Medicinal Chemistry I Lecture 1 - Anti-Infective Drug PDF

1 MEDICINAL CHEMISTRY I (PC508) LECTURE 1 ANTI-INFECTIVE DRUG Pharmaceutical Chemistry Department  2 Course Specifications The current course aims at: The course h...

1 MEDICINAL CHEMISTRY I (PC508) LECTURE 1 ANTI-INFECTIVE DRUG Pharmaceutical Chemistry Department  2 Course Specifications The current course aims at: The course handles different classes of antibiotics and antimicrobials (natural and synthetic), beside other synthetic chemotherapeutic agents (including antivirals, antifungals and antiparasitic). Additionally, various anticancer therapies, steroidal hormones and related drugs are also covered. Moreover, endocrine-related drugs (Diabetes, thyroid and calcium regulating agents), antihistamines (H1, H2 blockers and anti-ulcer PPIs are also handled.  3 Course Specifications, CLO 1. Define the principles of physicochemical properties on the bioavailability and biological activities of the antimicrobial drugs and anticancer drugs. (1-1-4-1) 2. Identify the pharmacological properties of the studied agents including mechanisms of action, uses, adverse reactions, and interaction with other agents. (1-1-4-1) 3. Interpret the information about tumor cells and their hallmarks in the development of therapeutic solutions for cancer. (1-1-5-1) 4. Analyze representative drugs from different classes. (2-2-1-1) 5. Apply the pharmacopeial methods in detecting the purity of natural and synthetic materials. (2-2-1-2)  4 6. Utilize safely synthetic laboratory materials and glassware. (2-3-1-1) 7. Select the proper chemotherapeutic agent and hormones depending on the etiology and the pathophysiology of the infections/ diseases. (3-1-4-1) 8. Recommend the proper active drug to be used according to its pharmacological properties. (3-2-1-1) 9. Justify drug interactions and adverse effects of different chemotherapeutic classes and hormones. (3-2-1-1) 10. Build teamwork capabilities. (4-1-2-3)  5 Content Introduction Antimicrobial agents Antibacterial Antifungal Antiviral Anticancer agents Antihistaminic Antidiabetic  6 Medicinal chemistry It is a multifaceted discipline that encompasses synthetic organic chemistry, natural products chemistry, enzymology, chemical biology, structural biology and computational methods, all of which are aimed at the discovery and development of new therapeutic agents / Drugs.  7 Bacterial cell structure No defined nucleus. No organelles. The biochemistry of a bacterial cell is different. A cell membrane and a cell wall that protect it from lysis. Gram-negative bacteria have a thin cell wall. they have an additional outer membrane not present in Gram-positive bacteria Which is made up of lipopolysaccharides.  8 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.  9 Classification of Antimicrobials (1) According to M.O.A: inhibit cell wall, act on protein synthesis,…, etc. (2) According to spectrum of activity: Broad spectrum, narrow spectrum. (Gram negative or Gram positive or both) (3) Chemical classification: -lactams & non--lactam antibiotics.  10 The bacterial cell structure and sites for antibacterial agents:  11 What is the difference between antiseptic, disinfectants and preservatives? - For living tissues. For non-living They are agents bodies used to hinder - They are not microbial devoid of toxic -They destroy spoilage of food, effect; their the m.o. but pharmaceutical absorption may they don't preparations produce systemic necessary kill all and cosmetics in toxicity. of them. very low (FDA) - (EPA) concentration  12 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.  13 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 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 (linezolid) 14)Nalidixic acid and Quinolones  14 11. Nitrofuran derivatives Nitrofurantoin, Macrodantin Nifuroxazide,Antinal 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.  15 Uses: Nitrofurantoin, Macrodantin Nifuroxazide,Antinal Urinary tract infections that For colitis and diarrhea. were resistant to antibiotics Broad spectrum Effective against antibiotics resistant bacteria.  16 Structure Activity Relationship SAR 5-Nitro group The CH=N group in the in 5-position is 2- position is essential essential. (imine group) Replacement of furan with thiophene or pyrole →inactive compounds.  17 11. Nitrofuran derivatives Synthesis O O2N CHO + H2N N NH O 5-nitro-2- furfuraldehye O 1-amino hydantoin Nitrofurantoin  18 14) Nalidixic acid and Quinolones MOA: In gram negative: Inhibition of DNA gyrase enzyme (Inhibit negative super coiling) In gram positive: Inhibition of Topoisomerase IV – Inhibition of nicking and separation of daughter DNA strands after DNA replication (Inhibition of Decatenation) 19 20 21 22 23  24 History 1-naphthyridine-3-carboxylic acid derivatives as nalidixic acid F: better activity against G+ve, and uptake Piperazine: better pharmacokinetic property (Zwitter ion formation) 1962 1980s  25 Applications Nalidixic acid (Negram): is narrow spectrum, active against G-ve bacteria. useful in the short-term therapy of uncomplicated urinary tract infections but resistance is developed rapidly. It can be taken orally. Enoxacin: active against G-ve and G+ve bacteria. It also shows improved oral absorption, tissue distribution, and metabolic stability.  26 5 6 4 3 7 2 8 1  27 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.  28 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.  29 Norfloxacin Ciprofloxacin (Noroxin) (Ciprobay) O F COOH N N HN C2 H5 oral broad spectrum It is 100 times more active than the most Potent member. Nalidixic acid.  30 3rd Generation Sparfloxacin NH2 O 1. For lower respiratory infections (bronchitis) F COOH and bacterial gastroeneritis CH3 N N HN F 2. photosensitivity than other di-fluoro CH3 derivatives due to the presence of 5-amino group which counteracts the effect of 8-fluoro- substituent.  31 4th Generation 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.  32 Metabolism 7-methyl is converted into CH2OH (Alcoholic group) which is more active then to 7-CH2OH COOH which is inactive. active 7-COOH inactive 7- glucuronide inactive  33 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. 3- CYP450 inhibitors.  34 Exercise 35  36 Arrange according to phototoxicity? Lomifloxacin˃ sparfloxcin˃Norfloxacin  37 NH2 O F COOH CH3 N N HN F lomefloxacin CH3 sparfloxacin 38