156 Antibacterial agents

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3 156 Antibacterial agents prontosil

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5 158 Antibacterial agents

6 Antibacterial agents which

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8 others. Antibacterial agents which act against cell metabolism (antimetabolites) 161

9 162 Antibacterial agents MeO OMe Fig Sulfamethoxine.

10 Antibacterial agents which act against cell metabolism (antimetabolites) 163 I S NHR" O Reversible Inhibition

11 164 Antibacterial agents Fig Sulfonamide prevents PABA from binding

12 Antibacterial agents which

13 166 Antibacterial agents drug would have

14 Antibacterial agents which inhibit cell wall synthesis 167 but was actually placed above the surface of the disinfectant. It says much for Fleming's observational powers that

15 168 Antibacterial agents -CH2- R C- Acyl side chain -^- Benzyl Penicillin PEN G -O CH 2 - Phenoxymethylpenicillin PEN V

16 Antibacterial agents which inhibit cell wall synthesis

17 170 Antibacterial agents Ineffective when taken orally. Penicillin G can only be administered by injection. It is ineffective orally since it breaks down in the acid conditions of the stomach.

18 is tolerated Antibacterial agents which inhibit cell wall synthesis 171

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20 Antibacterial agents which inhibit cell wall synthesis 173 H ^S Fig Reduction

21 174 Antibacterial agents The problem of fi-lactamases became critical in 1960 when the widespread use of penicillin

22 Antibacterial agents which inhibit cell wall synthesis

23 176 Antibacterial agents Permeability barrier. It is difficult for penicillins to invade a Gram-negative bacterial cell due to the make up of the cell wall. Gram-negative bacteria have a coating on the outside of their eel wall which consists

24 Antibacterial agents which inhibit cell wall synthesis 177

25 178 Antibacterial agents H0 2C C CH 2CH 2CH 2 C NH Penicillin

26 groups Antibacterial agents which inhibit cell wall synthesis 179

27 180 R

28 Antibacterial agents which inhibit cell wall synthesis 181 probenicid slows down the rate at which penicillin is excreted by competing with it in the excretion mechanism. As a result, penicillin levels in the bloodstream are enhanced and the antibacterial activity increases a useful tactic if faced with a particularly resistant bacterium Cephalosporins Discovery and structure of cephalosporin C The second major group of (3-lactam antibiotics to be discovered were the cephalosporins.

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30 Antibacterial agents which inhibit cell wall synthesis 183 Analogues of cephalosporin C by variation of the 7-acylamino side-chain Access to analogues with varied side-chains at the 7-position initially posed a problem. Unlike penicillins,

31 184 Antibacterial agents Fig Cephalothin. CO 2 H reacted with an alcohol to give an imino ether. This product is now more susceptible

32 Antibacterial agents which inhibit cell wall synthesis 185 r\ IU H H

33 186 Antibacterial agents = CH 3 C0 2Me C0 2 Me - ttx I 3 C0 2 Me Fig Synthesis of 3-methylated cephalosporins. synthesis, which was first demonstrated by Eli Lilly, involves a ring expansion, where the five-membered thiazolidine ring in penicillin is converted to the six-membered dihydrothiazine ring

34 Antibacterial agents which inhibit cell wall synthesis

35 188 Antibacterial agents Second- and third-generation cephalosporins oximinocephalosporins Research

36 Antibacterial agents which inhibit cell wall synthesis

37 190 Antibacterial agents Fig Clavulanic acid as an irreversible mechanism based inhibitor. Plays a role in 6-lactamase < resistance Acylamino side Opposite chain ^fcsent stereochemistry OH i to penicillins H N / Carbon / H / i^^--\ H 3 C^'***', ' // ) S " N-*^/^ C0 2 Carbapenam nucleus Fig Thienamycin. Double bond leading

38 Antibacterial agents which inhibit cell wall synthesis 191 Olivanic acids The olivanic acids (e.g. MM13902) (Fig ) were isolated from strains of Streptomyces olivaceus

39 192 Antibacterial agents

40 Antibacterial agents which inhibit cell wall synthesis

41 194 Antibacterial agents [Normal Mechanism) Peptide Chain ^ c* D-Ala D-Ala COzH OH /Transpeptidase Enzyme Peptide Chain C ^ D-Ala I X X Peptide Peptide Peplide Chain Chain ^> X-D-Ala Gly [Mechanism Inhibited

42 Antibacterial agents which

43 196 Antibacterial agents L-Valine Me L-Lactate D-Valine Me NH / D ' Hyi D-Valine D-Hyi = D-Hydroxyisovaleric acid D-Hyi Fig Valinomycin. groups

44 Antibacterial agents which

45 198 Antibacterial agents L-LEU L-DAB / \ D-PHE L-DAB L-DAB L-DAB L-DAB L-THR POLYMYXIN B L-DAB C=0 I (CH 2) 4 CH-CH 3 Fig Polypeptide antibiotic. CH 2 CH 3 such as nucleosides from the cell. The drug is injected intramuscularly and is useful against Pseudomonas strains which are resistant to other antibacterial agents Antibacterial agents which impair protein synthesis Examples of such agents are the rifamycins which act against RNA, and the aminoglycosides, tetracyclines, and chloramphenicol which all act against the ribosomes. Selective toxicity

46 Antibacterial agents which impair protein synthesis

47 200 Antibacterial agents which was discovered in It is a broad-spectrum antibiotic, active against both Gram-positive and Gram-negative bacteria. Unfortunately, it does have side-effects

48 Agents which

49 202 Antibacterial agents o,co2h HN > J Cl-LCKt, HNL NALIDIXIC ACID ENOXACILIN CIPROFLOXACIN Fig Quinolones and fluoroquinolones. compounds. It is active against Gram-negative bacteria and is useful in the short-term therapy

50 Drug resistance Drug resistance With such

51 204 Antibacterial agents transferred by means of bacterial viruses (bacteriophages) leaving the resistant cell and infecting a non-resistant cell. If the plasmid brought to the infected cell contains the gene required for drug resistance, then the recipient cell will be able to use that information and gain resistance. For example, the genetic information required to synthesize (3-lactamases can be passed on in this way, rendering bacteria resistant to penicillins.

52 11- The peripheral nervous system cholinergics, anticholinergics, and anticholinesterases In Chapter 10, we discussed the medicinal chemistry of antibacterial agents and noted

53 206 The peripheral nervous system your home computer software, or perhaps trying to trace where a missing letter went, or finding the reason for the country's balance of payments deficit. However,

54 Motor nerves

55 208 The peripheral nervous system Skeletal " Muscle SOMATIC AUTONOMIC Smooth Muscle Cardiac Muscle Fig Motor nerves of the peripheral nervous system. N, Nicotinic receptor; M, muscarinic receptor. parasympathetic nerves. However, they synapse with different receptors on the target organs

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57 210 The peripheral nervous system Note that the sympathetic and parasympathetic nervous systems oppose each other in their actions and could be looked upon as a brake and an accelerator. The analogy is

58 The cholinergic system 211 I j V Acetyl Choline

59 212 The peripheral nervous system 11.6 Agonists at the cholinergic receptor One point might have occurred to the reader. If there is a lack of acetylcholine acting at

60 Agonists

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62 Agonists at the cholinergic receptor 215 RECEPTOR SITE (MUSCARINIC) Fig

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64 Agonists at the cholinergic receptor 217 but since they are ring structures, the left-hand portion of the acetylcholine molecule is

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66 Water Design of acetylcholine analogues 219

67 220 The peripheral nervous system

68 Design

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70 Antagonists

71 224 The peripheral nervous system Hyoscine ( ) Hyoscine

72 Structural analogues based Antagonists of the muscarinic cholinergic receptor 225

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74 A large variety Antagonists of the muscarinic cholinergic receptor 227

75 228 The peripheral nervous system In practice, the procedure is not always as simple as this, since the highly react electrophilic centre might react with another nucleophilic group before it reaches receptor binding site.

76 Antagonists

77 230 The peripheral nervous system pleasing that theory

78 Antagonists

79 232 The peripheral nervous system ; ^.---- Acetyl choline skeleton Atracurium Acetyl choline '^X^-^/' skeleton Fig Pancuronium and vecuronium. R = H VECURONIUM R = Me PANCURONIUM The design of atracurium (Fig ) was based on the structures of tubocurarine and suxamethonium. It is superior to both since it lacks cardiac side-effects and is rapidly broken down in blood. This rapid breakdown allows the drug to be administered as an intravenous drip. MeO, OMe MeO' Me CH:,CH2-C O (CH2)5 O C CH2 'OMe OMe 'OMe Fig MeO' Atracurium. OMe

80 drug design Other cholinergic antagonists 233

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82 Anticholinesterases

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84 Anticholinesterases

85 238 The peripheral nervous system ro ^ii 0 CH3 C O CH2CH2NMe3 '0- fn x I " *> u 0»<^1 ^\ NH CH3 C O 3 -. CH3 C j jt^ww l Stage 1 o i Senne Histidine Histidine (Nucleophile) (Base) (Acid catalyst) ROH^O Co u> i *' ^r NH StageB ^v^&v ^ CH3 - "" C^\ ^/^NH Stage O N I O

86 Anticholinesterase drugs PyrrolidineN Fig Physostigmine. Me discovered in 1864 as a product of the poisonous calabar beans from West Africa. The structure was established in 1925 (Fig ). Structure-activity relationships :

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88 Anticholinesterase drugs

89 242 The peripheral nervous system Me O

90 Anticholinesterase drugs

91 244 The peripheral nervous system Fortunately, there

92 Pralidoxime an organophosphate antidote