Antibacterial agents & Related Drugs_023621.pptx

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1. ANTIBACTERIAL AGENTS & RELATED DRUGS

2. ANTIBIOTICS 6/24/2024 Monas K. 2 Are drugs that either destroy bacteria or prevent their reproduction Antibiotics that kill bacteria are called “ bactericidal ” The ones that stop the growth of bacteria are called “ bacteriostatic ” They can be produced from a living microorganism (Natural), semisynthetic or synthetic derivatives

3. ANTIBIOTICS cont. 6/24/2024 Monas K. 3 The antibiotic age began in the late 1920s when Alexander Fleming saw that the mold, penicillium, inhibiting bacterial growth Many antibiotic compounds used in modern medicine are produced and isolated from living organisms , such as The penicillin class produced by fungi in the genus penicillium Streptomycin from bacteria of the genus streptomycin

4. Classification of Antibiotics 6/24/2024 Monas K. 4 Classification Based on Activity Against Gram positive Most penicillins, erythromycin, bacitracin Against Gram negative Polymixin, colistin Broad spectrum Ampicillin, chloramphenicol, tetracyclines, cephalosporins Antitubercular Streptomycin, cycloserine Antifungal Griseofulvin, nystatin Antitumor Puromycin, dactinomycin

5. Classification of Antibiotics 6/24/2024 Monas K. 5 Classification Based on Chemical Structure β -Lactam Penicillins, cephalosporins, monobactams, carbapenems Aminoglycosides : Streptomycin, kanamycin, neomycin Fused rings : Tetracyclines, griseofulvin Macrolide : Erythromycin, oleandomycin Polypeptide : Actinomycin, bacitracin, polymixin Polyene : Nystatin, amphotericin B Unclassified : Chloramphenicol, cycloserine

6. β -Lactam Antibiotics 6/24/2024 Monas K. 6

7. β - Lactam Antibiotics 6/24/2024 Monas K. 7 All β -lactam antibiotics have a Four membered ring structure (the β -lactam ring) Fused with 5- or 6- membered heterocyclic ring except monobactams They act by interfering with penicillin binding proteins (PBP) e nzymes involved in the synthesis and maintenance of peptidoglycan The ring is very strained and the bond between the carbonyl and the nitrogen in the β -lactam ring is very labile and hence, makes the molecule reactive

8. β - Lactam Antibiotics cont. 6/24/2024 Monas K. 8 The group of antibiotics known as the β -lactams include: Penicillin’s Cephalosporin’s Monobactams and Carbapenems

9. PENICILLINS 6/24/2024 Monas K. 9 Antibiotic drugs originally isolated from Penicillium molds Some are biosynthesized or produced synthetically The term “penicillin” refers to benzyl penicillin ( penicillin G ), obtained from P.notatum Structure of Penicillins All penicillins have the same general formula and differ only in the R group

10. Structure of Penicillins 6/24/2024 Monas K. 10 The structure consists of a bicyclic system formed of a highly unstable 4-membered β -lactam ring fused to a 5-membered thiazolidine ring The penam skeleton is essential for the antibiotic activity The penam skeleton indicates that it is derived from 2 amino acids : L-cysteine and L-valine

11. NATURAL PENICILLINS 6/24/2024 Monas K. 11 Benzylpenicillin (Penicillin G) was the first antibiotic isolated from the fungus Penicillium notatum It will be taken as a prototype to discuss its biologic and chemical properties Since these led to the introduction of a variety of new penicillin molecules to medicine

12. Weakness of Benzylpenicillin (Penicillin G) Molecule 6/24/2024 Monas K. 12 Several problems limit the clinical use of penicillin G , the most important are: Acid sensitive Ineffective orally , it breaks down by the acidity of the stomach β - Lactamases sensitive Narrow spectrum Active against Gram-positive and some Gram-negative bacteria Allergic reactions Deactivation by metal ions, oxidizing and reducing agents

13. NATURAL PENICILLINS cont. 6/24/2024 Monas K. 13 Instability of Benzylpenicillin The instability of benzylpenicillin towards nucleophilic and electrophilic attacks is due to: Ring Strain In β-lactam , the N is highly strained The carbonyl becomes more electrophilic than usual and more susceptible to attack by nucleophiles

14. PENICILLINS cont. 6/24/2024 Monas K. 14 Penicillin Sensitivity to β -Lactamases

15. SAR OF Penicillin 6/24/2024 Monas K. 15 Penicillins have been well studied and scientist were able to determine the following SAR:   Position 1: When the sulfur atom of the thiazolidine ring is oxidized to a  sulfone  or sulfoxide , it improves acid stability, but decreases the activity of the agent Position 2: No substitutions allow at this position, any change will lower activity. The methyl groups are necessary Position 3: The carboxylic acid of the thiazolidine is required for activity. If it is changed to an alcohol or ester, activity is decreased Position 4: The nitrogen is a must Position 5: No substitutions allowed

16. SARs of Penicillin cont. 6/24/2024 Monas K. 16 Position   6 : Substitutions are allowed on the side chain of the amide. An electron withdrawing group added at this position will give the compound better acid stability because this substitution will make the amide oxygen less nucleophilic A bulky group added close to the ring will make the compound more resistant to   -lactamases Steric hindrance provides protect to the   -lactam ring

17. 6/24/2024 Monas K. 17 The spectrum of activity becomes broader when a polar group is added to this position allowing the compound to pass through the  porins  of the Gram negative bacteria cell wall   Position 7 : The carbonyl on the   -lactam ring is a must These structural activity relationships have helped scientist design more effective penicillins to combat many different prokaryotes

18. β-LACTAMASE INHIBITORS 6/24/2024 Monas K. 18 Clavulanic acid An Oxapenam derivative Coadministered with amoxicillin (Augmentin) Sulbactam Coadministered with ampicillin ( Unacyn ) 6,6-dibromopenicillanic acid sulfone , which on catalytic hydrogenation provided sulbactam Tazobactam Derivative of the penicillin nucleus and is a penicillanic acid sulfone Added to the extended spectrum beta-lactam antibiotic piperacillin to produce Tazocin or Zosyn or Piprataz

19. CEPHALOSPORINS 6/24/2024 Monas K. 19 The first isolated cephalosporin was cephalosporin C (1948) The structure of cephalosporin C has similarities to that of penicillin G Has a bicyclic system containing a four β -lactam ring fused with a six membered dihydrothiazine ring

20. Properties of Cephalosporin C 6/24/2024 Monas K. 20 Highly polar side chain ( Difficult to isolate & purify) Low potency (1/1000 of Pen. G) Not absorbed orally Non toxic Relatively stable to acid hydrolysis compared to penicillins More stable to penicillinase than penicillin G There is no cross penicillin allergenicity

21. SAR Relationships 6/24/2024 Monas K. 21 Saturation of the double bond leads to inactivation 2-Cephem derivatives are inactive Removal of COOH at C-4 leads to inactivation Replacement of S with O , CH 2 does not affect activity Replacement of 7 α –H by a methoxy group increases resistance against β-lactamases

22. Structure-Activity Relationships cont. 6/24/2024 Monas K. 22 The acetoxy group at C-3 is an easy leaving group It is hydrolyzed in vivo to a hydroxyl methyl group which undergoes lactonization with the adjacent 4-COOH group yielding inactive product

23. Cont’d… 6/24/2024 Monas K. 23 Replacement of the acetoxy group by a suitable non-leaving group may lead to: Increase in acid stability The drug can be administered orally Broadening of the spectrum Increase in activity against resistant strains by increasing penetration Decrease in allergenicity

24. Cont’d… 6/24/2024 Monas K. 24 The  -lactam ring is crucial to the mechanism The carboxylic acid at position 4 is important to binding The bicyclic system is important in increasing ring strain Stereochemistry is important The acetoxy substituent is important to the mechanism Possible modifications 7-Acylamino side chain 3-Acetoxymethyl side chain Extra substitution at C-7

25. Generations of Cephalosporins 6/24/2024 Monas K. 25 Cephalosporins are grouped into “ 5 generations “ Based on their time of discovery and their antimicrobial properties Each newer generation has greater Gram-negative antimicrobial activity than the preceding generation In most cases decreased Gram-positive antimicrobial activity Each newer generation shows enhanced resistance to β -lactamases Fourth generation cephalosporins considered as true broad spectrum activity

26. First Generation Cephalosporins (1960-1970) 6/24/2024 Monas K. 26 Moderate spectrum agents, not significantly active against Gram-negative organisms Poor ability to penetrate cerebrospinal fluid Inactive against Pseudomonas

27. First Generation Cephalosporins cont. 6/24/2024 Monas K. 27 Oral First Generation Cephalosporins Parenteral First Generation Cephalosporins Good for absorption but usually bad for activity

28. Second Generation Cephalosporins (1970–1980) 6/24/2024 Monas K. 28 Have greater Gram-negative spectrum and some activity against Gram-positive Cocci More resistant to β -lactamase Some drugs can pass the cerebrospinal fluid

29. Second Generation Cephalosporins cont. 6/24/2024 Monas K. 29 Parenteral Second Generation Cephalosporins Oral Second Generation Cephalosporins

30. Third Generation Cephalosporins (1980) 6/24/2024 Monas K. 30 Broader spectrum against Gram-negative organisms and less Gram-positive activity Some drugs have high activity against Pseudomonas aeruginosa Many drugs are for parenteral use Better resistance to β -lactamases

31. Third Generation Cephalosporins cont. 6/24/2024 Monas K. 31 Replacing the furan ring of the aforesaid oximinocephalosporins with an aminothiazole ring enhances the penetration of cephalosporins through the outer membrane of Gram-negative bacteria It also increase affinity for the transpeptidase enzyme As a result, third generation cephalosporins containing aminothiazole ring have a marked increase in activity against gram-negative bacteria Examples: Ceftazidime , cefotaxime, ceftizoxime and ceftriaxone

32. Third Generation Cephalosporins cont. 6/24/2024 Monas K. 32 Parenteral Third Generation Cephalosporins Ceftazidime (Fortax, Taxidime); Cefotaxime (Claforan) Ceftriaxone (Rocephin); Cefoperazone (Cefobid)

33. Third Generation Cephalosporins cont. 6/24/2024 Monas K. 33 Oral Third Generation Cephalosporins Cefixime (Suprax) Cefpodoxime (Vantin, Orelox) Cefpodoxime Proxetil A cephalosporin prodrug esters on the 4-carboxylic group

34. Fourth Generation Cephalosporins 6/24/2024 Monas K. 34 They are zwitter ions that can penetrate the outer membrane of Gram-negative bacteria They have a greater resistance to beta-lactamases than the third-generation cephalosporins Many can cross the blood-brain barrier and are effective in meningitis They are also used against Pseudomonas aeruginosa Example:-Cefepime (Maxipime, Axepin, Cepimex, Neomed, Maxcef); Cefpirome (Cefir, Cefrom, Broact)

35. Fourth Generation Cephalosporins cont. 6/24/2024 Monas K. 35 Cefepime hydrochloride is a semi-synthetic, broad spectrum, cephalosporin antibiotic for parenteral administration

36. 6/24/2024 Monas K. 36

37. Fifth generation’ Cephalosporins 6/24/2024 Monas K. 37 Ceftaroline Active against Methicillin-resistant Staphylococci aureus (MRSA) Ceftobiprole Approved in Canada and EU

38. Reading Assignment 6/24/2024 Monas K. 38 Aminoglycosides

39. Tetracyclines 6/24/2024 Monas K. 39 They are a family of broad spectrum antibiotics Some tetracyclines are obtained Naturally from Streptomyces species Others are semisynthetically prepared Basic system octahydronaphthacene with annulated 6– membered ring group named -“ Tetracyclic system ’’ Nomenclature: 1,4,4a,5,5a,6,11,12a-Octahydronaphthacene

40. Contraindications of Tetracyclines 6/24/2024 Monas K. 40 Tetracyclines are contraindicated to children It react with calcium of newly forming bones and teeth Yielding tetracycline-calcium phosphate complexes Disposition in teeth causes yellow discoloration that darkens over time Tetracyclines are contraindicated to pregnant or lactating mothers Since they cross the placental barrier into the fetus and distribute into milk of lactating mothers

41. Mechanism of Action of Tetracyclines 6/24/2024 Monas K. 41 They are specific inhibitors of bacterial protein synthesis They bind to a ribosomal subunit (30S) Preventing the aminoacyl tRNA from binding to its site on the ribosomal subunit leading to termination of the peptide chain growth Both tetracyclines and the aminoacyl tRNA binding procedures require magnesium ions

42. Structure of Semisynthetic Tetracyclines 6/24/2024 Monas K. 42 They are highly stable towards acids and bases Doxycycline is the tetracycline of choice because it causes Fewer gastrointestinal disturbances and not participating in degradation process due to absence of 6-hydroxy group Minocyclin e is primarily used to treat acne and other skin infections Sancycline : the structure is the minimal requirement for activity

43. SAR 6/24/2024 Monas K. 43 The 4 fused rings are essential for the activity The 4-dimethylamino group is essential for activity & must have α -orientation Removal of the 6-OH group leads to increase in stability and no change in activity Removal of the 6-CH 3 group leads to no change in activity Conjugation between C-10 to C-12 is essential for biological activity

44. SARs of Tetracyclines cont. 6/24/2024 Monas K. 44 A 7-C l (as in Demeclocycline) or a 7-N(CH 3 ) 2 (as in Minocycline) increases activity Replacement of amino at C-2 with other functions, such as aldehyde or nitrile reduces or abolishes activity A ( Cis –A/B ring fusion with a  -hydroxyl) group at C-12 is essential Esters of 12a-OH is active, except formyl ester Alkylation at C-11a leads to inactive compound

45. Macrolides 6/24/2024 Monas K. 45 Macrolides are a group of closely related antibiotics produced by Streptomyces Have three common chemical characteristics A large lactone ring (so termed as macrolide antibiotics ) ketone group Usually the lactone ring has 12, 14 or 16 atom in it and often unsaturated with olefinic group conjugated with ketone function The most common drugs have 14 atoms A glycosidically linked amino sugar (Usually cladinose & Desosamine) Dimethyl amino group on sugar moiety, base that form salt (p ka =6-9)

46. Macrolides cont. 6/24/2024 Monas K. 46 The clinically used drugs of this group are: erythromycins, clarithromycin, azithromycin, oleandomycin, spiramycin, leucomycins and josamycin They usually have 2 sugars attached to the ring One sugar of them carries a substituted amino group So these drugs are weakly basic and form salts with acids The macrolides are chemically unstable in acid due to the formation of inactive internal cyclic ketal The 6-OH group is essential to the process, and is initiated by protons (H + ) It is one of the causes of intestinal cramping that is encountered with macrolide use

47. Macrolides cont. 6/24/2024 Monas K. 47 Antimicrobial Activity They have a narrow antibacterial spectrum of activity They are often used for the treatment of upper and lower respiratory tract infections caused by Gram-positive microorganisms and Are also used in some sexually transmitted disease as gonorrhea Some derivatives induce the stimulation of gastrin production resulting in hyperperistalsis This causes gastrointestinal cramps in some patients

48. Macrolides cont. 6/24/2024 Monas K. 48 Mechanism of Action They inhibit bacteria by interfering with programmed ribosomal protein biosynthesis Resistance Resistant bacteria possess “ R-factor enzymes ”, which can methylate a guanine residue on their own ribosomal RNA Making them less efficient at protein synthesis and inhibit binding to some 14-membered ring macrolides and azalides But not 16-membered ring macrolides or ketolides macrolides

49. 14-Membered Ring Macrolides 6/24/2024 Monas K. 49 Includes : Erythromycin A , Clarithromycin , Troleandomycin, Oleandomycin Erythromycin A Erythromycin is a complex of 6 components (A-F) and is produced from Saccharopolyspora erythraea Erythromycin A is only clinically used and is available for oral administration

50. 14-Membered Ring Macrolides cont. 6/24/2024 Monas K. 50 Clarithromycin A semisynthetic derivative of erythromycin A converting the 6-OH group to a -OCH 3 group, thus preventing internal ketal formation through this group Conversion to the 6-OCH 3 leads to better blood levels and better absorption Internal ketalization and inactivation may occur b/n 9-keto group and 12-OH group Clarithromycin is associated with less gastric upset

51. 15-Membered Ring Macrolides 6/24/2024 Monas K. 51 Azithromycin (An azalide) Semisynthetic derivative of erythromycin prepared by removal of “O” on C-9 and a ring expansion by inserting an N-CH 3 group between C-9 and C-10 , and given the number 9a More stable to acid degradation (lacks 9-keto function) than erythromycin

52. 15-Membered Ring Macrolides cont. 6/24/2024 Monas K. 52 Azithromycin (An azalide) Has long half-life due to great tissue penetration, thus allowing once-a-day dosage Has higher activity against Gram negative organisms than erythromycin and clarithromycin The drug should be taken on an empty stomach 16-Membered Ring Macrolides Includes: Spiramycin, Leucomycins, Josamycin

53. Sulphonamides & Related Drugs 6/24/2024 Monas K. 53

54. Sulfonamides and folate reductase inhibitors 6/24/2024 Monas K. 54 General structure The general term “ sulphonamide “ has been used for derivatives of p-aminobenzene sulphonamide ( sulfanilamide , R=H) Whereas specific compounds are described as N1- or N4-substituted sulfanilamides depending on whether the substitution is on the amido or aromatic amino group , respectively

55. Sulfonamides (Sulphonamides) 6/24/2024 Monas K. 55 Group of related compounds collectively called sulfa drugs Inhibit growth of Gram-positive and Gram-negative organisms Through competitive inhibition of enzyme that aids in production of folic acid Structurally similar to para-aminobenzoic acid (PABA) PABA is a substrate in folic acid pathway Human cells lack specific enzyme in folic acid pathway Basis for selective toxicity Develop resistance due to plasmid codes for enzyme that has lower affinity to drug

56. Trimethoprim 6/24/2024 Monas K. 56 Inhibits folic acid production interferes with activity of enzyme following enzyme inhibited by sulfonamides Often used synergistically with sulfonamide Does not have high affinity for the malaria protozoan’s folate reductase , but it does have high affinity for bacterial folate reductase However, it also has some affinity for the mammalian folate reductase, which cause toxicity

57. Discovery of sulphonamides 6/24/2024 Monas K. 57 The antibacterial activity of sulphonamides was first discovered by the observation that Azo dye prontosil caused remarkable cure of Streptococcal infections of mice However, Prontosil was inactive on bacterial cultures Prontosil is inactive in vitro , but has excellent activity in vivo Confirmed that sulphonamide portion of prontosil is the responsible for the observed antibacterial action

58. . Mode of Action 6/24/2024 Monas K. 58 Folic acid is essential for the growth of many bacteria PABA is essential for the synthesis of folic acid Sulfonamides are PABA analogs and thus competitively inhibit the dihydropteroate synthetase Preventing the addition of PABA to pteridine diphosphate and blocking the net biosynthesis of folate coenzyme This action arrests the bacterial growth and cell division , which are bacteriostatic

59. Classification of Sulphonamides 6/24/2024 Monas K. 59 Systemic sulfonamides Intestinal sulfonamides Sulfonamides for ophthalmic infections & Topical sulfonamides for burn therapy

60. Structure Activity Relationships (SAR) 6/24/2024 Monas K. 60 R’ =H or acyl The SO 2 group must attach to the benzene ring The para nitrogen (N 4 ) is required for activity and must be a free amino group However, prodrugs are available which must be converted to the free amine for activity Major route of metabolism is acetylation of N 4 that actually reduces water solubility The free amino group is essential for activity , if it is replaced by groups which can be converted in vivo to free amino group Activity is maintained in vivo but not in vitro such as NO 2 , NO , NHOH, -N=N- , NHCOR

61. Structure Activity Relationships (SAR) cont. 6/24/2024 Monas K. 61 Compounds with alkylated aromatic amino groups showed no activity If the amino group is replaced by an alkyl or alkoxy or other functional groups no activity is observed If the amino group is changed to the 2 or 3 position on the benzene ring, inactive compounds result N4 -acylation with dicarboxylic acids such as succinic acid or phthalic acid Yields sulfonamide that is not absorbed in the small intestine , but hydrolyzed in the large intestine to free sulfonamides (intestinal sulfonamides)

62. Structure Activity Relationships (SAR) cont. 6/24/2024 Monas K. 62 Substitution on the amidic nitrogen with various groups results in a wide fluctuation in activity and this is the most important type of modification that has been used in the design of antibacterial sulfonamides Substitution on the aromatic ring of the sulfonamides either Diminishes or completely destroys the activity Also replacement of the benzene ring by other ring systems decreases the activity

63. Structure Activity Relationships (SAR) cont. 6/24/2024 Monas K. 63 N 1 is acidic and must have one free H attached (cannot be tertiary) Increasing acidity (decreasing pka) Increases enzyme affinity Increases water solubility which has less risk of crystalluri a formation and shorter duration due to more renal excretion unchanged So, N 1 substituents should be electron withdrawing The more electron withdrawing the lower the pka With a pka of 10.4, the drug is mostly unionized at urinary pH and so crystalluria is a problem With a pka of 4.9, the drug is mostly ionized at urinary pH and variety of studies shown that the active form is N 1 -ionized salt

64. URINARY TRACT ANTI-INFECTIVES 6/24/2024 Monas K. 64

65. Introduction 6/24/2024 Monas K. 65 The urinary tract (UT) is an organ that produces, stores & eliminates urine In humans, it includes the Two kidneys Two ureters The urinary bladder Two sphincter muscles & The urethra Urinary tract infections (UTIs) are bacterial infections that affect any part of the urinary tract Urinary tract anti-infectives are agents used to treat UTIs

66. Introduction cont. 6/24/2024 Monas K. 66 UT anti-infectives generally fail to achieve adequate concentrations in the plasma or tissues for the treatment of systemic infections following oral or parenteral administrations They are concentrated in urine & are effective for eradicating UTIs A number of compounds (drugs) used as urinary tract anti-infectives

67. Quinolones 6/24/2024 Monas K. 67 Are a family of broad spectrum antibiotics Comprises a group of synthetic substance possessing in common an N-1-alkylated-3-carboxy pyrid-4-one ring fused to another aromatic rings The parent of the group is Nalidixic acid The first quinolone to be marketed in 1965 Primarily reserved for oral treatment of uncomplicated UTIs caused by susceptible micro-organisms usually Escherichia coli Useful in the treatment of UTIs in which gram negative bacteria predominate

68. Quinolones cont. 6/24/2024 Monas K. 68 Isosteric heterocyclic groupings in this class includes the Quinolone s e.g. ( Norfloxacin, Ciprofloxacin ) Naphthyridines ( Nalidixic acid and Enoxacin ) and Cinnolines (e.g. Cinoxacin ) Analog design of nalidixic acid lead first generation quinolones: Oxolinic acid, cinoxacin & enoxacin but are not popular today

69. Quinolones cont. 6/24/2024 Monas K. 69 Mechanism of Action Quinolones and fluoroquinolones are bactericidal agents , actively killing bacteria Quinolones inhibit the bacterial DNA gyrase ( topoisomerase II ) There by inhibiting DNA replication and transcription DNA gyrase is an enzyme that is responsible for Introducing negative supercoils into circular duplex DNA Facilitates unwinding & thereby allowing transcription & replication to occur In many cases, bacterial strains that have developed resistance to other antibacterial antibiotics , such as Penicillin resistant Gonococcus Methicillin resistant S. aureus , and Aminoglycoside resistant P. aeruginosa Are susceptible to the quinolones

70. Structure Activity Relationships of Fluoroquinolones 6/24/2024 Monas K. 70 The 1, 4-dihydro-4-oxo pyridine -3-carboxylic acid moiety is essential for antibacterial activities The pyridone system must be annulated with aromatic ring Alteration of 3-COOH group produce compounds with decreased activity Quinolones bind to the DNA gyrase via carboxyl group at position-3 in quinolone ring Isosteric replacement of nitrogen for carbon atoms at position 2 (cinnolines) 5 (1,5 – naphthyridines) 6 (1, 6 naphthyridines) 8 (1, 8 naphthyridines) Are consistent with retention of activity Fluorine atom at position 6 is associated with significantly enhanced antibacterial activity

71. SARs of Fluoroquinolones cont. 6/24/2024 Monas K. 71 Alkyl substitution at position 1 (R2) is essential for activity Lower alkyl (methyl, ethyl, cyclopropyl) compounds possess progressively greater potency Aryl substitution retains antibacterial activity ( 2,4-difluorophenyl group is optimal ) Position 5,6,7 (esp.) & 8 of the annulated ring may be substituted with good effect E.g. Piperazinyl & 3-aminopyrrolidinyl substitutions at position 7 enhanced activity against P. aeruginosa Ring condensation at 1,8; 5,6; 6,7; & 7,8 position leads to active compounds E.g. Ofloxacin- an alternative to ciprofloxacin

72. SARs of Fluoroquinolones cont. 6/24/2024 Monas K. 72 Addition of fluorine atom at position 6 enhances DNA gyrase inhibitory activity & furthermore, extends activity against Staphylococci & Piperazine group at position 7 extends antibacterial activity against Staphylococci & P. aeruginosa E.g. Ciprofloxacin Additional fluorine atom at position 8 provides better absorption & longer half-life (Decreases rate of degradation) E.g. Lomefloxacin

73. SARs of Fluoroquinolones cont. 6/24/2024 Monas K. 73 Substitution of methyl group for piperazine group results in better absorption & longer half-life E.g. Lomefloxacin & Sparfloxacin Addition of cyclopropyl group at N-1, amino group at C-5 & Fluorine at C-8 extends spectrum against Mycoplasma & Chlamydia E.g. Sparfloxacin

74. Other Urinary Tract Anti- Infectives 6/24/2024 Monas K. 74 Nitrofurans Are the first nitro heterocyclic compounds to be introduced into chemotherapy The nitrofurans are derivatives of 5-nitro-2-furaldehyde formed on a reaction with appropriate hydrazine or amine derivative Antimicrobial activity is present only when the nitrogen is in the 5- position Mechanism of action Nitrofurans inhibit microbial DNA synthesis It has broad-spectrum of activity against G + and G  bacteria but it is not effective against fungi Nitrofurantoin Active against many G + & G - UT pathogens Antibacterial activity is higher in acidic urine

75. Methenamine and its salts 6/24/2024 Monas K. 75 Methenamine The activity of methenamine depends on the liberation of formaldehyde Methenamine is used internally as a urinary antiseptic for treatment of chronic urinary tract infections The free base has practically no bacteriostatic power so formaldehyde release at the lower P H of the kidney is required  

76. Urinary Analgesics 6/24/2024 Monas K. 76 Pain and discomfort frequently accompany bacterial infections of the urinary tract For this reason, certain analgesic agents, such as salicylates or phenazopyridine , which concentrate in urine because of their water solubility properties, are combined with urinary tract anti-infectives Phenazopyridine It is used as a local analgesic on the mucosa of UTs

77. Thank You 6/24/2024 Monas K. 77