloyl ester of the serine. The ring cannot close again, because that would rebuild the strained four-membered ring, and the PBP hydrolyses this ester only extremely slowly, so the enzyme stays blocked, cross-linking stops and the growing bacterium lyses. In the mechanisms of this topic the serine is modelled by methoxide and methanol, and lysine by methylamine.

β-Lactamases and their inhibitors

Serine β-lactamases use the same acylation chemistry, but their active site also positions a water molecule activated by a general base (a glutamate in class A enzymes). That water hydrolyses the penicilloyl ester within milliseconds, regenerating the enzyme and releasing inactive penicilloic acid, so one β-lactamase destroys many antibiotic molecules. Clavulanic acid and sulbactam are β-lactams with little antibacterial activity of their own. A β-lactamase opens them like a substrate, but the acyl-enzyme then fragments: in clavulanate the second ring opens to an iminium ion and then a conjugated enamine that resists hydrolysis or reacts further with the enzyme. These mechanism-based (suicide) inhibitors are given with a β-lactamase-sensitive penicillin: amoxicillin with clavulanate, ampicillin with sulbactam. Metallo-β-lactamases, which use zinc instead of serine, are not inhibited by them. Drawn: sulbactam.

Side chains: acid stability, resistance and spectrum

Penicillin G decomposes in stomach acid because its own side-chain amide oxygen attacks the protonated β-lactam carbonyl, forming a five-membered oxazolone ring and destroying the β-lactam. An electron-withdrawing group on the side-chain α-carbon makes that amide oxygen less nucleophilic: the phenoxy oxygen of penicillin V and the ammonium group of ampicillin and amoxicillin make these penicillins acid-stable enough to be taken by mouth. Bulky groups next to the side-chain carbonyl, as in the 2,6-dimethoxybenzoyl group of methicillin, block β-lactamases. The polar amino group of ampicillin and amoxicillin helps them cross the porins of Gram-negative bacteria and broadens their spectrum. All these drugs are semisynthetic: 6-aminopenicillanic acid (6-APA), obtained by enzymatic removal of the phenylacetyl group of penicillin G, is acylated on its free amine. Drawn: 6-APA, penicillin V and amoxicillin.

Aspirin: an acetyl donor

Aspirin is a phenyl ester. Phenoxide is a much better leaving group than an alkoxide (phenol pKa about 10, methanol about 15.5), so aspirin transfers its acetyl group to nucleophiles. In cyclooxygenase-1 it acetylates a serine hydroxyl near the channel that leads to the active site, blocking prostaglandin and thromboxane synthesis irreversibly. Platelets have no nucleus and cannot make new enzyme, so one dose suppresses their thromboxane production for the platelet's lifetime of about a week to ten days. The same ester bond makes aspirin hydrolyse in water to salicylic acid and acetic acid: in strong acid by acid catalysis, and between about pH 4 and 8 with help from its own ortho-carboxylate, which acts as an intramolecular general base for the attacking water.

Prodrugs activated by hydrolysis or acid

A prodrug is converted into the active drug in the body. Enalaprilat, the ACE inhibitor, is a dicarboxylic acid that is absorbed poorly from the gut. Enalapril masks one carboxylic acid as an ethyl ester; it is absorbed and then hydrolysed by liver carboxylesterase to enalaprilat. Omeprazole is activated by acid. A weak base (pyridine pKaH about 4), it accumulates as its protonated form in the very acidic secretory canaliculi of stomach parietal cells (pH about 1). There the benzimidazole is protonated, the pyridine nitrogen attacks the benzimidazole C2, and the rearranged intermediate breaks its C–S bond to give a sulfenic acid. Loss of water closes a cyclic sulfenamide, and a cysteine thiol of the H⁺/K⁺-ATPase attacks its sulfur to form a disulfide, switching the proton pump off covalently. Drawn: enalapril and omeprazole.

What to carry forward

A β-lactam is an amide that has lost most of its resonance protection and carries ring strain, so it acylates serine hydroxyls the way an ester or anhydride would; what happens next (a blocked PBP, a recycled β-lactamase, a fragmenting inhibitor) depends on whether the acyl-enzyme can be hydrolysed. Side chains tune acid stability, β-lactamase resistance and spectrum. The same acyl-transfer logic explains aspirin's irreversible acetylation of cyclooxygenase and the hydrolytic activation of ester prodrugs, while omeprazole shows how acid can unmask a covalent warhead exactly where it is needed.

Problemas de prática (40)

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Desenhe o mecanismo 15

Side chains, acid stability and semisynthesis

  • Amoxicillin from 6-APA and an amino acid chlorideDraw the acylation of 6-APA by the hydrochloride of 4-hydroxyphenylglycyl chloride to give amoxicillin, and explain why the side-chain amino group must stay protonated.
  • Penicillin G in stomach acid: side-chain attack on the β-lactamDraw the acid-catalysed attack of the side-chain amide oxygen of penicillin G on its own β-lactam carbonyl, ending with the oxazolone that destroys the β-lactam.
  • Penicillin V from 6-APA and phenoxyacetyl chlorideDraw the N-acylation of 6-aminopenicillanic acid by an acid chloride, the key step in making semisynthetic penicillins.

Aspirin, prodrugs and omeprazole

  • Hydrolysis of aspirin in aqueous acidDraw the acid-catalysed hydrolysis of the aryl ester of aspirin to salicylic acid and acetic acid, using only hydronium and water as acids and bases.
  • Aspirin hydrolysis assisted by its own carboxylateDraw the hydrolysis of aspirin near neutral pH in which the ortho-carboxylate acts as an intramolecular general base for the attacking water.
  • Aspirin acetylates a model serineDraw the acetyl transfer from aspirin to a serine hydroxyl model, the covalent step by which aspirin inhibits cyclooxygenase.
  • Enalapril to enalaprilat: hydrolysis of the ester prodrugDraw the hydrolysis of the ethyl ester of enalapril that unmasks the carboxylate of the active ACE inhibitor enalaprilat.
  • Omeprazole: cyclic sulfenamide and disulfide formationDraw the dehydrative cyclisation of the omeprazole-derived sulfenic acid to the cyclic sulfenamide and the attack of a cysteine thiol that forms the covalent disulfide with the proton pump.
  • Omeprazole in acid: rearrangement to the sulfenic acidDraw the acid-triggered rearrangement of omeprazole: benzimidazole protonation, attack of the pyridine nitrogen on benzimidazole C2, and C–S bond cleavage to the sulfenic acid.

The β-lactam ring

  • Ring opening of a β-lactam by methoxideDraw the addition of methoxide to the carbonyl of a simple β-lactam and the collapse of the tetrahedral intermediate that opens the four-membered ring to a β-amino ester.

Acylation, β-lactamases and inhibitors

  • Cephalothin acylates a model serine and expels acetateDraw how opening the β-lactam of a cephalosporin with a 3′-acetoxy group releases acetate through the ring C=C bond.
  • Clavulanate acylates a model serine and fragmentsDraw the acylation of a serine model by clavulanate and the opening of its second ring that converts the acyl-enzyme into a conjugated enamine, the basis of β-lactamase inhibition.
  • Penicillin G acylates a model serine (methoxide)Draw the acylation of a serine-model nucleophile by penicillin G: addition to the β-lactam carbonyl and ring-opening collapse that gives a penicilloyl ester.
  • Penicillin G acylates an amine: the penicilloyl haptenDraw the aminolysis of the penicillin β-lactam by an amine, the reaction that attaches penicilloyl groups to proteins and underlies penicillin allergy.
  • Hydrolysis of the penicilloyl ester (β-lactamase deacylation model)Draw the hydrolysis of the penicilloyl ester that releases penicilloic acid and frees the serine, the step that β-lactamases perform quickly and penicillin-binding proteins cannot.

Preveja o produto 4

Aspirin, prodrugs and omeprazole

  • The active form of enalaprilPredict the structure of enalaprilat, the active metabolite of the prodrug enalapril.
  • Omeprazole from capsule to covalent adductOrder the events that convert omeprazole into the disulfide-linked proton-pump adduct.

Side chains, acid stability and semisynthesis

  • Making methicillin from 6-APAPredict the product of acylating 6-APA with an aroyl chloride.

Acylation, β-lactamases and inhibitors

  • The serine-model productPredict which bond of penicillin G is cleaved when it acylates an oxygen nucleophile.

Classificar 4

The β-lactam ring

  • From penam to carbapenemState the two structural changes that relate the penam nucleus of penicillins to the carbapenem nucleus.
  • Spot the β-lactamRecognise a β-lactam as a four-membered cyclic amide and distinguish it from a β-lactone, a γ-lactam and a cyclic amine.
  • Which is the cephalosporin?Identify a cephalosporin by its six-membered sulfur-containing ring fused to the β-lactam.

Acylation, β-lactamases and inhibitors

  • Evidence for a suicide inhibitorChoose the kinetic evidence that identifies clavulanic acid as a mechanism-based inactivator rather than a reversible competitive inhibitor.

Comparar 2

Aspirin, prodrugs and omeprazole

  • Rank acetyl donors toward a serine hydroxylRank acetyl donors by their ability to acetylate a serine hydroxyl, using the acidity of the leaving group's conjugate acid.

The β-lactam ring

  • Amide carbonyl stretches from normal to strainedOrder amide carbonyl stretching frequencies by ring strain and loss of nitrogen conjugation.

Calcular 3

Side chains, acid stability and semisynthesis

  • Theoretical yield of amoxicillinCalculate the theoretical yield of a semisynthetic penicillin from the mass of 6-APA acylated.

Aspirin, prodrugs and omeprazole

  • Acetic acid from a hydrolysed aspirin tabletCalculate the mass of acetic acid released by complete hydrolysis of a dose of aspirin.
  • How strongly omeprazole is protonated in the canaliculusCalculate the ratio of protonated to free omeprazole at canalicular pH from the pyridine pKaH.

Encontre o erro 1

  • Which analogue is a dead end?Diagnose which penicillin-related structure lacks the feature essential for antibacterial activity, distinguishing it from a prodrug.

Interprete as evidências 2

The β-lactam ring

  • Which band is the β-lactam?Assign the high-wavenumber carbonyl band of a penicillin to its β-lactam.

Acylation, β-lactamases and inhibitors

  • How penicillin shuts down a transpeptidasePut the events of transpeptidase inhibition by a penicillin in the order they occur.

Trabalhe de trás para frente 1

  • Where 6-APA comes fromIdentify the bond of penicillin G that is cut to produce 6-aminopenicillanic acid.

Planeje uma síntese 1

  • Beating a β-lactamaseChoose a drug combination that overcomes resistance caused by a serine β-lactamase.

Explique por quê 7

Side chains, acid stability and semisynthesis

  • Why penicillin V survives the stomachExplain how an electron-withdrawing side-chain substituent makes penicillin V acid-stable.
  • What the amino group of ampicillin doesDescribe how the α-amino group of ampicillin affects acid stability and antibacterial spectrum.
  • A steric shield against penicillinaseExplain how the bulky side chain of methicillin gives resistance to staphylococcal β-lactamase.

Aspirin, prodrugs and omeprazole

  • A short-lived drug with a long-lived effectExplain why low-dose aspirin suppresses platelet thromboxane for days although aspirin itself is cleared within an hour.
  • Why give enalapril instead of enalaprilat?Explain how esterifying one carboxylic acid improves the oral absorption of an ACE inhibitor.

Acylation, β-lactamases and inhibitors

  • Why penicillin fits the transpeptidaseExplain why penicillins are recognised by bacterial transpeptidases.

The β-lactam ring

  • What the fused ring addsExplain why a bicyclic penam β-lactam is more reactive than a monocyclic β-lactam.

Travou em antibióticos β-lactâmicos e fármacos de transferência de acila? Escaneie o problema.

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