Medicinal Chemistry II: CHEMOTHERAPEUTIC AGENTS PDF

1 Medicinal Chemistry II CHEMOTHERAPEUTIC AGENTS By: Abeer Hussain Course content Dr. Abeer Hussain Abbas Antibacterial agents (3 Lectures) Antifungal-anti T.B- antiprotozoals-antimalarials- antiseptics(2 lectures) Dr.Mai Shahin Anticancer agents (2 lectures) Sulfonamides and...

1 Medicinal Chemistry II CHEMOTHERAPEUTIC AGENTS By: Abeer Hussain Course content Dr. Abeer Hussain Abbas Antibacterial agents (3 Lectures) Antifungal-anti T.B- antiprotozoals-antimalarials- antiseptics(2 lectures) Dr.Mai Shahin Anticancer agents (2 lectures) Sulfonamides and Antiviral agents (1 lecture) Steroidal Hormones(2 lectures)  3 Chemotherapeutic agents include: ❑ Antimicrobial Agents ❑ Antiparasitic Agents ❑ Anticancer Agents Antimicrobial Agents Antimicrobial Agents include: Beta lactam Antibiotics ✓ Antibacterial Agents Non-Beta lactams ✓ Antimycobacterial Agents Fluoroquinolones ✓ Antifungal Agents Sulfonamides ✓ Antiviral Agents ✓ Anti-infectives  4 Antibacterial agents 1. Antibacterial agents which act against cell metabolism (Synthetic Antimetabolites). e.g. sulphonamides and trimethoprim. 2.Agents act on nucleic acid transcription and replication (Synthetic Antibacterial Agents) e.g. fluoroquinolones. 3. Antibacterial agents which inhibit cell wall synthesis (- Lactam Antibiotics). 4.Antibacterial agents which inhibit protein synthesis e.g.Tetracyclines, Aminoglycosides, macrolides, & chloramphenicol 5.Antibacterial agents which act on the plasma membrane structure e.g. valinomycin & gramicidin.  5 Β-LACTAM ANTIBIOTICS (Antibacterials which Inhibit cell wall synthesis)  6 Lecture outlines 1) Structure and nomenclature of β-lactam antibiotics 2) Mode of Action of β-lactam antibiotics. 3) Penicillins: a) Preparations and SAR of penicillin b) Problems of penicillin G & its molecular optimization i. Short duration of action and tackling this problem ii. The acid sensitivity and tackling this problem iii. The sensitivity of penicillin G to ß-lactamases iv. Narrow activity spectrum of penicillin G v. Allergic reactions  7 Chemical Classification of β-Lactam antibiotics  8 Mechanism of action of Penicillins and Cephalosporins: ❑ The uniquely lethal antibacterial action of these agents has been attributed to a selective inhibition of bacterial cell wall synthesis through inhibition of transpeptidase enzyme.  9 Peptidoglycan structure of bacterial cell wall N-Acetylmuramic acid N-Acetylglucosamine 10  11 Cross-linking of bacterial cell wall catalyzed by bacterial Transpeptidase enzyme  12 Structure of penicillins compared to that of Acyl D-alanine-D-alanine moiety  13 Inhibition of bacterial transpeptidase enzyme by penicillins  14 Penicillins; Structure and stereochemistry 6 -a m in o p e n i ci ll a n i c a ci d O H (6 -APA) R= CH 2 H H C N Be n zyl p e n i cil l i n S CH3 (penicillin G) R Acyl side chain N CH3 O R= O CH 2 COOH Ph e n o xym e th yl p e n i ci l li n (penicillin V )) ß-Lactam ring T hiazolidine ring C(2):S, C(5):R & C(6):R.  15 Nomenclature Simplified forms of Penicillin nomenclature have been adopted for general use: 1) Penicillins are considered as derivatives of 6- aminopenicillanic acid. 2) Nomenclature using the name penicillin as suffix and the acyl portion (R) as prefix e.g. benzyl penicillin (penicillin G). H 6-am inopenicillanic acid (6-APA) N H H S CH3 N CH3 O COOH  16 Preparations of penicillin 1) Natural penicillins: They obtained naturally from fermentation of the fungus penicillium chrysogenum. e.g. benzylpenicillin. 2)Biosynthetic penicillins: They obtained by altering the culture media by addition of certain different carboxylic acids that may be incorporated as acyl groups e.g. phenoxymethylpenicillin (penicillin V) which is prepared by addition of phenoxyacetic acid. 3)Semisynthetic penicillins: The fermentation yielded 6- APA which could then be treated synthetically to give penicillin analogues. This was achieved by acylating the isolated 6-APA with a wide range of acid chlorides. Carboxylic acids can be used for the acylation using N,N-dicyclohexylcarbodiimide (DCC).  17 Structure-activity relationships  18 I. Penicillin G: properties & problems 1) Active versus Gram-positive bacilli and some (not all) of Gram negative cocci. (narrow spectrum of activity) 2) Non-toxic! Penicillins are amongst the safest drugs known to medicine. 3) Ineffective when taken orally since it breaks down in the acid conditions of stomach. Penicillin G can only be administered by injection. 4) Sensitive to all known -lactamases. These are enzymes produced by penicillin-resistant bacteria which catalyze the degradation of penicillins. 5) Allergic reactions are suffered by some individuals.  19 I. Penicillin G: problems (I) Short duration of action (II) Acid sensitivity (III) Penicillinase sensitivity (IV) Narrow spectrum of activity (V) Allergic reactions Therefore, we need to develop semisynthetic penicillins aiming to tackle these limitations  20 (I) Short duration of action of penicillin G and tackling this problem ❑ Penicillin G is rapidly eliminated through the kidney. Therapeutic serum level lasts only about 3-6 hours. ❑ For the prolongation of the duration of action, suspension of high molecular weight amine salts is used e.g. Penicillin G procaine. (less soluble salts, thus longer duration of action) H H CH 2 N H C S CH 3 H5C2 O + O N (C H 2 )2 O C NH 2 N CH 3 O H 5C 2 H - COO  21 (I) Short duration of action of penicillin G and tackling this problem ✓ Penicillin G procaine Suspension- Injection ✓ Penicillin G benzathine (quite insoluble, stable at gastric pH) can be taken Orally H Ph CH2 N H H H H H C S CH3 H3 C S N CH2 Ph C O N CH3 O CH2 CH2 H3C N O - + + - O COO H 2N (C H2) NH2 OOC  22 (I) Short duration of action of penicillin G (II) The acid sensitivity of penicillin G There are three reasons for the acid sensitivity of penicillin G: (1) Ring strain (2) A highly reactive -lactam carbonyl group (3) Influence of the acyl chain  23 (II) The acid sensitivity of penicillin G: 1. Ring strain: H H ✓ Large angle & torsional strain O ✓ Acid catalyzed ring opening H of β-lactam ring relieves this strain 2. A highly reactive -lactam carbonyl group: ✓ highly susceptible to nucleophiles  24 (II) The acid sensitivity of penicillin G: 3. The influence of the acyl chain (neighboring group participation:  25 Tackling the problem of acid sensitivity ❑ Nothing can be done about the first 2 factors ❑ Only the 3rd factor can be tackled……. How???? By reducing the tendency of the carbonyl to act as a nucleophile Can be achieved by attaching a strong electron withdrawing group next to the carbonyl Examples: 1. Penicillin V 2.Ampicillin & amoxacillin 3. Isoxazolyl penicillins  26 Acid resistant penicillins (Orally active) (reduction of neighbouring group participation with EWG) 2. Penicillin V, Ampicillin, Amoxacillin and Oxacillin  27 (I) Short duration of action of penicillin G (II) The acid sensitivity of penicillin G (III) The sensitivity of penicillin G to ß- lactamases H N H S CH3 N S CH3 O N CH3 O O HN CH3 O OH COOH O COOH B-latamase H2O B-latamase H N S CH3 O O HN CH3 OH COOH Penicilloic acid  28 Tackling the problem of ß-lactamases sensitivity Two approaches to overcome this problem: 1. To modify the structure of ß-lactam antibiotic so as to increase its stability toward ß-lactamases e.g. Methicillin, Nafcilin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin. 2. To use agents (ß-lactamase inhibitors) those were capable of inhibiting the bacterial enzyme to protect the ß-lactam antibiotic from destruction.  29 Tackling the problem of ß-lactamases sensitivity 1. Modification of the structure of ß-lactam antibiotic: ✓ The strategy is to block the penicillin from reaching the penicillinase active site. ✓ To do this is: place a bulky group on the side chain. ✓ This bulky group can then act as a “shield”, and prevent the binding of penicillins.  30 Tackling the problem of ß-lactamases sensitivity Oxacillin, Cloxacillin, Methicillin & Nafcillin Dicloxacillin & flucloxacillin ❑ Penicillinase resistant Resistant to acid and ❑ But acid-sensitive penicillinase:  31 H O CH2OH 2) ß-lactamase inhibitors N O A) Natural ß-lactamase inhibitors.. COOH i) Clavulanic acid Clavulanic acid ❑ Isolated from streptomyces clavuligerus. ❑ It has weak antibacterial activity; lacks the 6-acylamino side chain of penicillins. ❑It is an oxapenam (ß-lactam fused with oxazolidine ring). Mechanism of action of clavulanic acid ❑ An excellent irreversible inhibitor of most ß-lactamases. ❑ Classified as a mechanism-based inhibitor (or so-called suicide substrate). ❑ The drug fits the active site of ß-lactamases, the ß-lactam is opened by a serine residue as in penicillin. ❑ Then subsequent rearrangement takes place to give a more stable acyl-enzyme complex  32 Clinical importance of clavulanic acid ❑ Clavulanic acid and amoxicillin (Augmentin) have pronounced synergistic activity against ß- lactamases producing strains. H O CH2OH N O COOH Amoxacillin Clavulanic acid Augmentin  33 A) Natural β-lactamase inhibitors ii) Carbapenems…Thienamycin ❑ In case of Carbapenems, the sulfur atom is not part of the 5-membered ring and replaced by CH2 (bioisostere). ❑ Thienamycin was isolated from Streptomyces Cattleya. (not available for use now) OH H H H H3C SCH 2CH 2NH 2 N O COOH Thienamycin  34 B) Semisynthetic β-lactamase inhibitors Sulbactam, Tazobactam, Avibactam: ❑ Has weak antibacterial activity but has synergistic activity in combination with many penicillins and cephalosporins. ❑ They are poorly absorbed orally.  35 B) Semisynthetic β-lactamase inhibitors Sulbactam: ❑ To solve problem of bioavailability; formation of mutual prodrug sultamicillin: A double ester of formaldehyde hydrate in which one of hydroxyl group has been esterified with ampicillin and the other with sulbactam. ❑ This resulted in high serum levels of sulbactam and ampicillin in a balanced proportion after oral administration. H OH H N H H O C S C S CH3 H 3C NH2 O N N CH3 H3C O Am picillin O Sulbactam COO OOC C H H Sultamicillin  36 (I) Short duration of action of penicillin G (II) The acid sensitivity of penicillin G (III) The sensitivity of penicillin G to ß- lactamases (IV) Tackling the problem of Narrow spectrum of activity ❖ Hydrophobic groups on the side chain (e.g. penicillin G) favor activity against Gram-positive bacteria, but result in poor activity against Gram- negative bacteria. ❖ Hydrophilic groups on the side chain resulted in an increase in activity against Gram-negative bacteria. ❖ Enhancement of Gram-negative activity can be achieved if the hydrophilic group (e.g. NH2 and COOH) is attached to the carbon that is alpha to the carbonyl on the side chain.  37 (IV) Tackling problem of Narrow spectrum of activity: Broad spectrum penicillins (Activity against Gram – ve bacteria) ❑ There are two categories of penicillins having an alpha hydrophilic group: ❖ Class I: (Early members) taken orally and the hydrophilic group is an amino function, as in ampicillin and amoxicillin. ❖ Class II: They are taken parenterally: The hydrophilic group is an acid group: e.g. Carbenicillin &Ticarcillin, Acylureido group: e.g. mezlocillin, piperacillin.  38 Broad spectrum penicillins: Class I: Amino penicillins: Ampicillin & Amoxacillin Ampicillin is the first member of this class. ❑ It is analogue of benzylpenicillin in which one of the hydrogen atoms of the side chain methylene has been replaced with a primary amino group. Amoxicillin differs merely in having a phenolic group. It has similar properties but it is better absorbed through the gut wall. NH2 H N S CH3 O N CH3 R O COOH R = H : Ampicillin R = OH : Amoxacillin  39 Properties of ampicillin and amoxicillin ❑ Show activity against Gram-positive bacteria and against those Gram-negative bacteria which do not produce penicillinase. ❑ Non toxic. ❑ Acid resistant and orally active (Why?). NH2 EWG ❑ Sensitive to ß-lactamases (Why?) (think how to overcome) ❑ Inactive against Pseudomonas aeruginosa (a particularly resistant species). ❑ Ampicillin can cause diarrhea because of poor absorption through the gut wall, leading to disruption of gut flora. (why?) ❑ But, amoxicillin can cause less diarrhea due to its better GIT absorption (Why?).  40 Prodrugs of ampicillin: i) Pivampicillin & Bacampicillin ❑ The problem of poor absorption of ampicillin stems from the dipolar nature of the molecule. (free NH2 group and a free COOH group. ❑ This problem can be alleviated by using a prodrug in which one of the polar groups is masked. This ester is removed metabolically once the prodrug is absorbed through the gut wall.  41 Prodrugs of ampicillin: i) Pivampicillin & Bacampicillin ❑ These are called “double ester prodrugs” or extended esters contain a second ester group further away from the penicillin nucleus, and which is more exposed to attack. + H + H PEN PEN PEN O H C O CH 2 O CMe3 C O CH 2 O C OH O O O Enzym e Form a lde hyde  42 Broad spectrum penicillins: Class II: Parentral penicillins A) Carbenicillin & Ticarcillin (carboxypenicillins) ❑ Carbenicillin is a benzylpenicillin analog having an alpha carboxylic moiety. ❑ The introduction of this carboxyl group enhanced antiGram (-) activity.  43 Broad spectrum penicillins: Class II: Parentral penicillins Carbenicillin…… properties, problems ❑ Its clinical use is primarily restricted to high dose therapy of P.aerugenosa and Proteus vulgaris, some enterobacter and Serratia infections. ❑ It is susceptible to ß-lactamases ❑ It can decarboxylate readily to produce benzylpenicillin, this degradation products has no activity against the organisms for which carbenicillin is indicated.  44 Broad spectrum penicillins: Class II: Parentral penicillins A) Ticarcillin (with alpha COOH) ❑ A sulfur-based bioisostere of carbenicillin, (Bioisosterism) ❑ Similar to carbenicillin in the antibacterial spectrum. ❑ It has better pharmacokinetic properties including higher serum levels and a longer duration of action. ❑ Susceptible to b-lactamases. (no bulky group) ❑ Active against Gram –ve bacteria. ❑ Active against P.aeruginosa and some Enterobacter ❑ Available in combination with clavulanic acid (Timentin) ❑ Not taken orally (although electron withdrawing group,not but v.polar)  45 Broad spectrum penicillins: Class II: Parentral penicillins B) Acylureidopenicillins… Mezlocillin & piperacillin ❑ Ampicillin derivatives in which the side chain amino group has been chemically converted different ureas. ❑ They have both antiGram (+) & antiGram (-) potencies. ❑ It is speculated that the added side chain moiety mimics a longer segment of the peptidoglycan chain than ampicillin does. Hence, more points of attachment to the penicillin-binding proteins (PBPs) which may be responsible for their enhanced antibacterial proper ties. ❑ Piperacillin + Tazobactam combination (Zosyn)  46 Penicillinase-Sensitive Penicillinase-resistant Parentral Penicillin G (short duration) Steric sheild ▪ Methicillin Broad Spectrum ▪ Ticarcillin ▪ Nafcillin Alpha COOH Broad Spectrum ▪ Mezlocillin acylureido ▪ piperacillin Orally Less soluble ▪ Penicillin G active salts, longer benzathine duration E.W.G. on acyl ▪ Penicillin V E.W.G + ▪ Oxacillin side chain ▪ Ampicillin & Steric sheild ▪ Cloxacillin Amoxacillin ▪ Dicloxacillin ▪ Flucloxacillin E.W.G. + ▪ Pivampicillin Br. spectrum + ▪ Bacampicillin Prodrugs  47 (V) Allergic reactions ❑ The penicillins that are most frequently implicated as causes of allergic reactions are penicillin G, ampicillin, and amoxicillin. However, all commercially available penicillins have been reported to cause such reactions. ❑ Penicillins or their arrangement products formed in vivo (e.g. penicillenic acids) react with lysine terminal amino groups of proteins to form penicilloyl proteins, which are major antigenic determinants.  48 (V) Allergic reactions ❑ Polymerization of ampicillin also cause allergic reactions: ✓ Ampicillin is known to undergo pH-dependent polymerization reactions especially in concentrated solutions ✓ This involve nucleophilic attack of the side chain amino group of one molecule on the ß-lactam carbonyl carbon atom of a second molecule and so on. ✓ Polymeric impurities in ampicillin dosage forms have been implicated as possible antigenic determinants. To be continued Part 2 B-lactam Antibiotics Cephalosporins