Lecture 1 Anti-infective Agents PDF

Medicinal Chemistry I (PC 508) Lecture 1 Anti-infective Drugs by: Prof. Hanan Hanna Georgey Dr. Mai Hatem Office Hours: Monday: 10:30-12:30 Thursday: 10:30-12:30...

Medicinal Chemistry I (PC 508) Lecture 1 Anti-infective Drugs by: Prof. Hanan Hanna Georgey Dr. Mai Hatem Office Hours: Monday: 10:30-12:30 Thursday: 10:30-12:30 12 Course Calendar Week no. Content 1 Introduction to medicinal chemistry + Anti-infective agents and fluoroquinolones 2 Sulphonamides and Anticancer drugs 3 Anticancer drugs (Continue) and Group discussion activity 4 Antifungal drugs 5 Antiviral drugs 6 Hormones (Estrogen and Progestins) 7 Hormones (Androgens and Corticosteroids) and Open Discussion activity 8 B-lactams (Penicillins) B-lactams (cephalosporins) ,Antibiotics affecting protein synthesis (Tetracyclines + 9 Aminoglycosides) and Think-Pair Share activity Antibiotics affecting protein synthesis (Macrolides + Chloramphenicol+ fusidic acid) 10 Educational cooperation and Open Discussion activity 11 Autonomic nervous system 12 Revision 13 Chemotherapy Chemicals used for the treatment or the control of diseases caused by pathogenic invading organisms or cells. Antimicrobial Agents ◦Antibiotics: Chemical compounds produced by a living m.o. to defend itself against other m.o. by inhibiting their life process. ◦ Synthetic Antibacterial agents: Fully synthetic compounds that act against bacteria but they are not antibiotics. 14  What is the difference between antiseptic, disinfectants and preservatives? For living tissues. For non living They are agents - They are not bodies used to hinder devoid of toxic -They destroy the microbial spoilage effect; their m.o. but they don't of food, absorption may necessary kill all of pharmaceutical produce systemic them. preparations and toxicity. [Food and [Environmental cosmetics in very Drug Administration Protection Agency) low concentration (FDA)] (EPA)] 15  Biochemical target for anti-infective agents: Inhibition of nucleic acid synthesis. Inhibition of bacterial cell wall synthesis. Alteration of cell membrane permeability or inhibition of active transport across cell membranes. Inhibition of protein synthesis All the antibacterial targets are applied. 16 Classification: 1)Alcohols (70% ethyl alcohol) 2) Phenols Chloroxylenol (dettol) 3)Aldehydes 4)Acids 5)Halogen containing compounds (I, Cl) 6)Oxidizing agents 7)Mercury compounds (Merbromine) 8)Silver salts 9)Medicinal dyes (crystal violet should be dissolved in alcohol) 10)Cationic surfactants 11)Nitrofuran derivatives 12)Esters of p-hydroxybenzoic acid (Parabens) 13)Oxazolidinones (linzolid) 14)Nalidixic acid and Quinolones 17 Formaldehyde solution Methenamine or Hexamine HCHO (CH2)6N4 They cause direct non specific Alkylation of nucleophilic functional groups such as NH2, OH or SH of proteins and nucleic acids. RXH + HCHO → RXCH2OH (X = N, O and S). It is a Prodrug releasing HCHO in acid medium So it is given with urinary acidifier like NH4Cl 18  Uses Methanamine Formaldehyde It is used internally as urinary tract Germicidal. antiseptic. The use of urotropine The gas used to mandalate because it has its own acidity. disinfect rooms, instruments and Resistance: clothes. urease enzyme From bacteria Urea ammonia Thus, pH increases. This problem can be overcome by the co-administration of a urease inhibitor [Acetohydroxamic acid ]CH3-CO-NHOH 19  The role of each one is_____ Hexamine Ammonium chloride Acetohydroxamic acid 20 Used as disinfectant 21  It releases the hypochlorous acid (HOCl) when dissolved in water especially in presence of acid. It is an oxidizing agent that destroy the DNA structure. It is slightly soluble in water and very soluble in alkaline solution. Sodium salt is used to disinfect drinking water. 22  2% I2 with 2.5% NaI (as solubilizing N O. I2 agent) in 50% alcohol. Soluble in water. CH CH2 n They inactivate proteins by Iodination of phenyl alanine and tyrosine residues of protein and oxidation of SH group (sulfhydryl gp). releases iodine slowly, non-toxic, less irritant, Irritation , staining toxicity. non-volatile (stable) & less staining. good penetration into the damaged tissues. Used locally as bactericidal and fungicidal. used as antiseptic to damage skin. vaginal antiseptic. Aqueous solution : Skin antiseptic 23  Hydrogen Peroxide (H2O2) KMNO4 It causes denaturation of the It causes denaturation of the protein protein by direct oxidant action by liberation of oxygen in the tissues - The effervescent action of oxygen dislodges foreign material. The effectiveness is somewhat limited by their poor penetration into the tissues 24 Nifuroxazide, Antinal For colitis and diarrhea. Broad spectrum Effective against antibiotics resistant bacteria. Nitro group is reduced to hydroxyl amine then to amino group. They produce (ROS) lead to destruction of DNA and proteins. -They block the conversion of pyruvic acid to acetyl CoA →energy production in bacteria is diminished. They block the energy transfer by the organism required for the cell division. - They inhibit bacterial respiratory enzymes. 25 SAR 5-Nitro group The CH=N in 5-position is group in the 2- essential. Replacement of furan position is with thiophene or essential pyrole →inactive compounds. Synthesis 26  MOA- In gram negative – Inhibition of DNA gyrase enzyme (Topoisomerase II) responsible for the relaxation of supercoiling. In gram positive – Inhibition of Topoisomerase IV responsible for the relaxation of supercoiling. Why did human cells are not affected ? What is the side effect of quinolone? 27 30 31 32 33  MOA- In gram negative – Inhibition of DNA gyrase enzyme (Topoisomerase II) responsible for the relaxation of supercoiling. In gram positive – Inhibition of Topoisomerase IV responsible for the relaxation of supercoiling. Why did human cells are not affected ? What is the side effect of quinolone? 34  Quinolones & fluoroquinolones History: 1-naphthyridine-3-carboxylic acid derivatives as nalidixic acid F: better activity against G+ve, and uptake 1980s 1962 35 2D and 3D drawings of Ciprofloxacin in the active sites of DNA gyrase. 36  1,4-Dihydro-4-oxo-3- Must be pyridine carboxylic acid aromatic with or is essential for activity. without N 6 5 4 3 Reduction of 2,3-double 7 2 bond →↓Inactive 1 8 Position2: If N → Still active. Position1: Any other Alkyl substitution with lower alkyl group(methyl substitution→↓activity. or cyclopropyl) is essential for activity. Aromatic Substitution gives active compound especially 2,4-difluorophenyl group which is optimum for activity  Substitution with amino decrease phototoxicity Substitution with F → ↑ Activity 6 5 4 3 Position7: 7 2 Piperazine → ↑ Activity & broadens 8 1 spectrum # G-ve BUT → ↑ affinity to GABA receptor (blockade of these Substitution with F at position 8 cause receptors) leading to CNS side effects phototoxicity Replacement of the nitrogen at (convulsions). position 8 with carbon r →↓ adverse reactions and ↑ activity against S. aureus. Adding of methyl or ethyl to piperazine or placing bulky group on N1 →↓ GABA receptor binding SAR Summary 1. Fluoro at position 6 increase activity. 2. Fluoro at position 8 causes phototoxicity. 3. Amino at position 5 prevents phototoxicity. 4. Substitution on N-piperazine prevent CNS side effect. 5. Lipophilicity increase bioavailability. 6. Introduction of a cyclopropyl substituent at position-1 further increases broad-spectrum activity 7. Replacement of the nitrogen at position 8 with carbon reduces adverse reactions and increased activity against S. aureus. 39 2nd Generation fluoroquinolones: They are used mainly for UTI and infections resistant to other antibacterials. Advatange over 1st generation: Excellent and broad antibacterial activity. Fewer side effects when compared to nalidixic acid. Low ability for inducing bacterial resistance. 40 2nd Generation fluoroquinolones: Ciprofloxacin Norfloxacin (Ciprobay) (Noroxin) O F COOH N N HN C2 H 5 the most Potent member. oral broad spectrum It is 100 times more active than Nalidixic acid. 41 3rd Generation fluoroquinolones: Sparfloxacin NH2 O 1. For lower respiratory infections (bronchitis) and bacterial gastroeneritis F COOH 2. photosensitivity than other di-fluoro derivatives due to the presence of 5- CH3 N N amino group which counteracts the effect HN F of 8-fluoro-substituent. 3. Single dose against streptococci. CH3 42 Trovafloxacin (Trovan®) 1. Reports of liver toxicity and pancreatitis →limited use to people with potentially life- threatening infections treated in hospitals. 2. Against Anaerobic bacteria. 43 Incompatibilities of quinolones: 1- Chelation of polyvalent metal ions (Ca, Mg, Al & Fe) forms less water-soluble complexes with low potency. Therefore, it is contraindicated to co-administer antacids, hematinics, tonics and consumption of dairy products soon after quinolone administration. 2- Not given to children less than 18 years old. 44 45  Exercise Arrange the following compounds in order of decreasing bioavailability NH2 O F COOH CH3 N N HN F lomefloxacin CH3 sparfloxacin 46  Antiinfective Agents Formaldehyde Methenamine Chlorine Tinc. Iodi Povidone iodine Hydrogen KMNO4 solution or Hexamine 2% I2 with Peroxide HCHO 2.5% NaI N O.I (H2O2) 2 CH CH 2 n Nifuroxazide Nalidixic acid Norfloxacin Ciprofloxacin Sparfloxacin Trovafloxacin NH2 O O F COOH F COOH CH3 N N N N HN F HN C2 H 5 CH3 48 53