Organic Medicinal Chemistry PDF - RJAV 2022

By purchasing this material, you agree to the following terms and conditions: you agree that this soft copy/ebook and all other media produced by RJAV (phtransbestie) are simply guides and should not be used over and above your course material and professor instruction in pharmacy school. These guid...

By purchasing this material, you agree to the following terms and conditions: you agree that this soft copy/ebook and all other media produced by RJAV (phtransbestie) are simply guides and should not be used over and above your course material and professor instruction in pharmacy school. These guides and other media created by RJAV (phtransbestie) are not intended to be used as medical advice or clinical practice; they are for educational use only. You also agree to NOT DISTRIBUTE or share these materials under any circumstances; they are FOR PERSONAL USE ONLY. © 2022 RJAV. This transcription is property of RJAV and https://twitter.com/phtransbestie. Replication and distribution of this material is prohibited by law. All digital products (PDF files, ebooks, resources, and all online content) are subject to copyright protection. Module 1 – Organic Medicinal Chemistry Page 1 of 15 RJAV 2022  MODULE 1│PHARM CHEM 2 ORGANIC MEDICINAL CHEMISTRY ORGANIC MEDICINAL CHEMISTRY 3. Glycine & Glutamine Conjugation The practice of medicinal chemistry devoted to the discovery Conjugate Carboxylic acid, particularly aromatic acids & and development of new drugs arylalkyl acid HIGHER FORM OF CHEMISTRY! Glycine – common to mammals Glutamine – humans & other primates METABOLISM Minor pathway Benzoic acid → Hippuric acid- The first mammalian The biotransformation of drugs in the body metabolite discovered from glycine conjugation Important in the elimination of drugs from the body Converts drugs to hydrophilic, inactive and nontoxic 4. Glutathione Liver is the primary organ Has 2 Phases: Functionalization & Conjugation For detoxifying chemically reactive Electrophilic compounds Glutathione is composed of 3 amino acids: PHASE I (FUNCTIONALIZATION) Cysteine - (-SH) is responsible for detoxification Glycine Introduce a polar functional group (OH, COOH, NH2, SH) by: Glutamine Direct introduction Modifying/Unmasking existing functionalities 5. Acetylation Produce a handle on the molecule for Phase II Reactions: Oxidation, Reduction, Hydrolysis For termination of activity & detoxification Important route of primary amino groups 1. Oxidation Acetyl group supplier: Acetyl-CoA TE: N-acetyltransferase Most common phase I reaction Undergone by sulfonamides Undergone by Olefins, Alcohols, Aldehydes & Aromatic Acetylation polymorphism – variation in acetylating activity moieties Slow acetylators – Europeans, Caucasians, Egyptians (Low ex. Phenylbutazone – aromatic hydroxylation → dose) oxybutazone Fast acetylators – Eskimos & Asians (High dose) 2. Reduction 6. Methylation Carbonyl compounds → Alcohol derivatives Coenzyme: S-Adenosylmethionine (SAM) Nitro and Azo compounds → Amine derivatives TE: Methyl transferase ex. Chloral hydrate → Trichloroethanol Minor pathway that leads to non-polar & inactivated Prednisone – Ketone reduction → Prednisolone compounds Biosynthesis of epinephrine, melatonin 3. Hydrolysis Inactivation of norepinephrine, dopamine, serotonin, histamine Commonly undergone by lactams, esters and amides ex. Aspirin → Salicylic acid + Acetic acid First-Pass Metabolism / Pre-systemic metabolism PHASE II (CONJUGATION) When orally administered drugs are extensively metabolized before reaching the systemic circulation Attach small. Ionizable, endogenous compounds to the Drugs with extensive first pass effect: functional handles Isoproterenol Reactions: Glucuronidation, Sulfation, Glycine & Glutamine Lidocaine conjugation, Glutathione, Acetylation, Methylation Morphine Purpose: Meperidine 1. Form excretable & inactive metabolites Nitroglycerin 2. Terminate/Attenuate activity Pentazocine 3. Detoxify Propoxyphene Propranolol 1. Glucuronidation Salicylamide Coenzyme: Uridine-5’-diphospho-α-D-glucuronic acid ENZYME INHIBITORS ENZYME INDUCERS (UDPGA) “SICKFACES.COM” “GPPPRS CAM” Transferase enzyme (TE): Glucuronyltransferase ↓ enzyme activity ↑ enzyme activity Most common because: ↓ drug metabolism ↑ drug metabolism Readily available supply of D-glucuronic acid ↑ drug effect ↓ drug effect Numerous functional groups can combine with glucuronic Sodium valproate Griseofulvin acid Isoniazid Phenobarbital (Barbiturates) The glucuronyl moiety produces hydrophilic product Cimetidine Phenytoin Not yet developed in neonates Ketoconazole Phenylbutazone Fluconazole Rifampicin 2. Sulfation Alcohol (Acute) Sulfonylurea Ciprofloxacin Carbamazepine Coenzyme: 3-phosphoadenosine-5-phosphosulfate Erythromycin Alcohol (chronic) (PAPS) TE: Sulfotransferase Sulfonamide Meprobamate Yields water soluble and inactive conjugates Chloramphenicol Conjugate endogenous compounds such as steroids, Omeprazole St. John’s wort heparin, chondroitin, catecholamines, thyroxine Metronidazole Valencia oranges In neonates, sulfation is the major process. Grape fruit Module 1 – Organic Medicinal Chemistry Page 2 of 15 RJAV 2022  ANTI-INFECTIVE AGENTS 3. Ethylene alcohol Antisepsis – application of agent to living tissue to prevent infection Decontamination – destruction or reduction in the number C2H4O of microorganisms MOA: alkylation of bacterial protein by nucleophilic opening Disinfection – chemical or physical tx on inanimate surfaces of oxide ring Sanitization – reduction of microbial load on inanimate used to sterilize (gas sterilant) temperature sensitive surface to a level acceptable for public health purposes pharmaceuticals and equipment that can’t be autoclaved Sterilization – kill or remove all types of microorganisms Carboxide – 10% ethylene oxide + 90% CO2 Pasteurization – kills nonsporulating microorganisms by hot water @ 65C-100C 4. Formaldehyde Germicides – anti-infective agents used locally Cidal – kill Static – prevent growth aka: Methanal, HCHO A. ALCOHOLS & RELATED COMPOUNDS MOA: direct and nonspecific alkylation of nucleophilic functional groups of proteins SAR: contains nlt 37% of formaldehyde 1. ↑ # of C - ↑ antibacterial activity up to C8 only Uses: embalming fluid, disinfectant 2. ↑ 9C – nonpolar ↓ water solubility, ↓ antibacterial activity 3. Branching decreases antibacterial property (except 5. Glutaraldehyde isopropyl alcohol = more potent, cheaper, less toxic; 60%EtOH = 40% Isopropyl Alcohol) 4. Isomeric alcohol potency decreases in the order: Primary > Secondary > Tertiary aka: Glutarol MOA: Protein denaturation/precipitation sterilizing solution for equipment and phcals that cannot be autoclaved 1. Alcohol, USP used in medical mission in remote areas Cidex® ethanol, grain alcohol, wine spirit, cologne spirit, spiritus vini B. PHENOL & ITS DERIVATIVES rectificatus most widely abused of all recreational drugs 1. Phenol, USP commercial ethanol (95%) o Manufactured by: Fermentation of grains and other CHOs Hydration of ethene o Metabolism: Ethanol → Acetaldehyde → Acetic acid Ethanol to Acetaldehyde Enzyme: alcohol aka: Carbolic acid, C6H5OH dehydrogenase discovered by Joseph Lister Acetaldehyde to Acetic acid Enzyme: aldehyde SAR: dehydrogenase Substitution at para position increases bacterial activity Activity: straight chain alkyl> branched DRUGS THAT INTERFERE WITH ALCOHOL METABOLISM Germicidal standard Phenol coefficient = Dilution of a disinfectant a. Fomepizole Dilution of phenol that is required to kill a strain of Salmonella typhi Inhibits alcohol dehydrogenase Used as an antidote for methanol poisoning 2. Liquefied phenol phenol with 10% water b. Disulfiram 3. p-chloro-m-xylenol used as a deterrent for alcohol addiction aka: PC-MX, Metasep inhibits aldehyde dehydrogenase antibacterial & antifungal accumulation of aldehyde = extreme hangover like symptoms (nausea, vomiting, vasodilatory flushing) 4. Hexachlorophene aka: pHisoHex Types of Alcohols in soaps, lotions, shampoos Absolute alcohol 95% alcohol 5. Cresol 99% alcohol, prepared by azeotropic Dehydrated alcohol Methylphenol distillation From coal tar or petroleum by alkaline extraction Diluted alcohol 49-50% alcohol EtOH rendered unfit for use in 6. Thymol Denatured alcohol beverages by the addition of subs. Isospropyl m-cresol contains added wood alcohol and from oil of Thymus vulgaris (Thyme) Completely Antifungal property benzene unsuitable for internal or denatured alcohol external use 7. Eugenol treated with subs. so that its use is 4-allyl-2-methoxyphenol Specially denatured permitted for specialized purpose from clove oil alcohol ex. Iodine in alcohol dental analgesic “toothache drops”, used in mouthwashes 2. Isopropyl alcohol 8. Resorcinol m-dihydroxybenzene keratolytic agent aka: 2-propanol 9. Hexylresorcinol substitute for ethanol in throat lozenges Prepared by sulphuric acid catalyzed hydration of propylene Module 1 – Organic Medicinal Chemistry Page 3 of 15 RJAV 2022  C. OXIDIZING AGENTS F. PRESERVATIVES effective against anaerobic bacteria added to prevent microbial contamination MOA: liberation of oxygen in the tissues (peroxides) Ideal preservative Effective at low concentrations 1. Hydrogen Peroxide (H2O2) Nontoxic, compatible with other constituents of the Used for cleansing contaminated wounds preparation Transient action (rapid action, short duration) Stable for the shelf life of the preparation 2. Carbamide Peroxide 1. Parabens complex of urea and H2O2 esters of p-hydroxybenzoic acid have antifungal properties 3. Hydrous Benzoyl Peroxide Vanoxide, Panoxyl a. Methylparaben most effective topical OTC agent for acne Methyl-p-hydroxybenzoate Effective against molds D. HALOGEN CONTAINING COMPOUNDS b. Propylparaben 1. Iodine (I2) Propyl-p-hydroxybenzoate oldest germicide in use today Effective against yeast MOA: Inactivate proteins by Iodination of aromatic residues (phenylalanyl & tyrosyl) c. Butylparaben & Ethyl paraben Oxidation (sulfhydryl groups) Preferred preservatives for drugs in oil or lipophilic bases Official iodine preparations in the USP Iodine solution 2% in H2O with NaI 2. Chlorobutanol camphor like aroma Strong Iodine Solution (Lugol’s) 5% I2 in H2O with KI bacteriostatic agent in pharmaceuticals for injection, Iodine Tincture 2% in 50% alcohol with NaI ophthalmic use, and intranasal administration a. Inorganic iodide salts 3. Benzyl alcohol Admixed to increase the solubility of I2 and to reduce its aka: phenylcarbinol, phenylmethanol volatility from oil of jasmine Ex. I2 + NaI preservative in vials of injectable drugs a/e: gasping syndrome b. Iodophors complexes of iodine and non-ionic surfactants 4. Benzoic acid retained germicidal properties, reduced volatility and Naturally from gum benzoin and in peru and tolu balsams removed irritant properties effective as a preservative in food and pharmaceutical example: Povidone-Iodine (Betadine, [PVP]-Iodine) products at low pH A complex with the non-ionic surfactant polymer, polyvinylpyrrolidone 5. Sodium propionate Antifungal 2. Chlorine (Cl2) Used for disinfection of water supplies 6. Sorbic acid MOA: chlorination of amide nitrogen atoms in proteins, Antifungal preservative in preserve syrups, elixirs, ointments, oxidation of sulfhydryl groups and lotions containing components such as sugars a. Hypochlorous acid (HClO) G. DYES active germicidal species formed when Cl2 is dissolved in water Cationic dyes are active against gram (+) and fungi but gram b. Halazone (-) are generally resistant c. Chloroazodin d. Oxychlorosene sodium 1. Triphenylmethane dyes E. CATIONIC SURFACTANTS a. Gentian Violet crystal violet, methyl violet, methyl- quaternary ammonium compounds that ionize in water and rosaline chloride exhibit surface active properties Pessaries for that tx of yeast infections inactivated by soaps and other anion detergents (1-3%) tissue constituents, blood, serum, and pus tend to reduce the Anthelminthic for strongyloides effectiveness of these substances (liquid form) MOA: adsorb onto the surface of the bacterial cell, at which they cause lysis b. Basic Fuschin mixture of chlorides of rosaniline 1. Benzalkonium chloride (Merthiolate, Zephiran) and p-rosaniline new generic name of Merthiolate ingredient of carbol fuschin aka Castellani’s paint 2. Methylbenzethonium Chloride (Diaparene) Tx of fungi, ringworm & athlete’s used to control diaper rash in infants caused by Candida foot albicans 2. Thiazine dye 3. Cetylpyridinium chloride antiseptic in mouthwash and lozenges a. Methylene blue FDA approved for the Tx of gingivitis Antidote for cyanide poisoning Antiseptic property in Tx of 4. Chlorhexidine gluconate (Hibiclens) cystitis and urethritis Classified under biguanides Bacteriostatic not a cationic surfactant but share many physical, a/e: blue-green color of stool chemical and antimicrobial properties used in oral surgery, mouthwash, and irrigation Module 1 – Organic Medicinal Chemistry Page 4 of 15 RJAV 2022  H. MERCURY COMPOUNDS ANTIPROTOZOAL AGENTS Mercurial protozoal infections: malaria, amoebiasis, giardiasis, trichomoniasis, toxoplasmosis, P carinii pneumonia 1. Nitromersol at one time very popular antiseptic for skin and ocular Amoebiasis (8 DIME) infections because it is nonirritating and non-staining Amebicides that are effective against both intestinal & 2. Thimerosal extraintestinal forms of the disease: preservative of vaccines, antitoxins, and immune sera old generic name of Merthiolate 1. Emetine and Dehydroemetine alkaloids from Ipecac ANTHELMINTICS MOA: inhibit protein synthesis by preventing protein elongation (protoplasmic poison) are drugs that are capable of eliminating parasitic worms or Also used for balatidial dysentery, fascioliasis, helminths paragonimiasis helminths: Cestodes (tapeworms), Trematodes (flukes), Limited use due toxic effects (GI, cardiovascular, Nematodes (roundworms neuromascular) Nematodes 2. Metronidazole (Flagyl, Protostat) MOA: covalent binding of reactive intermediate from the 1. Piperazine reduction of 5-nitro group to the DNA → lethal effect MOA: block response of ascaris muscle to Ach → leading to Tx of amoeba, giardiasis, trichomonas, anaerobic bacterial placid paralysis infections Tx of pinworm roundworm a/e: disulfiram like effect (if taken with alcohol) 2. Pyrantel Pamoate 3.Tinidazole MOA: depolarizing Nm blocking agent → spastic paralysis should not be used with piperazine (opposite effects) Amebicides that are effective only against intestinal form: Tx of pinworm, roundworm (ascaris) 1. 8-hydroxyquinoline 3. Thiabendazole MOA: chelation of metal ions MOA: inhibit fumarate reductase / antimitotic / antimicrotubule 2. Iodoquinol broad spectrum anthelminthic a derivative of 8-hydroxyquinoline In veterinary practice as anthelmintic in livestock for acute and chronic intestinal amebiasis 4. Mebendazole 3. Diloxanide MOA: irreversibly blocks glucose uptake → depleted Tx of asymptomatic carriers of E. histolytica glucose/ antimitotic/ antimicrotubule from discovery of α-dichloroacetamides broad spectrum (whip, pin, round, hook) Pneumocystis carinii pneumonia (CAP) 5. Albendazole MOA: antimitotic/ antimicrotubule 1. Cotrimoxazole broad spectrum Sulfamethoxazole + Trimethoprim DOC for PCP 6. Ivermectin from Streptomyces avermitilis 2. Pentamidine Isethionate MOA: stimulating gaba → blocked interneuron-motor neuron prophylaxis for African trypanosomiasis (rapidly distributed to transmission tissues where it is stored) Tx of onchocerciasis (river blindness) – Oncocerca volvulus 3. Atovaquone 7. Diethylcarbamazine (DEC) analog of Ubiquinone a component of mitochondrial electron MOA: unknown transport chain Tx of Filiariasis MOA: Interfere with the electron transport chain as it is antimetabolite for ubiquinone Trematodes Trypanosomiasis (BS MEN) 1. Praziquantel MOA: increase Ca2+ membrane permeability → loss of Ca 1. Eflornithine → contraction → paralysis → phagocytosis (DEATH) MOA: irreversible inactivation of Ornithine decarboxylase Broad spectrum Tx of African sleeping sickness Agent of choice for blood flukes (schistosomes) myelosuppressive (→ anemia, leukopenia, thrombocytopenia) 2. Niridazole for schistosomiasis 2. Nifurtimox Tx of South American trypanosomiasis (T. cruzi) 3. Oxamniquine MOA: inhibit DNA, RNA, Protein synthesis 3. Benznidazole Tx of Schistosoma mansoni Tx of Chagas disease 4. Bithionol 4. Melarsoprol Agent of choice for liver fluke (Fasciola hepatica) and lung DOC for later stages of both forms of African fluke (Paragonimus westermani) trypanosomiasis Cestodes 5. Suramin Bisurea derivative containing six sulfonic acid groups 1. Niclosamide used as a long-term prophylactic agent for trypanosomiasis MOA: inhibit Oxidative phosphorylation (due to high protein binding, effect can last up to 3 months) Module 1 – Organic Medicinal Chemistry Page 5 of 15 RJAV 2022 Toxoplasmosis d. Mechanism of action (MOA) Irreversibly inhibits transpeptidase by covalently binding to 1. Sulfadiazine + Pyrimethamine the serine residue of the active site thus inhibiting cell wall most effective therapy synthesis Leishmaniasis e. Classification of Penicillin 1. Sodium Stibogluconate MOA: inhibit phosphofructokinase e.1. Narrow spectrum penicillins / Natural penicillins aka Sodium antimony gluconate Tx of Leishmaniasis 1. Penicillin G aka Benzyl penicillin ANTISCABIES & ANTIPEDICULAR AGENTS given IV depot forms: Benzathine penicillin & Procaine penicillin Scabicides – agents that control the mite Sacroptes scabei DOC: Syphilis Pediculicides – used to eliminate head, body, and crab lice 2. Penicillin V Scabicides aka Phenoxymethyl penicillin given PO 1. Benzyl Benzoate from Peru balsam, also from benzyl alcohol + benzoyl e.2. Penicillinase-resistant penicillins / Antistaphylococcal chloride penicillins topical scabicide 1. Methicillin 2. Crotamiton Prototype antipruritic (local anesthetic action) s/e: Interstitial nephritis 10% - lotion/cream for scabies emergence of MRSA A colorless, odorless oily liquid 2. Nafcillin Scabicides & Pediculicides Can be given to px with renal problems 1. Permethrin 3. Oxacillin, Cloxacillin, Dicloxacillin MOA: acts on nerve cell membranes → disrupt Na+ channel Isoxazolyl penicillins – Contains 3-phenyl & 5-methyl conductance → paralysis Dicloxacillin – best absorbed synthetic pyrethrin 1% lotion- for the treatment of lice; 5% cream - for the e.3. Broad spectrum penicillins / Aminopenicillins treatment of scabies 1. Ampicillin 2. Lindane given IV MOA: direct contact poison, fumigant effect, stomach poison Prodrugs: Bacampicillin, Hetacillin, Ciclacillin chlorinated benzene (benzene hexachloride) + Sulbactam = Unasyn DOC: Listeria monocytogenes ANTIBACTERIAL AGENTS 2. Amoxicillin given PO I. Mechanisms of Antibacterial action + clavulanic acid = Co-Amoxiclav commonly used in respiratory infections Inhibition of cell wall synthesis Inhibition of protein synthesis e.4. Extended spectrum penicillins / Antipseudomonal Inhibition of cell metabolism penicillins Inhibition of nucleic acid transcription and replication Interactions with plasma membrane 1. Carbenicillin, Ticarcillin Carboxypenicillin Inhibition of cell wall synthesis Carboxyl at the α-position A. BETA-LACTAM ANTIBIOTICS 2. Piperacillin, Azlocillin, Mezlocillin Ureidopenicillin PENICILLINS Urea at the α-position Piperacillin – most potent DRUGS AND ITS CHEMICAL STRUCTURE & NAME Drug Chemical name Pen G Benzylpenicillin a. History Discovered by Alexander Fleming Old: Penicillium notatum New: Penicillium chrysogenum Isolated by Florey & Chain by freeze drying/ lyophilization Pen V Phenoxymethylpenicillin b. Properties Contains an unstable bicyclic system Beta-lactam & Thiazolidine ring Nucleus: 6-Aminopenicillanic acid (6-APA) Precursors: Cysteine & Valine Methicillin 2,6- Shape: half open book Dimethoxyphenylpenicillin c. Structure-activity relationship (SAR) Addition of electron withdrawing group – acid stability Addition of bulky groups – penicillin’s resistant Addition of amino group – increase spectrum activity Module 1 – Organic Medicinal Chemistry Page 6 of 15 RJAV 2022  Nafcillin 2-Ethoxy-1-Napthylpenicillin CEPHALOSPORINS a. History Cephalosporin C – the first cephalosporin Old: Cephalosporium acremonium New: Acremonium chrysogenum Oxacillin 5-Methyl-3-phenyl-4- b. Properties isoxazolylpenicillin Contains an unstable bicyclic system Beta-lactam & Dihydrothiazine Nucleus: 7-Aminocephalosporanic acid (7-ACA) Precursors: Cysteine & Valein Better acid stability & resistance to B-lactamase Cloxacillin 5-methyl-3-(2-chlorophenyl)- c. Mechanism of action (MOA) 4-isoxazolyl penicillin Irreversibly inhibits transpeptidase by covalently binding to the serine residue of the active site thus inhibiting cell wall synthesis d. Generation of Cephalosporin Based on their bacterial spectrum of activity and B- lactamase resistance 1st Gen Dicloxacillin 5-methyl-3-(2,6- Cefalexin dichlorophenyl)-4- Cefadroxil isoxazolylpenicillin Cefazolin Cephalotin Cephradine 2nd Gen Cefaclor Cefoxitin Ampicillin D-a-amino benzylpenicillin Cefuroxime Cefonicid Cefamandole Cefpodoxime Cefprozil Amoxicillin D-a-amino-p-hydroxybenzyl Cefotetan penicillin Loracarbacef 3rd Gen Cefoperazone Ceftriaxone Ceftibuten Cefdinir Carbenicillin a-carboxybenzylpenicillin Cefixime Cefotaxime Moxalactam Ceftidoxime Cefditoren 4th Gen Cefepime Ticarcillin a-carboxy-3- Cefpirome thienylpenicillin e. Clinical Uses Cefalexin – used for UTI in pregnant Cefazolin – pre-surgical prophylaxis Ceftriaxone – New DOC: Typhoid fever Antipseudomonal cephalosporins (Cefoperazone, Mezlocillin a-(1-methanesulfonyl-2- Cefotaxime, Ceftazidime, Ceftriaxone, Moxalactam) – have oxoimidazolidino- useful antipseudomonal activity carbonylamino) benzylpenicillin f. Side effects / Adverse effects Hypersensitivity Disulfiram-like reaction & Hypoprothrombinemia N-Methyl-5-thiotetrazole (MTT) containing cephalosporins: Cefamandole, Cefotetan, Moxalactam, Cefoperazone Piperacillin CARBAPENEMS a. Properties Differ from penicillin in that the sulfur atom has been replaced by carbon atom Broad spectrum of activity, including P. aeruginosa b. Drugs 1. Thienamycin isolated from Streptomyces cattleya inactivated by Renal dehydropeptidase-I Module 1 – Organic Medicinal Chemistry Page 7 of 15 RJAV 2022 2. Imipenem 2. Colistin N-formimidoylthienamycin aka Polymyxin E + Cilastin (renal dehydropeptidase inhibitor) = Tienam source: Aerobacillus colistinus For refractory urinary tract infections & gram-negative 3. Meropenem infections 2nd generation carbapenem Resistant to dehydropeptidases & B-lactamases B. GRAMICIDIN A 4. Ertapenem Source: Bacillus brevis Benzoic acid contributes to high protein binding and prolongs MOA: acts as ionophore allowing the loss of K+ ions the half-life of the drug C. DAPTOMYCIN MONOBACTAM Cyclic lipopeptide from Streptomyces roseosporus a. Properties Use: reserve agent for SSTIs Monocyclic B-lactams Inactive against gram positive. Moderate activity against a Inhibition of Protein Synthesis narrow group of gram-negative bacteria, including P. aeruginosa. A. AMINOGLYCOSIDES b. Drugs a. Properties Amino sugars joined by a glycosidic linkage 1. Aztreonam derived from Streptomyces spp (mycin) or Micromonospora isolated from Chromobacterium violaceum spp. (micin) given IV (except: neomycin) B. CYCLOSERINE + penicillins = synergism for the treatment of serious infections caused by gram- Sources: Streptomyces garyphalus, S. orchidaceus, S. negative bacilli lavendulus MOA: Prevent the formation of D-ala-D-ala (inhibits L-alanine b. Mechanism of action (MOA) racemase & D-ala, D-ala ligase) Bind to 30s ribosomal subunit to prevent the reading of the Use: Second-line drug for tuberculosis mRNA C. BACITRACIN c. Drugs A polypeptide from Bacillus subtilis, isolated from a fracture 1. Gentamicin fragment from Margaret Tracy source: Micromonospora purpurea MOA: Binds to the lipid carrier Use: + Polymyxin B for the topical treatment of skin 2. Tobramycin infections. source: Streptomyces tenebravius s/e: nephrotoxic & hematotoxic Action is enhanced by zinc 3. Amikacin semi synthetically derived from Kanamycin D. VANCOMYCIN first prepared in Japan A glycopeptide from Streptomyces orientalis 4. Neomycin MOA: Inhibits transglycosidation, inhibits synthesis of source: Streptomyces fradiae mucopeptide polymer DOC: MRSA (IV), C. difficile induced Pseudomembranous 5. Kanamycin colitis (PO) source: Streptomyces kanamyceticus s/e: red-man syndrome (remedy: slow infusion) 6. Streptomycin E. TEICOPLANIN source: Streptomyces griseus 1st aminoglycoside discovered A glycopeptide from Actinoplanes teichomyceticus 1st effective agent used against tuberculosis MOA: long alkyl chain anchors the antibiotic to the outer surface of the cell membrane d. Side effects Use: treatment of gram-positive infections Allergic reactions Ototoxicity F. FOSFOMYCIN most ototoxic: KAN most vestibulotoxic: SG Synthetic derivative of Phosphoric acid Nephrotoxicity MOA: inhibits UDP-N-acetyl glucosamine enolpyruvyl most nephrotoxic: NTG transferase Neuromuscular paralysis Use: UTI cause by E. coli B. TETRACYCLINES Interactions with Plasma Membrane A. POLYMYXINS Cation polypeptides MOA: bind to phospholipids on the cell membrane of gram- negative bacteria a. Properties s/e: Nephrotoxic and neurotoxic Consists for 4 fused rings with a system of conjugated double bonds. 1. Polymyxin B Broadest spectrum of the antibiotics source: Bacillus polymyxa Have activity against gram positive & negative, spirochetes & + Bacitracin for skin infections atypical bacteria + Dexamethasone & Neomycin for eye infections *Chlortetracycline – Streptomyces aureofaciens DOC: Lime disease, rickettsia Module 1 – Organic Medicinal Chemistry Page 8 of 15 RJAV 2022 b. Mechanism of action (MOA) 4. Roxithromycin Binds to the 30s subunit of ribosomes which prevents Semisynthetic macrolide derived from erythromycin (+N- aminoacyl-tRNA from binding to the mRNA ribosome oxime side chain) complex D. LINCOSAMIDES c. Classes of tetracyclines Short Acting a. Properties Tetracycline Sulfur containing antibiotics Oxytetracycline Intermediate Acting b. Mechanism of action (MOA) Metacycline Binds to 50s ribosomal subunit (same with macrolides) Demeclocycline Long Acting c. Drugs Doxycycline Minocycline 1. Lincomycin Very long acting source: Streptomyces lincolnensis Tigecycline d. Interactions 2. Clindamycin Products containing metals Dairy products and drugs containing divalent and trivalent metals Decreased absorption of tetracycline due to chelation Penicillin – antagonism 7-chloro-7-deoxy derivative of lincomycin e. Side effects / Adverse reactions potent drug for anaerobic bacteria Photosensitivity a/e: Clostridium difficile induced pseudomembranous colitis Fanconi-like syndrome DOC: Vancomycin, Metronidazole taking expired tetracycline Tooth discoloration & stunting of growth E. CHLORAMPHENICOL Contraindicated to pregnant women & young children C. MACROLIDES Source: Streptomyces venezuelae MOA: Binds to 50s subunit, inhibiting peptidyl transferase DOC: Typhoid fever (new: Ceftriaxone) + palmitic acid = chloramphenicol palmitate (reduced bitterness) a/e: Aplastic anemia, Gray baby syndrome Toxicophore: Nitro group F. STREPTOGRAMINS a. Properties Common chemical characteristics: MOA: Binds to different regions of the 50s subunit and form 14-membrane lactone ring a complex with it Ketone group Glycosidically linked amino sugar 1. Pritinamycin source: Streptomyces pristinaespiralis b. Mechanism of action (MOA) Quinupristin & Daflopristin Binds to the 50s ribosomal subunit, inhibiting translocation. 2. Quinupristin c. Drugs inhibits peptide chain elongation 1. Erythromycin (Ilotycin) 3. Daflopristin source: Streptomyces erythraeus, from Iloilo interferes with the transfer of the peptide chain from one Ester salts tRNA to the next Estolate – lipid soluble, acid stable prodrug with better oral absorption; s/e: Cholestatic jaundice G. LINEZOLID Ethyl succinate – prodrug with more lipophilicity – longer duration of action Gluceptate – water soluble salt of glucoheptanoic acid for parenteral use Lactobionate – also used for parenteral means classified under oxazolidinones, synthetic antibiotics Substitute for penicillin in allergic patients MOA: Binds to 50s preventing the formation of the 70s Motilin agonist complex DOC: Legionnaire’s disease DOC: VRSA 2. Clarithromycin Inhibition of DNA Replication Methylated erythromycin More stable in gastric acid and has improved oral absorption A. QUINOLONES Use: treatment of ulcers causes by H. pylori 3. Azithromycin Contains a 15-membered macrocycle with N-methyl group Extensive tissue distribution Food decreases absorption Hydrate forms: patterned after Nalidixic acid (NegGram) o synthetic Dehydrate - Zithromax antibacterial agent Monohydrate – Azytha Module 1 – Organic Medicinal Chemistry Page 9 of 15 RJAV 2022 a. Mechanism of action (MOA) b. Mechanism of action (MOA) inhibits DNA Gyrase Topoisomerase Inhibits dihydropteroate synthetase, thus preventing folic acid synthesis b. Generations of Quinolones Active form: Ionized Generation Drugs Activity c. Structure Activity Relationship (SAR) 1st gen Nalidixic acid, Moderate gram (-) act para-amino group is essential for activity and must be Cinoxacin unsubstituted 2nd gen Ciprofloxacin, Improved act against gram (-), The aromatic ring and the sulfonamide functional groups are Lomefloxacin, has act against G (+) & both required Ofloxacin, Atypical microorganism Both the sulfonamide and amino group must be directly Norfloxacin, attached to the aromatic ring Enofloxacin The aromatic ring must be para-substituted only 3rd gen Gatifloxacin, Retained gram (-) act, The sulfonamide nitrogen must be primary or secondary Gemifloxacin, improved gram (+) & atypical Sparfloxacin, act d. Side effects / Adverse effects Moxifloxacin, Crystalluria, Hypersensitivity (rash SJS), Hemolytic anemia Levofloxacin in G6PD, Nausea, Kernicterus 4th gen Trovafloxacin Retained gram (-), gram (+), atypical microorganism, also e. Other antimetabolites (PYRIMIDINES) for anaerobic microorganism 1. Trimethoprim c. Structure Activity Relationship (SAR) MOA: Bacterial dihydrofolate reductase inhibitor Nucleus: 1,4 dihydro-4-oxo-3 pyridine carboxylic acid At 2, addition of groups greatly reduces or abolishes activity 2. Pyrimethamine At 5,6,7,8, may be substituted with good effects MOA: Protozoal dihydrofolate reductase inhibitor At 6, + F increases antibacterial activity Fluoroquinolones – broad spectrum (+, -) f. Drugs / Drug combinations At 7, + Piperazine provides activity against Pseudomonas aeruginosa 1. Sulfalazine At 1, small alkyl substitution provides greater potency Prodrug of 5-aminosalicylic acid At 8, + Halogen, side effect is photosensitivity Used in ulcerative colitis Highest – Lomefloxacin Lowest – Sparfloxacin 2. Co-trimoxazole Sulfamethoxazole + Trimethoprim (synergistic combination) d. Interactions Uses: 1st attack of UTI, P. carinii pneumonia (DOC) Enzyme inhibitor Products containing divalent and trivalent metals 3. Co-trimazine Sulfadiazine + Trimethoprim B. NITROFURANS 4. Sulfadiazine + Pyrimethamine Used in Toxoplasmosis 5. Sulfadoxine + Pyrimethamine Nitro heterocyclic compounds Used in Malaria Derivatives of 5-nitro-2-furaldehyde 6. Silver sulfadiazine + Mafenide a. Mechanism of action (MOA) Used in Burns Inhibit Nucleic acid synthesis B. SULFONES b. Structure Activity Relationship (SAR) Nitro at 5th position – antibacterial activity MOA: inhibit dihydropteroate synthetase c. Drugs 1. Dapsone Used in leprosy Contraindicated in G6PD deficiency, may 1. Nitrofurantoin cause hemolytic anemia used in UTI MISCELLANEOUS AGENTS 2. Nitrofurazone used topically in Burns 1. Methenamine (Urothropin) 3. Furazolidone Urinary antiseptic used in UTI used in bacterial or protozoal Diarrhea Formaldehyde release in low pH is required for antibacterial effect 4. Metronidazole Given with acidifying agents (NH4Cl) to optimize the Effective against trichomonas, amoeba, giardia, anaerobic effect bacteria Certain bacteria produce urease, causing resistance DOC: C. difficile induced Pseudomembranous colitis Give acetohydroxamic acid (Lithostat) – urease inhibitor Inhibition of Cell Metabolism A. SULFONAMIDES a. History Discovered by Gerard Domagk Studied a bright red dye, Prontosil, which was metabolized in vivo to sulfanilamide Module 1 – Organic Medicinal Chemistry Page 10 of 15 RJAV 2022  ANTIMYCOBACTERIAL DRUGS 3. Ethionamide Analog of isoniazid TUBERCULOSIS s/e: hepatotoxicity FIRST LINE DRUGS 4. Cycloserine 1. Rifampicin (Rifampin, R) 5. Respiratory fluoroquinolones LEPROSY Drugs: 1. Clofazimine (Lamprene) A phenazine red dye MOA: bind to nucleic acids Used in Dapsone resistant lepromatous leprosy s/e: brownish-black skin discoloration 2. Dapsone Source: S. meditirranei MOA: inhibits RNA polymerase 3. Rifampicin most active agent in clinical use for TB patients S/E / Interactions: red-orange secretions, hepatoxicity, **For tuberculoid leprosy (mild), dapsone + rifampicin is given. enzyme inducer However, for lepromatous leprosy (severe), clofazimine is added to the regimen. 2. Isoniazid (H) ANTIFUNGAL DRUGS A. POLYENES Structure: contains conjugated double bonds in macrocyclic lactone rings MOA: forms “pores” channel on the cell membrane aka Isonicotinic acid hydrazine, INH MOA: inhibit synthesis of mycolic acid Drugs: S/E: peripheral neuropathy, hepatoxicity AD: Give pyridoxine/ vitamin B6 1. Amphotericin B source: Streptomyces nodosus 3. Pyrazinamide (Z) 2. Nystatin source: Streptomyces noursei DOC for candida infections 3. Natamycin aka Pyrazinecarboxamine, PZA source: Streptomyces natalensis MOA: unclear first line drug for short term treatment prodrug of pyrazinoic acid S/E: hyperuricemia, hepatotoxicity 4. Ethambutol (E) MOA: inhibits arabinosyl transferase inhibiting the formation of mycobacterial cell wall S/E: optic neuritis (blue-green vision) B. AZOLES 5. Streptomycin MOA: inhibits C-14 α-demethylase to block demethylation of lanosterol to ergosterol. SAR: a. Imidazole or 1,2,4-triazole ring bonded by a N-C linkage b. 2 or 3 aromatic rings increases potency c. Addition of halogen increases potency Groups of azoles (based on structure): Triazole – Ketoconazole, Itraconazole, Fluconazole Posaconazole, Voriconazole first and oldest antibiotic effective in the Tx of TB Imidazole – Clotrimazole, Miconazole, Econazole SECOND LINE DRUGS For systemic fungal infections: 1. Capreomycin 1. Ketoconazole (Nizoral) Source: S.capreolus Used in systemic fungal infections (before), topical (now) s/e: ototoxicity, nephrotoxicity needs acidic pH to be absorbed 2. 4-Aminosalicylic acid s/e, interactions: hepatoxicity, antiandrogenic effects, aka para-aminosalicylic acid, PAS enzyme inhibitor MOA: inhibits dihydropteroate synthetase reduced production of testosterone, impotence, loss of libido, One of the very first drugs used for tuberculosis gynecomastia, dec. sperm count Module 1 – Organic Medicinal Chemistry Page 11 of 15 RJAV 2022 2. Itraconazole (Sporanox) PARASYMPATHETIC SYSTEM Alternative to Ketoconazole Not hepatotoxic, no adrenal suppression aka cholinergic system Needs acidic pH to increase absorption Neurotransmitter: Acetylcholine (ACh) Receptors: Muscarinic (M), Nicotinic (N) 3. Fluconazole (Diflucan) Metabolism: Acetylcholinesterase (AChE) Lipophilic (crosses BBB) DOC & Prophylaxis for Cryptococcal meningitis 4. Posaconazole Broad acting synthetic antifungal Structurally similar to Itraconazole a/e: gastrointestinal disturbances (n/v, diarrhea), headaches 5. Voriconazole Broad acting synthetic antifungal Structurally similar to Fluconazole Biosynthesis of acetylcholine: DOC for invasive aspergillosis a/e: virtual & auditory hallucinations, hepatotoxicity I. L-serine → ethanolamine enzyme: serine decarboxylase For superficial fungal infections: II. ethanolamine → choline enzyme: choline-N-methyltransferase 6. Clotrimazole (Canesten) 7. Miconazole (Daktarin) III. choline → acetylcholine 8. Econazole enzyme: choline-acetyltransferase (ChAT) 9. Tioconazole Metabolism of acetylcholine: C. ALLYLAMINES I. Ach → choline + acetic acid enzyme: Acetylcholinesterase MOA: inhibit squalene epoxidase Cholinergic Agonists Drugs: 1. Naftifine (Naftin) 2. Terbinafine (Lamisil) 3. Tolnaftate (Tinactin) D. OTHER ANTIFUNGALS 1. Flucytosine Nucleoside antifungal (Pyrimidine antimetabolite) ACh – prototype Prodrug of 5-flurouracil Problems: Used in combination with Amphotericin B in Cryptococcal Prone to hydrolysis meningitis Non-selective MOA: inhibits DNA & RNA synthesis Requirements: Stability to stomach HCl and esterases 2. Griseofulvin Source: Penicillum griseofulvum II. Selectivity for cholinergic receptors MOA: “mitotic spindle/microtubule poison” – inhibiting mitosis SAR: Acetylcholine DOC for refractory ringworm infections of the body nails, hair, feet a. Addition of carbamate Long duration of treatment (3-6 mos) less prone to susceptibility Poor bioavailability Solutions: 1. Carbachol Micronized Taken with fatty food to increase abs E. ECHINOCANDINS More stable ester, resulting to long-acting effect MOA: inhibits synthesis of β (1,3)-D-glucan, thus inhibiting Used for glaucoma fungal cell wall synthesis Potent against Aspergillus & most Candida species b. Addition of alkyl group s/e: flushing (rapid infusion) less prone to susceptibility & more selective to muscarinic Drugs: Anidulafungin, Caspofungin, Micafungin than nicotinic F. TOPICAL AGENTS FOR DERMATOPHYTOSES 1. Methacholine FATTY ACIDS 1. Propionic acid More selective on muscarinic over nicotinic receptors & more 2. Sodium Caprylate stable from caprylic acid, component of coconut & palm oils Used for the diagnosis of asthma 3. Undecylenic acid c. Combination of the a & b from destructive distillation of castor oil 1. Bethanechol 4. Salicylic acid (SA) & Benzoic acid (BA) More selective on muscarinic over nicotinic receptors & more Whitfield’s ointment stable Used to stimulate GIT and urinary bladder after surgery Module 1 – Organic Medicinal Chemistry Page 12 of 15 RJAV 2022 Biosynthesis of neurotransmitters: RING A I. Tyrosine → L-DOPA At 7, + EWG substituent (↑EN = ↑activity) enzyme: Tyrosine hydroxylase Positions 6, 8, and 9 should not be substituted II. L-DOPA → Dopamine RING B enzyme: Aromatic L-amino acid decarboxylase At 5, + phenyl ring promotes activity III. Dopamine → Norepinephrine At 3, +/- OH has pharmacokinetic properties enzyme: Dopamine β-hydroxylase RING C IV. NE → Epinephrine enzyme: Phenyl ethanolamine N-methyltransferase + EWG at ortho position = ↑activity; at para position = (PENMT) reduced activity Norepinephrine – DOC: Septic Shock Epinephrine – DOC: Anaphylactic Shock Dobutamine – DOC: Cardiogenic Shock Triazolobenzodiazepines Metabolism of neurotransmitters: BZD fused with triazolo ring short acting I. Norepinephrine/Epinephrine ex. Triazolam, Alprazolam MAO & COMT → Vanillylmandelic acid (VMA) Imidazobenzodiazepine II. Dopamine BZD fused with imidazole ring MAO & COMT → Homovanillic acid (HVA) short acting ex. Midazolam Structure-Activity Relationship (SAR) Barbiturates Was used extensively as sedative hypnotic MOA: increase the DURATION of GABA mediated chloride ion channel opening SAR: Nucleus: 2,4,6-trioxohexahydropyrimidine (Barbituric acid) 1. Parent structure: β – phenyl ethylamine At 5, +alkyl/aryl groups confer activity At 2, if S replaces O → Thiobarbiturates 2. 2 carbon atoms separate the aromatic ring & the amino group More lipid-soluble (very high lipid water partition coefficient) 3. Optical isomerism: 1R configuration – more potent Rapid CNS penetration Short duration of action 4. Substitution on N: Increase in size and bulkiness Ex. Thiopental Increased β – agonist activity, α – agonist (reduced) activity 5. Substitution on alpha carbon Blocked oxidation by MAO, increased DOA Increased oral absorption, CNS activity +methyl → α2 selectivity, ex. Methyldopa 6. 3’&4’ OH groups – maximal α & β activity, provides direct acting activity. ANTIPSYCHOTICS 7. w/o 3’&4’ OH groups – resistant to COMT (increased DOA), TYPICAL ANTIPSYCHOTICS provides indirect activity 1. Phenothiazines 8. 3’-OH – important for α activity ex. Phenylephrine Aliphatic – Chlorpromazine, Promazine, Triflupromazine Piperidine – Thioridazine, Mesoridazine, Piperacetazine 9. 4’-OH – important for β activity Piperazine – Fluphenazine, Perphenazine, Trifluoperazine ex. Albuterol Butyrophenone – Haloperidol, Droperidol CNS DEPRESSANTS 2. Thioxanthene – Thiothixene, Chloprothixene, Flupenthixol Benzodiazepines Potency: Butyrophenones = Piperazine > Piperidine ≥ Most widely used anxiolytic Thioxanthenes >>> Aliphatic MOA: Increase the FREQUENCY of GABA-mediated chloride ion channel opening. SAR: Benzene ring A fused to a 7 – membered diazepine ring B Module 1 – Organic Medicinal Chemistry Page 13 of 15 RJAV 2022  ATYPICAL ANTIPSCHOTICS 3. Insulin Zn suspension 4. Mixture of crystallized and amorphous form of insulin in 1. Dibenzoazepine – Loxapine acetate buffer 2. Dibenzodiazepine – Clozapine 3. Dibenzothiazepine – Quetiapine Long-acting insulin 4. Benzoxazole – Risperidone 5. Thienobenzodiazepine – Olanzapine 1. Insulin Glargine (Lantus) 6. Dihydroindolone – Ziprasidone Asparagine at a-21 is replaced with Glycine 7. Dihydrocarbostyril – Aripiprazole 8. Benzamide – Amisulpride 2. Insulin Detemir (Levemir) Terminal threonine is dropped and myristic acid is attached Phenothiazines to the B29 lysine 3. Insulin Degludec (Tresiba) Threonine at B30 is removed and the lysine at B29 is conjugated to hexadecenoic acid ANTINEOPLASTIC AGENTS SAR prevent, inhibit or halt the development of a neoplasm or 6-6-6 system, two benzenes are linked by Sulphur and tumor. nitrogen At 2, + EWG substituent (↑EN = ↑activity) Tumor/Neoplasm – collection of abnormally proliferating cells Position 10 and amino nitrogen must be separated Benign neoplasm – does not invade surrounding tissues by a 3-carbon chain Malignant neoplasm – invade and metastasize to all parts 2 carbon chain (↑antihistaminic & anticholinergic of the body effect) Ex. Promethazine Phases of Cell cycle Amine is always tertiary 1. G0 phase or Resting phase Butyrophenones the cell is not committed to division 2. G1 phase RNA & proteins are synthesized. Cells grow larger. SAR 3. S phase At C-4, + tertiary amino group, essential for neuroleptic DNA synthesis & replication occurs activity Highest activity if cyclic form p-fluoro, aids activity 4. G2 phase (Fluorobutyrophenones) DNA synthesis ceases. RNA & other enzymes (e.g., modification of the 3-carbon propyl chain decreases topoisomerase I & II) are produced to prepare for cell neuroleptic potency. duplication ANTIDIABETIC AGENTS 5. M phase or mitosis cell divides into 2 daughter cells INSULIN Cell cycle non-specific agents Produced by B-cells of the pancreas are not dependent on the cell being in a particular phase of Promotes the absorption of glucose the cell cycle for them to work - they affect cells in all phases Hexamer: form for the storage of the cell cycle Monomer: form that is absorbed and interacts with the insulin receptor Cell cycle specific agents act on the cells in a specific phase CATEGORIES OF INSULIN: Rapid acting insulin 1. Insulin Lispro (Humalog) Lysine and Proline exchanged at positions B28 and B29 Stabilized by cresol preservative into hexamers 2. Insulin Aspart (Novolog) Formed by replacement of Proline at B28 w/ Aspartic acid I. CELL CYCLE NON-SPECIFIC AGENTS 3. Insulin Glulisine (Apidra) Glutamic acid replaces lysine at B29 and Lysine replaces A. Alkylating agents asparagine at B3 MOA: alkylation of reactive species on DNA Short acting insulin 1. Nitrogen mustards Mechlorethamine 1. Regular Insulin Melphalaan Soluble crystalline Zn insulin Chlorambucil Only IV Bendamustine Ifosfamide Intermediate acting insulin Cyclophosphamide 1. Neutral Protamine Hagedorn/ NPH/ Isophane Insulin Note: Cyclophosphamide/Ifosfamide due to tox: hemorrhagic cystitis 2. Suspension of insulin in a complex w/ Zn and protamine metabolite Acrolein in PO43- buffer AD: MESNA Module 1 – Organic Medicinal Chemistry Page 14 of 15 RJAV 2022 2. Ethyleneimine; Methylmelamines G2–phase specific Thiotepa Altretamine 1. Bleomycin source: S. verticillus 3. Alkyl sulfonate MOA: binds to DNA, generates free radicals Busulfan toxicity: pulmonary toxicity (pulmonary fibrosis) 4. Nitrosoureas 2. Epipodophyllotoxins Carmustine semisynthetic derivatives of podophyllotoxin, isolated from Streptozocin mayapple root MOA: inhibits Topoisomerase II 5. Triazene Drugs: Etoposide, Teniposide Dacarbazine Temozolomide M–phase specific 6. Methylhydrazine 1. Taxanes Procarbazine Isolated from the bark of pacific yew tree (Taxus brevifolia) MOA: stabilize microtubules, inhibit depolymerization 7. Platinum coordination Complexes Drugs: Paclitaxel, Docetaxel Cisplatin Carboplatin 2. Vinca alkaloids Oxaliplatin source: Catharanthus roseus leaves MOA: inhibit tubulin polymerization and microtubule Note: Cisplatin formation a/e: nephro- & ototoxicity Drugs: Vincristine, Vinblastine, Vinorelbine AD: Amifostine III. HORMONAL THERAPY B. Antibiotics 1. Glucocorticoid receptor agonist – Prednisone 1. Anthracyclines & Anthracenedione Anthracyclines – Doxorubicin, Daunorubicin, Epirubicin, 2. Selective Estrogen Receptor Modulator – Tamoxifen for Idarubicin premenopausal px w/ HR (+) breast ca Anthracenedione – Mitoxantrone MOA: inhibit topoisomerase II & intercalate DNA 3. Selective Estrogen Receptor Down regulator – Fulverstant S/E (Anthracyclines) – Cardiotoxicity AD: Dexrazoxane 4. Aromatase inhibitors – Anastrozole, Letrozole, Exemestane for 2. Others postmenopausal px with HR (+) breast ca Dactinomycin/Actinomycin D (Streptomyces spp) MOA: intercalates between GC base pairs of DNAS