a) A historical development of medicinal chemistry and chemotherapeutic agentsi) Chemotherapy is the treatment of disease by chemical agents. In 1909, Paul Ehrlich was one of the early pioneers of medicinal chemotherapeutic agents.ii) In 1932, the German dye manufacturing company, I.G. Farbenindustrie, patented a new compound, a sulfonamide, call PRONTOSIL, a red A20 dye used for dyeing woolen fabrics. iii) Dr. Gerhard Domagk, a German scientist, was successful in using Prontosil against Staphylococcal septcemia, a dreadful blood infection in 1937. He later used it successfully in controlling streptococcal infections. This important discovery paved the way for a tremendous amount of research on the chemotherapy of bacterial infections. His extensive and useful research work earned Domagk the Nobel Prize in Medicine in 1939. However, on order from Hitler prevented Domagk from accepting this honor.iv) Further work on prontosil revealed the fact that it is an effective antibacterial substance in vivo (injected into a live animal). However, the activity of prontosil is diminished completely when the compound is tested in vitro (a bacterial culture grown in the lab).v) In 1945, research at the Pasteur Institute inParis by a scientist by the name of J. Trefoul established the fact that prontosil is metabolized in animals to sulfanilamide.vi) Sulfanilamide is active both in vivo and in vitro. It was then concluded that the active part of the prontosil molecule was the Sulfonamide Moiety. This discovery led to a tremendous interest in the general area of sulfonamide derivatives. A series of antibacterial compounds referred to as sulfa drugs were then synthesized and tested. All of these have the sulfonamide moiety with different groups linked on to the sulfonamide nitrogen. b) The more complex sulfa drugs have a variety of important applications. They tend to be less toxic than the simpler compounds.i) Bacteriostatic versus Bacteriocidal compounds.(1) A bacteriostatic drug suppresses the growth of bacteria giving the body's own immune system time to respond and produce the necessary antibodies to destroy the bacteria.(2) A bacteriocidal drug kills the bacteria. The exact mechanism varies with the type of drug.ii) Sulfa drugs were used in the treatment of Malaria, TB, Meningitis, Pneumonia, Upper Respiratory infections, and infections of the intestinal and urinary tracts. However, they began to lose their importance as generalized antibacterials when antibiotics such as the Penicillin Group and the Tetracyclines appeared on the market. iii) Mode of Action(1) Bacterial growth, reproduction, and development require an enzyme catalyzed reaction which uses Folic Acid as a co-factor. Bacteria are capable of synthesizing folic acid using Para-Amino Benzoic Acid as one of the components. Sulfanilamide closely resembles the B part (PABA) of Folic Acid.(2) When a sulfa drug is introduced into the living tissue, it is metabloized into sulanilamide.(3) The structural similarity of sulfanilamde to PABA results in the sulfanilamide competing with PABA for the receptor site on the enzyme.1. Over the years hundreds of new local anesthetics have been synthesized and tested. For one reason or another most of them have not come into general use. In fact, the search for the perfect local anesthetic is still under way. All of the drugs which have been found to be active have the following structural features in common. At one end of the molecule is an aromatic ring. At the other is a secondary or tertiary amine. These two essential features are separated by a central chain of atoms usually 1 to 4 carbons long. The aromatic part is usually an ester.2. Aromatic esters metabolize faster than amides.Chapter 201) Introduction to Electrophilic Aromatic Substitution2) Examples os EAS Reactionsa) The First SubstitutionHHHHHH+E+EH+++Cl2Cl+HCl+AlCl3HNO3H2SO4NO2H2SO4SO3HCH3COCH3CH3XAlX3CH3COCH3ALX3The First SubstitutionHalogenationNitrationSulfonationAlkylationAcylation3) Mechanism of EAS Reactionsa) Bromination Mechanismi) Energy Diagram for Bromination2FeBr3+Br BrBr Br FeBr3A Molecular complex with a positive charge on the Bromineand a negative charge on the Iron.No formal bonds exist.Br Br FeBr3+HBrHBrHBrBrH+Br FeBr3Br+FeBr3Step 1Step 2Step 3H+Br2FeBr3Brb) Chlorination Mechanismc) Nitration Mechanism3 Cl Cl+AlCl3Cl Cl AlCl3H+Cl Cl AlCl3HClHClHClClH+Cl AlCl3Cl+ +AlCl4HClH+Cl2AlCl3HClAlCl4++ClH+HNO3H2SO4NO2+H2OSOOOHO HSOOOHO H++HO NOO+H+H2O NOONO2+H2OH+NO2NO2HNO2HNO2HNO2HSOOOHO+H2SO4+NO2Step1Step 2d) Sulfonation Mechanismi) Using SO3 + H2SO44+H+SOOOHOSOOOHO HSOOOHO H H++SOOOHO HHSOOHO+SOOOHSO3HHSO3HHSO3HHSO3HH+SOOOHOSO3HH2SO4+Step 1Step 2Step 3SO3+H2SO4SOOOHO HSOOOHO H++SOO O+H+SOO O HSOO O HElectrphile4) Friedel Craft Alkylation Mechanism5) Friedel Craft Acylation5CH3HCH3HCH3HCH3Cl+AlCl3CH3+Cl AlCl3+CH3CH3HCl AlCl3+CH3+HClH+CH3ClHCl+CH3Step 1Step 2Step 3AlCl3CHCH3OCHOCH3CHCH3OCH3COCl+AlCl3CH3C O AlCl3ClCH3C O++CH3C OCHCH3OAlCl3Cl+COCH3AlCl3+ +HClHCl+COCH3AlCl3CH3COCl+Step 1Step 2Step 3a) Note the following to F.C. Alkylationsi) Carbocation rearrangements during F.C.A.(1) Mechanismb) Alternative ways of doing F.C. Alkylations6+CH3CH2CH2ClCHCH3CH3n-Propylchloride IospropylbenzeneCHCH3CH3+CH3CH CH2H3PO4Propene Cumene+H3PO4Cyclohexenec) Using Alcohols6) Disubstitutiona) Electron Donation Activating Groupsi) Inductive Effect (1) Sigma Electrons / Sigma bonds(2) Weakly Activating (More reactive than benzene)7+(CH3)3C OHH3PO4CCH3CH3CH3 t-Butanol t-ButylbenzeneElectron Donation byActivating Group More reactive thanbenzene.Electron Withdrawl byDeactivating GroupLess reactive than benzeneReactivityInductive Effects:CH3Resonance Effects:NH2, OCH3, OHInductive Effects:Resonance Effects:Cl, Br, I, NR3C O NOOCH3ii) Resonance Effect(1) Operates through pi electrons(2) More effective negative charge at ortho and para carbons(3) Strongly Activating(a) Much more reactive than benzene(4) Moderately Activating8OCH3OCH3OCH3OCH3NH2NH2NH2NH2NHCOCH3NHCOCH3NHCOCH3NHCOCH3NHCOCH3NHCOCH3b) Deactivating Electron Withdrawing Groupsi) Inductive Effect(1) Inductive electron withdrawing effect deactivates the ring(2) Less reactive than benzeneii) Resonance effect(1) Strongly Deactivating9NR3COHCH OCH OCH OStrongly Deactivating Groups by Resonance EffectSOOHONOOC N10NH2NHRNR2OHNHCROOCRORArCH CR2HFClBrICHOCROCOROCOHOCClOC