Urinary Tract Anti-infective agents.pptx

A urinary tract infection (UTI) is an infection in any part of the urinary system - kidney, ureters, bladder and urethra.
It is defined as the presence of at least 1 lakh bacteria per ml of urine (normal bacterial count=1000 per ml of urine).
Most infections involve the lower urinary tract the bladder and the urethra.
It is a common disorder at all ages in both males and females.

1. Urinary Tract Anti-infective agents (Quinolones) Mr. S Maheen Abdul Rahman, M. Pharm. Assistant Professor Department of Pharmaceutical Chemistry PA College of Pharmacy (PACP) Mangalore, Karnataka.

2. A urinary tract infection (UTI) is an infection in any part of the urinary system - kidney, ureters, bladder and urethra. It is defined as the presence of at least 1 lakh bacteria per ml of urine (normal bacterial count=1000 per ml of urine). Most infections involve the lower urinary tract the bladder and the urethra . It is a common disorder at all ages in both males and females . urinary tract infection

3. UTI is the 2 nd most common infections present in community practices. World wide, about 150 million people are diagnosed with UTI each year. Prevalence: 35% of healthy women suffer symptoms of UTI at some time in their life.

4. The causative organism causing UTI are:- E.Coli , Pseudomonas aeruginosa, Streptococcus faecalis, Staphylococcus epidermis and Proteus mirabilis. Sexual transmitted diseases [ STD ] like gonorrhea causes urethritis Presence of tumor/ stones/ foreign bodies in the urinary tract.

5. In many cases, bacteria first travel to the urethra . When bacteria multiply, an infection can occur. An infection limited to the urethra is called urethritis . If bacteria move to the bladder and multiply, a bladder infection, is called cystitis . If the infection is not treated promptly, bacteria may then travel further up the ureters to multiply and infect the kidneys . A kidney infection is called pyelonephritis .

6. Quinolone Antibacterials Quinolones constitute a large class of synthetic antimicrobial agents that are highly effective in the treatment of many types of infectious diseases, particularly those caused by bacteria . Quinolones are potent, broad-spectrum antibacterial agents . The early congeners (nonfluorinated at the C-6 position, such as nalidixic acid ) were limited to certain gram-negative infections , such as urinary tract infections.

7. However, the modern generation of fluoroquinolones, containing C-6 fluoro substituent and a cyclic basic amine moiety at the C-7 position, surpasses their predecessors in terms of the spectrum of activity and potency . This has allowed for their use against a variety of gram-negative as well as some gram-positive pathogens.

8. Classification of QUINOLONE DERIVATIVES 1. Quinolones

9. Miscellaneous 2. Nitrofurans: Nitrofurazone, Nitrofurantoin, Furazolidone Furazolidone Nitrofurantoin Nitrofurantoin is an antibiotic that fights bacteria. It is used to treat and prevent uncomplicated urinary tract infections Methenamine Furazolidone is an antibacterial and protozoal medication that is used to treat diarrhoea or enteritis caused by bacteria Methenamine is a drug that stops the growth of bacteria in urine. It is used to prevent or control returning urinary tract infections caused by certain bacteria 3. Methenamine and its salts: Methenamine, Methenamine mandelate, Methenamine hippurate.

10. Quinolones inhibit the actions of bacterial DNA gyrase enzyme ( topoisomerase II ). This enzyme is responsible for supercoiling and compacting bacterial DNA molecules into the bacterial cell during replication. Modifying the topology of DNA via supercoiling and twisting of these macromolecules to permit DNA replication or transcription. Quinolones and Fluoroquinolones, inhibit bacterial DNA gyrase and then block the bacterial DNA replication and transcription by stabilizing the complex formed between DNA and topoisomerases. Mechanism of action

11. SAR of Quinolones Substituent at N-1 position: The optimum substituents at position 1 appear to be ethyl, butyl, cyclopropyl, and difluoro phenyl , and these substituents have resulted in potent compounds . Addition of a fluorine atom into the N-1 cyclopropyl group or the 1-butyl substituent resulted in compounds with overall improved activity against gram-positive bacteria.

12. 2. C2-Position: The simple replacement of C-2 hydrogen has generally decreased the activity (except Prulifloxacin ). 3. The carboxy functions at the C-3 position: Modification of the C-3 carboxylic acid group leads to a decrease in antibacterial activity. However, the replacement of the C-3 carboxylic group with the isothiazolo group afforded the most active isothiazolo quinolone, which has been 4–10 times greater in vitro antibacterial activity.

13. 4. The C-4-oxo group of the quinolone nucleus appears to be essential for antibacterial activity. Replacement with 4-thioxo or sulphonyl group leads to a loss of activity. 5. The incorporation of a group at the C-5 position has proven beneficial in terms of antibacterial activity. The order of activity is NH 2 : CH 3 >F, H>OH, or SH, SR. 6. The incorporation of a fluorine atom at the C-6 position of the quinolone is important . The order of activity is F>Cl, Br, CH 3 >CN.

14. 7. The introduction of a piperazine moiety at the C-7 position is essential. Other amino pyrrolidines also are compatible with activity. 8. In general, a C-8 fluoro substituent offers good potency against gram-negative pathogens , while a C-8 methoxy moiety is active against gram-positive bacteria . The order of activity is F, Cl, OCH3 >H, CF3 >methyl, vinyl, propargyl.

15. Synthesis of Ciprofloxacin

16. C 2 H 5 CO Formic propionic anhydride

17. Ciprofloxacin is an antibiotic that is FDA-approved to treat urinary tract infections (UTIs) caused by certain bacteria.  It can be used to treat the following types of UTIs: Bladder infections that begin suddenly in adult females.

18. Synthesis of nitrofurantoin (Z)-1-(((5-nitrofuran-2-yl)methylene)amino)imidazolidine-2,4-dione

19. HCl/H 2 O,140 o C Cyclization + + Condensation CH 3 COOH/H 2 SO 4

20. Reference Book: An Introduction to Medicinal Chemistry by GRAHAM L. PATRICK Text book of medicinal chemistry by K. Ilango and Valentina