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http://www.chemistryexplained.com/photos/chirality-3371.jpg PHRM 415: Pathophysiology, Drug Action, and Therapeutics (5) Antimicrobials...

http://www.chemistryexplained.com/photos/chirality-3371.jpg PHRM 415: Pathophysiology, Drug Action, and Therapeutics (5) Antimicrobials Dr. Reem Al-Wabli Dr. Hattem Abuelizz Office: S67 Office: [email protected] [email protected] Objectives Understand the different chemical classes of antibacterial agents covered in this course. Predict the biological response, if any, from a chemical structure on the therapeutic targets covered in this course. Relate the structural features of a compound to the physiochemical properties, which may have a major effect on its biological response, or on the design of modern therapeutic agents. 2 LECTURE CONTENTS Sulphonamides Trimethoprim. Penicillins. Cephalosporins. Carbenems. Monobactams Quinolones. Macrolides. Tetacyclines. Chloramphenicol. Agents Targeting Metabolic Processes  1- Sulphonamides The sulphonamide story began when it was discovered that a red dye called prontosil had antibacterial properties in vivo (i.e. when given to laboratory animals). Sulphonamides are the best example of antibacterial agents acting as antimetabolites. Sulphonamide prevents PABA from binding by mimicking PABA.  Structure–activity relationships of sulphonamides: The para amino group is essential for activity and must be unsubstituted (i.e. R1 = H). The only exception is when R1 = acyl (i.e. amides). The amides themselves are inactive but can be metabolized in the body to regenerate the active compound. The aromatic ring and the sulphonamide functional group are both Sulphonamide analogues general structure required; both the sulphonamide and amino group must be directly attached to the aromatic ring; the aromatic ring must be para - substituted only. The sulphonamide nitrogen must be primary or secondary. R2 is the only possible site that can be varied in sulphonamides. Some of the sulphonamide agents  Structure–activity relationships of sulphonamides The strongly electron withdrawing character of the aromatic SO2 group makes the nitrogen atom to which it is directly attached partially electropositive, thus increasing the acidity of the hydrogen atoms attached to the nitrogen so that this functional group is slightly acidic Replacement of one of the NH2 hydrogen by an electron withdrawing heteroaromatic ring was not only consistent with antimicrobial activity but also greatly acidified the remaining hydrogen and dramatically enhanced potency and dramatically increases the water solubility under physiologic conditions. The poor water solubility of the earliest sulfonamides led to occasional crystallization in the urine (crystalluria) and resulted in kidney damage because the molecules were unionized at urine pH values. Increased potency Increased Solubility 2-Trimethoprim Most commonly used in 1:5 fixed ratio with the sulfamethoxazole (Bactrim, Septra). This combination is not only synergistic but is less likely to induce bacterial resistance than either agent alone. These agents block sequentially at two different steps in the same pathway. we 6 Agents Targeting Cell-wall Synthesis  beta-lactam antibiotics. β-lactam is a cyclic amide with four atoms in its ring. Penicillins and cephalosporins are called beta-lactam antibiotics. The penicillin subclass of β-lactam antibiotics is characterized by the presence of a substituted 5-membered thiazoldine ring fused to the β- lactam ring. This fusion and the chirality of the β-lactam ring results in the molecule possessing a “V” shape. This drastically interferes with the planarity of the lactam bond and resonance of the lactam nitrogen with its carbonyl group. Consequently the β-lactam ring is much more sensitive to hydrolysis as compared with normal planar amides. The three-dimensional shape of penicillin  1- Penicillins Penicillins have three structural features: Fused beta-lactam and thiazolidine ring structure. Free carboxylic acid group. One or more substituted amino side chains. The penicillins were produced by fermentation of the fungus Penicillium chrysogenum. When a sufficient supply of :- Phenyl acetic acid → benzylpenicillin (penicillin G). Phenoxyacetic acid →phenoxymethyl penicillin (penicillin V). 89 Mechanisms of transpeptidase cross-linking and penicillin inhibition. Structure–activity relationships of penicillins The strained β-lactam ring is essential The free carboxylic acid is essential. This is usually ionized and the carboxylate ion binds to the charged nitrogen of a lysine residue in the binding site. The bicyclic system is important. This confers further strain on the β- lactam ring—the greater the strain the greater the activity, but the greater the instability. The acylamino side chain is essential. Sulphuruh is usual but not essential. The stereochemistry of the bicyclic ring with respect to the acylamino side chain is important. The conclusion that very little variation is tolerated by the penicillin nucleus and that any variations are restricted to the acylamino side chain. Structure–activity relationships of penicillins Acid sensitivity of penicillins The reason for the acid sensitivity of pencillin G: Ring strain: penicillin suffers large angle and torsional strains. Acid-catalysed ring-opening relieves these strains by breaking open the more highly strained β-lactam ring. highly reactive β-lactam carbonyl group: The carbonyl group in the β-lactam ring is highly susceptible to nucleophiles and does not behave like a normal tertiary amide. Influence of the acyl side chain (neighbouring group participation). Reduction of neighbouring group participation with an electron-withdrawing group (e.w.g.). sensitivity IN  β-Lactamase-resistant penicillins The strategy of steric shields was used to block penicillin from accessing the penicillinase or β- lactamase active site. However, If the steric shield was too bulky then it also prevented the penicillin from attacking the transpeptidase target enzyme. Methicillin was the first effective penicillin with resistance to the S. aureus β-lactamase. Nafcillin contains a naphthalene ring which acts as its steric shield. While, Temocillin has a 6-methoxy group present. The isoxazolyl penicillins The incorporation of an isoxazolyl ring into the penicillin side chain led to orally active compounds which were stable to the β-lactamase enzyme of S. aureus. The isoxazolyl ring acts as the steric shield but it is also electron withdrawing, giving the structure acid stability. Oxacillin, cloxacillin, flucloxacillin, and dicloxacillin are all useful against S. aureus infections. The only difference between them is the type of halogen substitution on the aromatic ring. These substituents affect pharmacokinetic Penicillin isoxazolyls B lactamase properties such as absorption and plasma protein binding. shield Him t.in  Broad-spectrum sensitive penicillins: The aminopenicillins Ampicillin and amoxicillin are orally active compounds that have a very similar structure. Both compounds are acid resistant because of the presence of the electron-withdrawing amino group. There are no steric shields present and so these agents are sensitive to β-lactamase enzymes. Both structures are poorly absorbed through the gut wall as both the amino group and the carboxylic group are ionized. This problem can be alleviated by using a prodrug. Prodrugs used to aid absorption of ampicillin through the gut wall  β-Lactamase inhibitors: They have weak and unimportant antibiotic activity, but it is a powerful and irreversible inhibitor of most β-Lactamases and can be classed as a suicide substrate. They are used in combination with traditional penicillins, such as:  Clavulanic acid with amoxicillin. Augmentin R  Clavulanic acid with ticarcillin.  Sulbactam with ampicillin.  Tazobactam with piperacillin. Clavulanic acid It is believed to acylate the active site serine by mimicking the normal substrate. While hydrolysis occurs with some β-lactamases, subsequent reactions occur which inhibit the enzyme irreversibly.  2- Cephalosporins The structure of cephalosporin C has similarities to that of penicillin. It has a bicyclic system containing β-lactam ring fused to a six-membered dihydrothiazine ring. Structure–activity relationships of cephalosporin: The importance of the β-lactam ring within the bicyclic system, an ionized carboxylate group at position 4, and the acylamino side chain at position 7. Edification There is a limited number of places where modifications can be made. These are as follows; variations of the 7-acylamino side chain; variations of the 3-acetoxymethyl side chain; acetylme extra substitution at carbon 7. SAR of cephalosporins First-generation cephalosporins Examples of first-generation cephalosporins include cephalothin, cephaloridine, cephalexin. Metabolic hydrolysis of cephalothin Good leaving group Second-generation cephalosporins a- Cephamycins Cephamycins contain a methoxy substituent at position 7, which has proved advantageous. Modification of the side chain of cephamycin C gave cefoxitin, which showed a broader spectrum of activity than most first-generation cephalosporins. b- Oximinocephalosporins These structures contain an iminomethoxy group at the α-position of the acyl side chain, which significantly increases the stability of cephalosporins against the β-lactamases. Goodleavinggroup Thirdgen 3rd 2nd lephaloriding 3rd 4th 4th 3rd Third- and fourth-generation oximinocephalosporins Cefepime synmethoxyimine 7 3 Aminothiazolyl Nmethyl pyrrolidine Cefepime (Maxipime) Cefepime is a semi-synthetic agent containing a syn-methoxyimine moiety and an aminothiazolyl group at C-7 broadening its spectrum and increasing its β-lactamase stability as well as increasing its anti-staphylococcus activity. The quaternary N-methylpyrrolidine at C-3 help penetration into Gram (-) bacteria Fifth-generation cephalosporins Ceftaroline fosamil is a fifth-generation cephalosporin that has activity against various strains of MRSA and multi-resistant Streptococcus pneumonia (MDRSP). It acts as a prodrug for ceftaroline , and the 1,3-thiazole ring is thought to be important for its activity against MRSA.  3- Carbapenems Thienamycin does not have sulphur atom and acylamino side chain, both of which were thought to be essential to antibacterial activity. Imipenem is susceptible to metabolism by a dehydropeptidase enzyme, whereas meropenem is more resistant as a result of the different substituent at position 2. Ertapenem similar in structure to meropenem so resistant against dehydropeptidases, while the ionized benzoic acid contributes to high protein binding and prolongs the halflife. Thienamycin and Imipenem nucleophilic formimino yl Because of thienamycin extremely intense and broad-spectrum of antimicrobial activity and its ability to inactivate β-lactamases, it combines in one-molecule the functional features of the best of the β-lactam antibiotics as well as the β-lactamase inhibitors. The carbapenem ring system is highly strained and very susceptible to reactions cleaving the β-lactam bond. The terminal amino group in the side chain attached to C-3 is nucleophilic and attacks the β-lactam bond of nearby molecules, so that the drug became less stable. This problem was overcome by changing the amino group to a less nucleophilic N-formiminoyl moiety by a semi-synthetic process to produce imipenem. Thienamycin and imipenem penetrate very well through porins and are very stable, even inhibitory to many β-lactamases. Imipenem and cilastatin o Imipenem is not orally active and when used in urinary tract infections, renal dehydropeptidase-I hydrolyse imipenem and deactivate it. So an inhibitor for this enzyme, cilastatin, is Co-administered with imipenem to protect.  Meropenem Meropenem Meropenem is a synthetic carbapenem possessing a more complex side chain at C-3 and a chiral methyl group at C-4. This methyl group conveys intrinsic resistance to hydrolysis by dehydropeptidase-1 so administered as a single agent for the treatment of severe bacterial infections Ertapenem It is used once daily parenterally, with special application against anaerobes. As with meropenem, the 4-β-methyl group confers stability toward dlehydropeptidase-1. It is relatively strongly bound to serum proteins, so it has a prolonged half-life, making it more convenient to use than the other carbapenems when its spectrum warrants this. 4- Monobactams Monocyclic β-lactams such as the nocardicins have been isolated from natural sources. Surprisingly, they contain a single β-lactam ring, demonstrating that a fused second ring is not always essential for antibacterial activity. One explanation for this is that nocardicins might have a different mechanism of action from penicillins and cephalosporins—possibly by inhibiting a different enzyme involved in cell wall synthesis. Aztreonam is an example of a monobactam which has reached the clinic. The monobactams demonstrate that a fused ring is not essential for antibiotic activity. The methyl group at C-4 is associated with the stability of aztreonam towards β-lactamases. Agents Targeting DNA  Quinolones The quinolone antimicrobials comprise a group of synthetic substances possessing in common an N-1-alkylated 3-carboxy pyrid-4-one ring fused to another aromatic ring, which itself carries other substituents. The first quinolone to be marketed was nalidixic acid, which since has been discontinued. Quinolones were of little clinical significance until the discovery that the fivity addition of a fluoro group at the 6-position of the basic nucleus greatly increased the biological activity. Clinically used quinolones Structure activity relationship of quinolones: The carboxy-4-pyridone nucleus is essential pharmacophore for activity. The carboxylic acid and the ketone are involved in binding with DNA- gyrase enzyme. Reduction of the 2,3-double bond or the 4-keto group inactivates the molecule. Substitution at C-2 interferes with enzyme-substrate complexation. Fluoro substitution at C-6 lipophilicity drug pentration through cell wall antimicrobial activity. Fluoro substitution at C-8 absorption and half life but also increases the photosensitivity. Heterocyclic substitution at C-7 improves the spectrum of activity. The piperazinyl and pyrrolidinyl represent the most significant antimicrobial improvement. The piperazinyl group at C-7 also increases binding to central nervous, which accounts for CNS side effects.  Structure activity relationship of quinolones: The cyclopropyl substitution at N-1 broaden the antibacterial activity. The introduction of a third ring to the quinolones nucleus gives rise to ofloxacin which has an asymmetric carbon at the C-3 position. The S-(-)-isomer (levofloxacin) is twice as active as ofloxacin and 8- to 128-fold more potent than the R(+)-isomer. A C-8 halogen appears to produce the highest incidence of photosensitivity. Substitution of a methoxy group at: C-8 has been reported lo reduce the photosensitivity (gatilfoxacin). Summary of structure-activity relationships (SARs) for the fluoroquinolones  Chemical incompatibility: The quinolones chelate polyvalent metal ions (Ca2+ Mg+2, Al+3, and Fe+2) to form less water-soluble complexes and reduced drug absorption. Chelation occurs between the metal and the 3-carboxylic acid and 4-keto groups. Thus co-administration of certain antacids, tonics and consumption of dairy products soon after quinolone administration is contraindicated Agents Targeting Protein Synthesis 1- Aminoglycosides: Structurally, the antibiotic aminoglycosides are glycosidic polycyclic structures, incorporating an aminocyclitol ring (streptamine, streptidine, or 2- deoxystreptamine), of which the 2-deoxystreptamine is most commonly found in clinical aminoglycosides, usually attached to two or three aminosugar rings. The aglycone aminocyclitol ring in each structure is easily identifiable as it does not have an O atom as part of the ring; the other cyclic parts of each molecule are sugars, recognisable as the five- or six-membered cyclic systems that include an O atom in the ring. Aminoglycoside antibiotics  SAR of aminoglycosides Two structural properties distinguish aminoglycoside antibiotics. The amino sugar part and the centrally located hexose ring, which is either 2-deoxystreptamine or streptidine. Amino sugar portion: The bacterial inactivating enzymes targets C-6 and C-2 position and the substitution with methyl group at C-6 increases the enzyme resistance. Cleavage of 3-hydroxyl or the 4-hydroxyl or both groups does not affect the activity Centrally placed hexose ring (aminocyclitol ring): Various modifications at C-1 amino group have been tested. The acylation (e.g. amikacyn) and ethylation (e.g. 1-N-ethylsisomycin) though does not increase the activity helps to retain the antibacterial potency. Bad In sisomicin series, 2-hydroxylation and 5-deoxygenation result in the increased inhibition of bacterial inactivating enzyme systems.  Gentamicin incompatibility o It is often combined with other anti-infective agents and an interesting incompatibility has been uncovered. o With certain β-lactam antibiotics, the two drugs react with each other so that N-acylation on C-1 of gentamicin by the β-lactam antibiotic takes place, thus inactivating both antibiotics. 2- Macrolide antibiotics The term macrolide is derived from the characteristic large lactone ring found in these antibiotics. The clinically important member of this family have two or more sugars attached to the 14-membered ring. One of these sugars usually carries a substituted amino group, so the overall chemical character is weakly basic. Macrolide antibiotics used clinically include azithromycin, clarithromycin, erythromycin, and roxithromycin. Macrolide antibiotics Chemical Reactivity The macrolides of the erythromycin class are chemically unstable in acid due to rapid internal cyclic ketal formation leading to inactivity. Many macrolides have an unpleasant taste, which overcome with water-insoluble dosage forms enteric coatings which also reduce acid instability and the gut cramps  Azithromycin Azithromycin has a 15-membered lactone ring which does not form a cyclic internal ketal so more stable to acid degradation than erythromycin and has longer half-life, attributed to greater and longer tissue penetration, allowing once-a-day dosage. The drug should be taken on an empty stomach. It does give a metallic taste.  3- Tetracyclines Tetracyclines is characterized by a highly functionalized, partially reduced naphthacene (four linearly fused six-membered rings) ring system from which both the family name and numbering system are derived. The α-stereo orientation of the C-4 dimethylamino moiety of the tetracyclines is essential for their bioactivity. The presence of the tricarbonyl system of ring A allows enolization invoking loss of the C-4 hydrogen. Reprotonation can either take place from the top or the bottom. If it take place from the top it will regenerate the tetracyclin but if from the bottom it will give the inactive 4-epitetracycline. Chemical incompatibility: The acidic functions of the tetracyclines are capable of forming salts through chelation with polyvalent metal ions such as Fe2+, Al3+, Ca2+, Mg2+, and are all quite insoluble at neutral pHs. So, the tetracyclines are incompatible with co-administered multivalent ion-rich antacids and concomitant consumption of daily products rich in calcium ion is also contraindicated The bones, of which the teeth are the most visible, are calcium rich structures and so accumulate tetracyclines in proportion to the amount and duration of therapy when bones and teeth are being formed. Which lead to permanent discoloration in which, in advanced cases, the teeth are even brown. SAR of tetracyclines: Tetracyclines  4- Chloramphenicol: With 2 asymmetric centers it is one of four diastereomers, only one of which (1R, 2R) is significantly active. The nitro group and both alcohol groups are involved in binding interactions. The dichloroacetamide group is also important, but can be replaced by other electronegative groups. Chloramphenicol is quite Chloramphenicol toxic and the nitro substituent is thought to be responsible for this. To overcome the low solubility of chloramphenicol, two prodrug forms were developed; chloramphenicol succinate as the ionised sodium salt, suitable for IV administration, and chloramphenicol palmitate , which is designed for oral administration.