Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Systemic Approaches in Teaching Courses of Pharmaceutical Chemistry & Pharmaceutical Sciences By Mohamed Abdel Hamid Ismail Prof. Organic & Pharmaceutical Chemistry & DEAN OF FACULTY OF PHARMASCT AIN SHAMS UNIVERSITY Department of pharmaceutical Chemistry • This department teach : • 1) Organic Chemistry • & • 2) Pharmaceutical • (Medicinal) Chemistry • Organic Chemistry courses deals with teaching the students • 1) Naming structure • 2) Predicting method of synthesis • • 3) Predicting chemical and Physical properties of chemical structures. • Pharmaceutical Chemistry courses deals with teaching the students: • Predicting Biological Activity of any molecules (if any) • Predict chemical and biological incompatibility of drugs` combinations. • Teaching methodologies: • 1) Linear approach • 2) Systemic approach • 3) New E-learning, Self-Learning, … etc. • Linear Approach; • • In studying classes of organic chemistry, if we do the study for each of the function groups separately without making the relation between them, this will be the linear approach of teaching. • • • • • • Examples: RH -C=C CC R-X R-NH2 R-OH R-O-R` R-CHO (or R-CO-R`) –> R-COOH R-COX R-COOR` • • Systemic Approach; It is the reversible relationship of each concept with other related concepts. • Nitrile Amides Acids Acid anhydrides Esters Acid Halides • Organic Chemistry courses deals with teaching the students • 1) Naming structure • 2) Predicting method of synthesis • 3) Predicting chemical and Physical properties of chemical structures. • The best systemic way is through the reported systemic approach by clusters of combined information Systemic Aproach for alkanes (reaction & synthesis) ? ? ? ? ? ? CH3-CH2-OH Ethanol ? CH3-CH2-Br Ethyl bromide H2C=CH2 ethylene ? ? ? (1) ? (8) ?(7) CH3-CH3 ethane ? (6) HC CH Acetylene ? ? ? ? (10) ? (5) ? ? H3C-CHO Acetaldehyde ?(2) CH4 ? ? ? (4) H3C-COOH Acetic acid CH3-Br ?(9) ? (3) SYSTEMIC APPROACH FOR STUDYING ALKENES IN RELATION TO ALKANES OH H3C C CH3 H 10 ? ?? Isopropanol H3C OH H3C ?? HgOAc C H C H2 ?? Br C H2 H C 9? CH2 Allyl bromide H3C C H2 C H2 n-Propyl bromide ?? H3C C H2 Propane Isopropyl bromide 13 ? 3? 1? 7? 2? H3C C CH2 H 5? 6? 14 ? CH3 H3C OH CH2 Propylene glycol 15 H3C C H ?? CH 2 Propylene Epoxide C H Br CH2 Bromohydrine ?? O C H2 ?? OH H3C C H Br vic-Dibromide 11 ? H3C ?? ?? Br 17 ? OH C H H2 Hydroboration 12 ? Propene 16 ? B C )3 C H2 ( H3C 4? 18 ? ?? Br H3C C CH3 H OH n-propanol 8? Br n-Propyl bromide C C H2 H 2 • SYNTHESIS & IMPORTANT REACTIONS • Alkynes: From alkene by halogenation by Cl2, followed by double dehydrohaogenation with strong base (Na NH2): • N. B: To convert alkyne into alkene, we make partial hydrogenation of alkyne using Li /Ethylamine. • Alkyl halides (R-X): • Prepared by either halogenation of alkane, hydrohalogenation of alkene, or substitution of alcoholic OH by halogens. R C H2 H2 C R H2 / Ni R C H Alkene H C Dilute H2SO4 HI Cl2 / hu Cl + HCl R R Alc. KOH ( - HCl ) ( H2O / H+) OH R H2 C CH Alcohol R Alkyl halides aqeous KOH Conc H2SO4 H2 C CH R Conc. HCl • SN reactions: R R Alkane O `R C O-R R Alkyl iodide R-MgX K OH aqeous R X Ester Na C N Alkyl nitrile Na NH2 or NH3 NaSR` R NH2 Amines R OH Na I K OCOR` R C N I Alcohol K SH aqeous R SH Thioalcohol Na OR` R O-R` R S-R` Thio-ether Ether (Williamsons Synthesis of ether) • Alcohols ( R-OH ) & Amines ( R-NH2 ): • Alcohols are prepared:From alkene by hydration, 2) From alkyl halide by SN using aqueous NaOH, 3) From aldehydes or ketones by reduction using NaBH4 or Li Al H4. & 4) From Acids or esters by reduction using Li Al H4. • * Amines are prepared from alkyl halides using NH3 or NaNH2. • * Amines could be converted to alcohols by nitrous acid (HNO2) + HX CH3-CH2-X alc. KOH Ethyl halide Na NH2 CH3-CH2-NH2 Ethyl amine CH2=CH2 Conc HX Na OH aqueous HNO 2 N2 + H2O ethene Conc H2SO4 H2O/H+ CH3-CH2-OH Ethanol Aldehyde (R-CHO) , Ketones (R-CO-R: • • • Aldehydes are prepared by oxidation of 1ry alcohol using selective weak oxidizing agent; (Cr2O3 in the presence of pyridine (Cr2O3 / Py). * Aldehydes can undergo further oxidization by KMnO4 into Carboxylic acid. * The reverse pass ways is by lithium tritertbutoxyaluminium hydride CH3-CH2-OH CrO3 / py O CH3-CH Acetaldehyde Na BH4 or LiAlH4 Ethanol Li AlH4 KMnO4 KMnO4 Li [(But-O)3Al H] Lithium Tri-tert-butox-aluminium Hydride (selective to Reduce acid into aldehyde) CH3-COOH Acetic acid • Acids Synthesis: O C CH3-CH2-MgX Grignard reagent Mg O O - 40 C carboxylation CH3-CH2-C-O-MgX HX (ASCENDING) CH3-CH2-X KC N Ethyl halide ASCENDING aqueous KOH (SN2) CH3-CH2-OH O CH3-CH2-C N Propion-nitrile (Ethyl cyanide) KMnO 4 ( NO ASCENDING ) H2O H2SO4 CH3-CH2-C-OH Propionic acid CH3-COOH Acetic acid • Acids derivatives: O CH3-CH2-C O Conc H3PO4 H2O CH3-CH2-C R-OH O O CH3-CH2-C-OH Propionic Acid H2O NH3 Propionic Acid Anhydride O R--OH / H SO 2 4 H2O / dil H2SO4 CH3-CH2-C-O-R NH3 Alkyl propionate ester R-OH PCl5 or SOCl2 O CH3-CH2-C-NH2 Propionaamide NH3 + H2O/H O CH3-CH2-C-Cl Acid Chloride H2O/H+ • Best wishes from Dr Mohamed. A. H. Ismail Systemic Approach in Aromatic Chemistry • Pharmaceutical Chemistry courses deals with teaching the students: • Predicting Biological Activity of any molecules (if any) • Predict chemical and biological incompatibility of drugs combinations. • The best systemic way is through • Structure Activity Relation-ship • (SAR) Summary of SAR for NALIDIXIC ACID & other quinolones as anti-infective TOPOISOMERASE ENZYME INHIBITION 4-One armomatic with or without N isoster at 5,6,7,or 8 O 5 Substitution by Florine 6 7 Ring fusion Substitution by alkyl, piperazines or bicyclic amines COOH 3-Carboxylic acid 4 1,4-dihydro 8 1 N Ring fusion Z (CH, or N) Alkyl Substitution by methyl, ethyl or cyclopropyl 5) OFLOXACIN (Tarivid) & 6) Levofloxacin (Tavanic) • Tarivid is racemic Tavanic is levo O COOH F N N H3C N O CH3 H Other recently introduced quinolones (novel ME-TOO DRUGS): • SPARFLOXACIN (Zagam), MOXIFLOXACIN (Avelox) & GATIFLOXACIN (Tequin) NH2 O NH2 O COOH F H3C HN F COOH F N N N HN OCH3 Moxifloxacin (Avelox) COOH F N H3C Sparfloxacin (Zegam) NH2 O N N HN OCH3 H3C Gatifloxacin (Tequin) Chemical Incompatabilities to quinolones • The quinolones chelate with heavy metals like (Ca2+, Mg2+, Al+, and Fe2+ to form less water-soluble complexes and thereby lose considerable potency. • So, these drugs are contra-indicated with Ca, Mg, Fe nutitions • The Metal Chelates M O O F O N R1 N N M = Ca, Mg, Al, Fe, R2 Metal Complex with Quinolones SARs for the substituted barbiturates CNS depressants • 1) At C-5 : both hydrogen must be substituted • 2) Introduction of polar groups (like OH, NH2, CO, COOH, SO3H, …etc., at the alkyl substituents destroy potency. • 3) Replacement of one oxygen by sulfur increases lipid solubility and increase rate of reaching to the brain O 6 R1 N 2 5 R2 R3 1 4 O 3 NH O 1,5,5-trisubstituted Barbiturate THE VITAMIN Ks Naphtho-quinones; The term vitamin K (Koagulation-Vitamin) O O 3 O phytonadione (Vitamin K1) O n, =1-12 O Menaquinone (Vitamin K2) O Menadione (Vitamin K3) SAR for Antihemorrhagic activity of Vitamin Ks • . : R= OH, CO, OCH3, OC2H5, OAc, R`=CH3 R R` Ring A= aromatic or dihydro aromatic A B R``=H, SO3H, NMe2, alkyl gp containing 10 Carbon, with unasturation at beta or gama position R`` Ring B= aromatic or dihydro aromatic R``` R```= H, OH, NH2, CO, OCH3, OC2CH5, OAc NICOTINAMID • . O NH2 Nicotinamide (Niacinamide) • Biologically, nicotinamide is present in the building block of the coenzyme II (called: Nicotinamide-Adenine DinucleotidePhosphate (NADP) which is responsible for biological REDOX system. • NADP / NADPH system H2N CONH 2 N O N N N P O HO 1)When R= H: O O OR O O P N O O O HO OH [ Nucleotide Adenine Dinucleotide (NAD+)] 2) When R= PO3- [Nucleotide Adenine Dinucleotidephosphate (NADP+)] • Biological REDOX reactions. c a H CON H2 CON H2 H O C + + N N O-H b Substrate • H NADP H Ribose Conenzym e I (NAD+) Oxidized Product Ribose Reduc ed Coenzym e I (NADH+) NADPH Nicotinic acid, ( Vitamine B3) O • 3-pyridine carboxylic acid OH N Nicotinic acid • Serious deficiency of niacin or tryptophan may lead to pellagra (from the Italian, pelle agra, for rough skin). 6) Pyridoxine Hydrochloride vitamin B6 • . OH HO H3C OH N Pyridoxine O NH2 HO H3C OH N Pyridoxamine H HO H3C OH N Pyridoxal RIBOFLAVIN (VITAMIN B2) OH HO • . HO HO H N N O NH N Riboflavin O • It Accelerate REDOX reactions of NAD/NADH R N R N O N H N O NAD+ NADH+ N Oxidized form O NH N H O Reduced form NH + ANTIOXIDANTS Highly conjugated double bonds, Electron rich molecules Anti-oxidants are those molecules which can quench free radical in the body and thus stop AGING Mechanism of quenching Free Radicals by conjugated systems: R + Conjugated drugs RO Reactive Free Radical R R OR Stable Free Radical by resonance and so it is inert and cannot attack protein,DNA or Lipids OR etc.. • • • • Electron rich molecules like: 1) Phenols, 2) Amines, 3) Alcohols or 4) Thiols They can trap and detoxify the free radicals by supplying electrons and forming stable radicals. O OH O O + ROH + RO R Reactive Free Radical R R R R R Stable unreactive Free radical R R IMPORTANT EXAMPLES OF ANTIOXIDANT THERAPIES Vitamine E O HO Tocopherol OH O HO HO O OH Vitamine C 1 6 HS 8 COOH 2 SH Lipoic Acid OH Vitamine A Carotein Lycopene (Derieved from tomatoes) OH O O O CO-ENZYME Q 10 • Computer Aided Drug Design •& • Molecular Modeling • As a systemic method of drug discovery Hypothesis Generation of the binding sites of Receptors and use for compare fit with data base molecules to predict their activity Comparison of the hypothesis with the following Data Base spreadsheet : Results of COMPARE / FIT searching of the hypothesis of methotrexate with the data base. Displaying the fitting Compare fitting of data base compounds with methotrexate hypothesis If the features of a Molecule could fit part of the cavity of these meshes (hypothesis), it will be considered as a biologically ACTIVE HIT molecule for drug discovery. Binding site Then Draw the New molecule inside the cavity based on complementarily • Systemic Approach • Between other •PHARMACEUTICAL SCIENCES •For drug discovery Drug Discovery Team-work: Synthesis Isolation of Natural Products Molecular Modeling Bio-Technology Analysis & Quality control Pharmacology & Toxicology X-Ray Clinical Studies Crystallography Stages Pharmaceutics & Technology To the Market THANK YOU For Your Interest Best wishes from Mohamed Abdel Hamid Ismail [16/4/2008]