Lecture-by-ms-noreen.pdf

MODULE 1: MEDICINAL CHEMISTRY Lecture by John Mitchell L. Lua I. INTRODUCTION ORGANIC MEDICINAL CHEMISTRY Is a branch of science that is devoted to the discovery and development of new agents for treating diseases. It deals with the p...

MODULE 1: MEDICINAL CHEMISTRY Lecture by John Mitchell L. Lua I. INTRODUCTION ORGANIC MEDICINAL CHEMISTRY Is a branch of science that is devoted to the discovery and development of new agents for treating diseases. It deals with the physicochemical properties of drugs that Reference for PC affect its biological action. Octanol – organic solvent Natural compounds: from natural resources; e.g., Water – aqueous solv Morphine from P. somniferum ­ PC, ­ Lipophilicity, ­ absorption Synthetic compounds: laboratory, e.g., Methadone, Phospholipid bilayer: Hydrophilic head, Lipophilic tail (L - similar effect with Morphine, ends withdrawal of absorption, H – excretion) Morphine Drug: is any agent intended for the use of Acidity and Basicity: ionization of acids and bases plays a Diagnosis (hydrophonium for Myasthenia Gravis role with substances that dissociate into ions. Treatment The ionization constant indicates the relative strength of Mitigation the acid and base. Prevention Strong A + B: 100% dissociation (HCl, Sulfiruc Acid) Cure Weak A + B = partial (80%) of disease in human or in other animals Þ Ionized: Polar, Excreted Þ Unionized: Non-polar, Absorbable ISOSTERISM The interchangeability of one molecule with another molecule ISOSTERES Compounds having the same number and arrangement of electrons *** Þ Example: Benzene and Pyridine (both planar and Lipophilic/Hydrophobic Hydrophilic interchangeable Unionized Ionized Non-polar Polar PHARMACODYNAMICS Absorbed Excrete This refers to the relationship between drug concentration at Salt Formation the site of action and the pharmacologic response Þ Depends on the desired physicochemical or pharmacological RECEPTOR properties A specialized target macromolecule (ligand) that binds a drug Þ Provide slower dissolution, slower and mediates its pharmacological action. (Lock-and-key bioavailability, and longer duration of concept) action Þ Other salts are selected to greater RESPONSE (interchangable) stability, less local irritation at the Ø Is due to the alteration the biological process that were absorption stem or less systemic toxicity present prior to the drug’s administration. If there’s a salt of aspirin = ­ stability Ø Magnitude related to the concentration of the drug E.g., *Diclofenac = Voltaren: Na salts; Cataflam: K salts achieved at the site of its action. (higher conc, high effect) Dissolution Particle size = ¯ PS, ­SA, ­ Solubility = ­ absorption ¯ DRUG ACTION Polymorphism = many shapes Ø Results from the interaction of drug molecules with Chirality = mirror images either normal or abnormal physiological processes Ø The ability of drug to elicit response is influences by II. DRUG METABOLISM various physicochemical properties DRUG METABOLISM / BIOTRANSFORMATION Plays a central role in the elimination of drugs and PHARMACOKINETICS xenobiotics (foreign compounds) from the body. This refers to the study of rate processes involved in the This is an essential tool for pharmacists in their role of absorption, distribution, metabolism, and excretion of drugs and selecting and monitoring appropriate drug therapy for their their relationship to the pharmacological, therapeutic or toxic patients responses in animals or humans. Conversion of a drug to a more readily polar, water- excretable product. *IV 100% absorption bioavailability, directly to systemic circulation FIRST PASS EFFECT PHARMACOKINETICS FACTORS AFFECTING DRUG ACTION A phenomenon in which the drug undergoes extensive metabolism before it reaches the systemic circulation. Drug Polarity: relative measure of a drug’s lipid and water solubility is usually expressed in terms of partition Oral, Rectal -erratic coefficient. Enterohepatic recirculation: Þ *Partition coefficient: ratio of solubility of the Þ 1/3 of the drug undergoes first pass effect passing compound in an organic solvent to the solubility through the portal hepatic vein. 2/3 to systemic of the same compound in an aqueous circulation environment.  III. PHASES OF METABOLISM PHASE I: FUNCTIONALIZATION REACTIONS EXEMPTIONS TO DRUG METABOLISM FUNCTIONALIZATION REACTION PRODRUGS Introduction of a polar group (-COOH, -SH, -OH, - Are inactive derivatives of active drug molecules that are NH2) into a xenobiotic molecule. converted to parent drug molecules in the body, typically Two ways: by enzymatic processes in the body, to circumvent Þ Direct introduction: Hydroxylation (H2O) problems related to the pharmacokinetics of a molecules Þ Unmasking of functional groups: Hydrolysis (+H2O- pharmacologically active form. decomposition) Inactive >>> active Enzyme system: Mixed function Oxidases / Active >>> active Monooxygenases Active >>> toxic Purposes: HYDROLYSIS Þ Mask the bitter taste (Chloramphenicol to Addition of water molecule to esters, amides, and their Chloramphenicol palmitate isosteres. Þ Increase lipophilicity *Susceptibility = Acyl halide > Anhydride (AAETCACU) Þ Ester (most s) (least stable) Þ Thioester Þ Carbonate Þ Amide Þ Carbamate *all ACEi are prodrug except Captopril, Enalaptilat, Lisinopril they are “acute ACEis” Þ Ureide (least s) (most stable) Types: Carboxylic acid derivatives usually undergoes on this reaction Þ Carrier-linked: activated by hydrolysis (H2O) = Example: Aspirin = Salicylic Acid + Acetic Acid decomposition § Bipartite – drug + carrier OXIDATION e.g., Prednisolone – drug (less soluble, but added carrier more soluble) Most important and common, main metabolic pathway in Phosphate – carrier Phase I § Tripartite – drug + linker + carrier Enzyme system: mixed function oxidases/monoxygenases e.g., Pivampicillin CYP450 enzyme: addition of oxygen to the substrate § Co-drug – synergistic drugs (1+1=3) Þ CYP1A2: Acetaminophen, Alcohol Sulfasalazine linked by Azo group Þ CYP2E1: Alcohol (For IBS) Þ CYP2D6: Most studied group, antidepressants Þ CYP3A4: Superfamily, majority of the drugs are Þ Bio-precursor drugs: metabolized here § Oxidative process – Add O2, remove H2, Example: Acetaminophen to NAPQI adda bond Acetanilide to Paracetamol § Reductive process – Add H2, remove O2, Phenylbutazone to Oxyphenbutazone remove bond REDUCTION NON-TOXIC METABOLIZED INTO TOXIC METABOLITE Nitro and Azo compounds are converted to amino Acetaminophen metabolized into N- derivatives. acetylparabenzoquinoneimine Þ Aldehyde & Ketone –1° alcohol & 2° alcohol (NAPQI) Þ NO2 – produces 1 amine ACT toxicity: N-acetylcysteine Þ N=N – produces 2 amines Hepatotoxicity Þ Disulfide – produces 2 SH Maximum dose/day: 4g Reduction on disulfiram yields 2 thiols Fever is every 4hrs; if not every 6 hrs Reduction of the red dye prontosil yields Sulfanilamide Sulfation, Glucuronidation, Oxidation Reduction of Chloral hydrate ACTIVE DRUG WITH ACTIVE METABOLITES Diazepam metabolized into Oxazepam and Temazepam Chloral Hydrate aka rohypnol, knock put drug, date rape and thru Glucuronic acid conjugation roofies = Anterograde amnesia Diazepam - long t1/2; OT short t1/2  PHASE II: CONJUGATION REACTIONS Co-factor: Acetyl-coa CONJUGATION REACTIONS Attachment of small polar endogenous molecules such as Examples: glucuronic acid sulfate and amino acids to the phase I Þ Hydralazine (vasodilator, antihypertensive) metabolites of parent drugs. Þ Isoniazid (antiTB) Increase in solubility/ polarity Þ Procainamide (antianginal) Enzymes: Transferases Þ Sulfonamide (antibiotics) Exceptions: Fast acetylators: more frequent, more dose Þ Methylation & Acetylation: terminate/attenuate METHYL CONJUGATION biological activity instead of increasing water Plays an important role in the biosynthesis of many solubility, endogenous compounds (epinephrine and melatonin) and Þ Glutathione Conjugation: protect body against in activation of numerous physiologically active biogenic chemically active compounds & metabolites. amines. Enzyme: Methyltransferases GLUCURONIDATION Co-factor: S-adenosylmethionine Most common metabolic pathway in Phase 2 Example: Morphine when methylated becomes Codeine Readily available supply of D-glucuronic acid Norepinephrine when methylated becomes Epinephrine Numerous fx groups that can be combined enzymatically (uses COMT, catechol-O-transferase) with glucuronic acid The glucuronyl moiety which when attached to xenobiotics greatly increases the water solubility of the conjugated product Enzyme: UDP-Glucuronyltransferase Co-factor: UDP-Glucuronic Acid Examples: Þ Chloramphenicol – may cause grey-baby syndrome in neonates - ­ Sulfation, ¯ glucuronidation - Tx: Phototherapy - *Nitro reduction – Aplastic Anemia Þ Unconjugated Bilirubin – Kernicterus - Conjugated – excreted - Unconjugated – brain = hyperbilirubinemia, jaundice, Kernicterus, CNS, GS ACTH - OGS SULFATION **memorize examples Phenolic group requirement (most drugs with phenol group will most likely undergo this metabolism). IV. STRUCTURE ACTIVITY RELATIONSHIP Enzymes: Sulfotransferase STRUCTURE ACTIVITY RELATIONSHIP Co-factor: 3’-Phosphoadenosyl-5’-phosposulfate (PAPS) Is an approach designed to find relationships between Example: chemical structure (or structural-related properties) and Þ Paracetamol to O-sulfate conjugate (or target property) biological activity of studied *** Methyldopa, Acetaminophen, Terbutaline, compounds Albuterol, Phenacetin Determination of fx groups that is responsible for exerting the target biological effect ACYLATION/ GLYCINE CONJUGATION Pharmacophore: molecular framework defining the The first mammalian drug metabolite isolated is important or necessary components responsible for the *hippuric acid, a product of benzoic acid conjugation. biological activity of the compound. Enzymes: N-acyltransferase Ø Mother drug/lead drug – standard or basis to Co-factor: Glycine develop newer sets of drugs Determination differences in activity, and know changes GLUTATHIONE CONJUGATION pharmacological properties by performing minor changes in Serves as a protective function by acting as an anti- drug molecules oxidant Develop a new drug that has, increased activity and fewer Glutathione metabolism to metabolize H2O2 side effects making it water, so it can be readily excretable. Enzyme: Glutathione-S-transferase NEW FUNCTIONAL GROUPS Co-factor: Glutathione FUNCTIONAL GROUPS Defined as an atom that have definite properties. They give functionality to a particular compound and determine their properties. New Nitrogen Functional Groups: Þ Azo vs Hydrazo Þ Azido ACETYL CONJUGATION Þ Nitroso vs Nitro Metabolism for N-containing groups Þ Carbinolamine vs Hydroxylamine Usually serves to deactivate drugs except N - New Sulfur Functional Groups Acetylprocainamide which is toxic Þ Sulfoxide Enzyme: N-acetyltransferase  Þ Sulfone Þ Sulfonamide New Ester and Amide Functional Groups Þ Carbamate Þ Ureide Þ Guanide HANTZSCH-WIDMAN NOMENCLATURE HANTZSCH-WIDMAN NOMENCLATURE Provides a more systemic method of naming heterocyclic compounds that is not dependent on prior carboxylic names. It makes use of the same heteroatom prefix defined on the table followed by a designated ring size and saturation. Heteroatom Prefix Oxygen Oxa- Sulfur Thia- Nitrogen Aza- Phosphorus Phospha- Silicon Sila- Boron Bora- Selenium Selena- As outlined in the table, each suffix consists of a ring size root and an ending intended to designate the degree of saturation in the ring. Ring Size Saturated Unsaturated 3 (ir) -irane -irine 4 (et) -etane -ete 5 (ol) -olane -ole 6 (in) -inane -ine 7 (ep) -epane -epine 8 (oc) -ocane -ocine 9 (on) -onane -onine 10 (ec) -ecane -ecine  Oxazole vs Thiophene COMMON HETEROCYCLIC RINGS COMMON HETEROCYCLIC RINGS Pyrrole vs Pyrrolidine Thiazole vs Thiazolidine Indole vs Indoline CHANGES IN STRUCTURE SIZE AND SHAPE OF MOLECULE Number of methylene groups in chain and rings Þ Example: Antipsychotics to Tricyclic Pyridine vs Piperidine Antidepressants Degree of unsaturation Þ The higher the degree of unsaturation, the more rigid the molecule is ­# of double bond ­ rigidity, ­restricted conformation to adapt Purine vs Pyrimidine ­ energy to break the bonding Most stable in degree of unsaturation: triple bond Addition/Removal of Ring Ø Example: Benzylpenicillin vs. Diphenicillin Ø It may affect the pharmacokinetic properties Pyrazine vs Piperazine STEREOCHEMISTRY – the study of diff spatial arrangement of atoms in molecules Enantiomers – isomers whose three-dimensional arrangement of atoms results in non-superimposable mirror images. Examples: Þ R-thalidomide vs S-thalidomide: S caused Phocomelia Quinoline vs Isoquinoline vs Quinazoline INTRODUCTION TO SUBSTITUENTS Addition of methyl ring Þ Results to lesser side effects Þ Results to loss of activity Steric effect – can affect the shape or reactivity of the ions and molecules; if maraming substituents = UNSTABLE Imidazole vs Imidazoline vs Benzimidazole Group Lipophilicity Water Solubility Methyl Increased Decreased Fluoro/chloro (EW) Increased Decreased Hydroxyl Decreased Increased Amino Decreased Increased due to salt formation Carboxylic/Sulfonic Decreased Increased Furan vs Pyran V. ANTI-INFECTIVE AGENTS SAR LOCAL ANTI-INFECTIVES aka GERMICIDES Anti-infectives that are used locally are called germicides Þ Disinfectant: used for inanimate objects Þ Antiseptic: used for living tissues; hands Disinfectants Antiseptic Chemical or physical tx that Application of an agent in a living Benzoxazole vs Triazole vs Tetrazole destroys most vegetative tissue in the purpose iof preventing microbes, but not spores, in infection inanimate objects Low-enough toxicity & non-irritating to tissues Rapid and sustained lethal action against microorganisms Low surface tension: spreadability Retain activity in the body fluids ANTI-INFECTIVES SAR  ALCOHOL AND ITS RELATED COMPOUNDS Depend on their ability to liberate oxygen in the tissues SAR: RULE!! Most effective against anaerobic bacteria and can be used Þ The antibacterial potencies of the primary for cleansing wounds alcohols increase with molecular weight until 8- MOA: carbon atom. Þ Peroxide and Perborates: liberation of nascent Þ Chain length: increases the ability to penetrate oxygen and oxygen radicals microbial membranes Þ Permanganate: Protein denaturation by direct Þ Branching: decreases the alcohol’s potency redox reaction Þ Potency: 10>20>30 Examples: MOA: Protein denaturation Þ Carbamide Peroxide – Urea + Hydrogen Peroxide Antiseptic & disinfectant in the treatment of oral ALCOHOL & RELATED COMPOUNDS ulceration Alcohol, USP (95%) Þ Hydrous Benzoyl Peroxide – most effective topical Common name: agent for acne control Ethanol MOA: protein denaturation by direct redox Grain Alcohol reaction Wine spirit Spiritus vini rectificatus HALOGEN-CONTAINING COMPOUNDS Ø Most widely abused of all recreational drugs Iodine – oldest germicide that is still used today Þ MOA: protein inactivation by iodination of aromatic Examples: residues (F&Y) or oxidation of sulfhydryl groups. Þ Denatured alcohol – rendered unfit for drinking Þ Iodophores/Iodine solubilizers: complexes of Due to: Benzene and Methanol iodine and non-ionic surfactants Þ Rubbing Alcohol, 70% - astringent rubefacient, Complexes retain the germicidal properties of mild local anesthetic iodine Þ Dehydrated Alcohol, 99% aka absolute alcohol – - Decreases volatility for lab solvents - Non-irritating Þ Ethylene oxide – aka gas sterilant; sterilize *** temperature-sensitive medical equipment MOA: alkylation of functional groups Aldehyde Þ Formaldehyde – aka Formalin; disinfectant and embalming fluid Methanol is added to prevent polymerization (clump) MOA: direct non-specific alkylation of functional groups Þ Glutaraldehyde – aka Cidex; sterilant – sterilizing sol’n for equipment & instruments that cannot be autoclaved (heat-labile equipments) In alkaline sol’n to prevent polymerization MOA: alkylation of functional groups PHENOL AND ITS DERIVATIVES Chlorine – releases hypochlorous acid when water is PHENOL, USP dissolved in water Ø Aka Carbolic acid* Þ Used as municipal water disinfectant* Remains the standard to which the activity of most Þ Halazone – disinfect drinking water germicidal substances is compared. Þ Oxychlorosene Na (Clorpactin) – marked rapid- Phenol coefficient: is defined as the ratio of dilution of a cidal action against most microorganisms, given test disinfectant to the dilution of phenol that is required to kill a strain of Salmonella typhi. CATIONIC SURFACTANTS >1 = more effective All of the cationic surfactants are quaternary ammonium used loss on antibacterial potency. vs gram (-) bacteria but is inactive against gram (+) and § **Enol – must be intact anaerobes § C2 sub – decrease activity § 4-dimethylamino – must be intact Þ C7 sub with EWG enhances activity *Cl – Increase phototoxicity (Demeclocycline) SIADH Syndrome of Inappropriate Antidiuretic Hormone; cannot pee DI: dry inside SIADH: soaked inside Doxy: prophylaxis of leptospirosis & malaria SAR: Þ 3-methoxy group: confers B-lactamase stability; weak antibacterial potency Þ 4-methyl group: increase stability to B- lactamases and gram (-) activity but lowers gram (+) activity Þ 4,4-gem-dimethyl substitution: slight decrease in antibacterial potency after oral administration. POLYPEPTIDES One of the most powerful antibiotics AMINOGLYCOSIDES T/E: Nephrotoxic Prototype: Streptomycin (1st aminoglycoside) Most important: Vancomycin Isolated from Streptomyces griseus All aminoglycosides are absorbed poorly when given Vancomycin orally. However, some of the administered for GI Infections Isolated from Streptomyces orientalis (Kanamycin and Neomycin) eyedrop Vs gram (+) bacteria MOST Toxic: Tobramycin MOA: binds with D-ala-D-ala (cell wall of bacterias) MOST Nephrotoxic: Neomycin S/E: nephrotoxic, ototoxic, vestibulotoxic PROTEIN SYNTHESIS INHIBITORS 30 s Inhibitors - 50s inhibitors CEL at 50 Tetracycline Clarithromycin all are macrolides (Azithro) Aminoglycoside Erythromycin buy TrenTa Lincosamide SAR: Þ Contains one or more amino sugar linked to an TETRACYCLINES aminocyclohexitol ring by a glycosidic bond One of the most important broad-spectrum antibiotics Þ Ring I – important for broad-spectrum activity that is obtained from fermentation or chemical § Amine functions at ‘2 and ‘6 confers transformation resistance to enzymatic acetylation at 6- amino group = increase activity § Methylation at C6 or at 6-amino – confers resistance to enzymatic acetylation of the 6-amino group Þ Ring II – few modifications may be made without appreciable loss of activity in most of Octahydronaphthalene aminoglycosides X metal containing compounds Þ Ring III – appears to be less sensitive to structural PC: don’t take dairy products coz it contains Calcium changes as compared to ring I and II which is a metal HCl salts – oral administration (chelates) Ø If bonded with metal = + size. Thus, low absorption Capsule – masks bitter taste MACROLIDES NUCLEIC ACID SYNTHESIS INHIBITORS QUINOLONES SAR Prototype: Erythromycin Has three common chemical characteristics Prototype: Nalidixic Acid* Þ Large lactone ring – 12, 14, 16 Synthetic antibacterial agents Þ Ketone group For urinary tract infection UTI Þ Glycosidically-linked amino sugar SAR: Þ 1,4-dihydro-4-oxo-3-pyridinecarboxylic acid – essential for the activity Þ Pyridine must be annulated with an aromatic rin Þ MOA: Inhibition of DNA gyrase or DNA topoisomerase Þ Substitution: § 2 – reduces activity § 5,6,7,8 – good effect § F at 6 – significant enhanced effect § Alkyl at 1 – essential for activity (lower alkyl preferred) ex. Methyl & ethyl (methyl is preferred) § Aryl at 1 – antibacterial activity (cyclics) § Halogen at 8 – phototoxicity SULFONAMIDES SAR Erythromycin First effective chemotherapeutic agents that could be used Ø The prototype drug systematically for the cure of bacterial infections *Salt forms: Prototype: Sulfanilamide 1. Stearate – film-coated to protect it from acid Prontosil – brilliant red dye that is reduced to degradation sulfanilamide (azo-linkage) 2. Ethylsuccinate – absorption is enhanced by food 3. Estolate – cholestatic hepatitis (toxic) LINCOMYCIN Isolated from Streptomyces lincolnensis Resemble macrolides in terms of broad spectrum and mechanism of action Prototype: Lincomycin Nomenclature Þ Aniline-substituted: Sulfanilamide Þ Prodrug: Sulfasalazine* Þ Non-aniline substituted: Furosemide, Tolbutamide (not antibiotics) CLINDAMYCIN SAR: Often used for anaerobic infections Þ Aniline-amino group – essential for the activity Also used for acne Þ Aromatic ring – must be para-substituted Topical clindamycin Þ Addition of Acyl groups on amide will make prodrugs Þ Must be structurally related to PABA MOA: Inhibits Dehydropeptidase synthase by being like suicidal drug. Þ ALL ARE ESSENTIAL TO ACTIVITY! MUST BE CHLORAMPHENICOL STRUCTURALLY RELATED TO PABA! Unclassified antibiotic Isolated from Streptomyces venezuelae S/E when it undergoes nitro reduction: Aplastic Anemia S/E lack glucuronidation: Grey Syndrome  VI. ANTI-FUNGAL AGENTS SAR ANTIFUNGALS: POLYENES Contains a system of conjugated double bonds in macrocyclic lactone ring that are larger and similar to Erythromycin 26-membered: Natamycin 38-membered: Nystatin, Amphotericin B MOA: Binds with ergosterol and acts as a false membrane Nucleoside 1. Flucytosine MOA: Taken up by fungi and is converted to 5-fluorouracil which inhibits thymidylate synthase. Taken with Amphotericin B to decrease its resistance. VII. ANTI-MALARIAL AGENTS SAR ANTIMALARIAL AGENTS: GENERALITIES Drug Source Other notes Have one common structural feature – a quinoline ring or a Amphotericin B Streptomyces Indicated for the tx of severe quinoline with additional benzene added (acridine) nodosus life-threatening infections; Used against Plasmodium spp. systemic mycoses Must never be given IM ANTIMALARIAL AGENTS: CINCHONA ALKALOIDS (toxic) Quinine and Quinidine – prophylactic use and is indicated Nystatin Streptomyces Not absorbed systematically for malaria caused by P.falciparum resistant to other noursei when given orally an is too agents like chloroquine. >> Quinine is given toxic to be given S/E: Cinchonism (nausea, vomiting, tinnitus and vertigo) parenterally. Hence, is administered topically. ANTIMALARIAL AGENTS: 4-AMINOQUINOLINE Closest of the anti-malarial that are based on quinine Griseofulvin structure. This group is substituted at the same position 4 as increase absorption, increased fats intake quinine and have an asymmetric carbon equivalent to Isolated from Penicillum griseofulvum quinine’s C9 position. Used for ringworm infections Just as the quinine, both isomers are active nd the 4- Oral bioavailability is poor aminoquinoline racemic mixtures are used. MOA: Mitotic spindle poison Hydroxychloroquine – used for DMARD, rheumatoid arthritis ANTIFUNGALS: ALLYLAMINES MOA: Inhibits ergosterol synthesis via inhibiting squalene epoxidase Examples: Terbinafine, Naftiline, Tolnaftate (not Chloroquine & Chloroquine PO4 an allylamine) Þ Prototype of antimalarials Þ DOC for erythrocytic malaria, also used in SLE and RA - HCl – parenteral - PO4 – oral Primaquine ANTIFUNGALS: AZOLES Þ 8-aminoquinoline MOA: Inhibits 14-a-demethylase Þ DOC exoerythrocytic malaria Þ High conc: Fungicidal (kill) WOF: hemolytic anemia – G6PD px Þ Low conc: Fungistatic (stop the proliferation) ANTIMALARIAL AGENTS: POLYCYCLIC Synthetic antifungal agents that can achieve selectively Artemisinin – newest drug of this class from Artemisia annua for the infecting fungus over host Þ Artesunate – water-soluble derivative Þ Artemether – combined with lumefantrine in co- SAR: artem, as a DOC vs falciparum malaria. Þ Must contain a weakly basic imidazole or Others: triazole ring bonded by a nitrogen-carbon Þ Doxycycline linkage Þ Lumefantri Þ Most potent azoles possess 2-3 aromatic rings ***** with at least one Halogen substituent (Cl or F) § F – yields the most potency Þ Substitution at other positions of the ring will yield inactive compounds Þ The large non-polar molecules mimics the non- polar steroidal part of lanosterol 14-a- demethylase § Non-polar functionality confers high lipophilicity except Fluconazole  B R I C K S N O T E S | 12 ANS AGENTS SAR CHOLINERGIC AGONISTS parasympathomimetic ADRENERGIC ANTAGONISTS CHOLINERGIC AGONISTS: ACETYLCHOLINE ADRENERGIC AGONISTS: DIRECT-ACTING Pharmacopore: Acetylcholine (sympathomimetic) Þ Acetoxy/ester portion Pharmacophore: Phenylethylamine Þ Ethylene bridge Alpha and Beat are the positions of the carbon with respect Þ Quaternary Nitrogen to amine Nitroge, Þ ALL ARE ESSENTIAL FOR THE ACTIVITY!! – Substitution at R1 overall structure should not be modified Ø Increase b-activitt Ø Decrease a-activity SAR: Ø Decrease degradation by MAO Þ Acetoxy/Ester Portion § The methyl group cannot be extended Substitution at R2: Methyl but may be replaced with NH2 Ø Increase a2 activity § Carbamates – not easily hydrolyzed and Substitution at R2: Ethyl longer DOA Ø Increase B-activity Þ Ammonium Group Ø Increase CNS & Oral activity § Cannot be altered Ø Decrease degradation by MAO Þ Ethylene Bridge Aromatic substitution § Addition of methyl – increases Ø 3-OH is for alpha activity muscarinic selectivity; longer DOA Ø 4-OH is for Beta activity Ø 3&4- OH – both Polar: decrease oral activity Metabolized by COMT leading to shorter DOA Aromatic substitution Ø 3-OH replacement by Methanol will CHOLINERGIC AGONISTS: CARBAMATES Increase Beta activity Indirect-acting cholinergic agonist: increase ACh Decrease degradation by COMT Prototype: Physostigmine Ø Moving 4-OH to 5-OH will Equivalent esters of ACh and is recognized by AChE but Increase B2 activity not easily hydrolyzed by the said enzyme. Decrease degradation by COMT Aromatic substitution Ø Lack of 1 OH – resistance to COMT Ø Absence of both OH – indirect activity ADRENERGIC ANTAGONISTS: ALPHA BLOCKERS (symoatholytic) CHOLINERGIC ANTAGONISTS Prototype: Prazosin CHOLINERGIC ANTAGONISTS: ATROPINE: Amino Alcohol Ester Pharmacopore: Quinazoline Ring Prototype: Atropine Contains tropane ring system SAR: Þ 4-amino group – essential for activity XI. CNS AGENTS SAR Þ Positions 5,6,7,8 – can be varied ANXIOLYTICS, SEDATIVE, AND HYPNOTIC AGENTS Þ Piperazine BENZODIAZEPINES § 2nd position of the quinazoline Pharmacopore: Benzodiazepine ring § Can be any heterocyclic ring MOA: Increase frequency of opening of GABA-gated Cl § Piperidine or Piperazine Channel ADRENERGIC ANTAGONISTS: BETA BLOCKERS Prototype: Propanolol C=O – is essential for the activity Pharmacopore: Aryloxopropanolamine Ø Fused triazole or Imidazole ring at positions 1 and 2 – increases activity Ø Fused ring – Imidazole = MIDAZOLAM Ø IMIDAZOLE = increase activity, lipophilic, BBB SAR: X – substitution with EWG increases the activity = ­ CNS SAR: act Þ Aryl ring – can be varied with other 5-phenyl group = increases the activity heteroaromatic ring Ø Prime numbering in the aromatic ting indicates the Þ Branching & extension – both beneficial to possible attachment of substituents activity Ø 2’ or 2’ and 6’ – subs with EWG will ­the drug activity Ø 4’ substitution – will decrease the activit  B R I C K S N O T E S | 13 BARBITURATES SAR: MOA: Increase duration of opening of GABA-gated Þ R2 EWG substitution – increases the potency Cl Channel Þ 30 Amine § R-group must have a N-containing side chain on the ring N and must be separated by at least 3C! § Essential for the activity SAR: ANTIDEPRESSANTS: TCA Þ R1 alkyl substitution Tricyclic Antidepressant § Increase lipophilicity § Quick onset SAR: § Shorter DOA Þ Structure is similar to antipsychotic Þ Replacing Oxygen with Sulfur Þ 30 Amine § Increase lipophilicity § The ring side and side chain § Ultra-short acting effect Nitrogenmust be separated by at least Þ R5 Alkyl or Aryl substitution 3C! § Increase lipophilicity § Essential for the activity Þ The central ring system (7 membered-ring) ANTIPSYCHOTICS AND ANTIDEPRESSANTS makes the two aromatic rings skewed which is ANTIPSYCHOTIC AGENTS: PHENOTHIAZINE required for the activity Schizophrenic Phenothiazine OPIOID ANALGESIC Isolated from Papaver somniferum **Pharmacophore: Þ Aromatic Ring Þ Phenol Þ Tertiary Amine SAR: Þ Ring A is the aromatic ring ANESTHETIC Þ Ring A + 3-OH is the Phenol LOCAL ANESTHETICS § Addition of Methyl will result to Codeine Pharmacopore: § Addition of methyl or ethyl Þ Lipophilic ring that may be subtituted will decrease the activity Þ Linker (ester – Cocaine or amide – Lidocaine Þ Ring D contains tertiary amine (Xylocaine) Þ Retained activity: Þ Amine group that is usually tertiary amine § Removal of Ring E: will result to morphinans such as Levorphanol which SAR: are more potent and longer acting than Þ Aromatic ring Morphine 7x § Adds lipophilicity to the anesthetic § Removal of a 6-OH or Alkene at 7 or 8 § Substituents may increase lipophilicity, § Removal of Ring C increase protein binding, increase DOA § Removal of Ring B and C § Para-substituted ester local § Removal of Ring C and D – will result to anesthetic has shown to increase Benzomorphans such as Pentazocine activity § Removal of ring B, C, E – will result to 4- § Para position – increase activity phenylpiperidines such as Fentanyl § Increase PB= decrease drug which is a flexible drug molecule 100x concentration more potent than Morphone Þ Decreased activity: § Removal of Ring D  B R I C K S N O T E S | 14 READ YOUR FOUNDATIONS To further understand organic medicinal chemistry, it is necessary to master the following subjects first: Þ General Chemistry Þ Organic Chemistry Þ Pharmacology Þ Biochemistry Þ Pharmacognosy Þ Microbiology The mentioned subjects will definitely help you correlate things to organic medicinal chemistry and strengthen your foundations MEMORIZE THE FUNCTIONAL GROUPS AND RINGS To easily identify structures, it is necessary first to memorize all the common heterocyclic rings. Not only will this be useful in organic medicinal chemistry but as well as other subjects such as Biochemistry and Pharmacognosy. Majority of the pharmacopore contains heterocyclic rings that will help you easily identify them. For easier memorization, master the different naming system such as Hantzsch-Widman nomenclature. APPLICATION After mastering the different concepts, go and try correlating the SAR of each drug class in Pharmacology. This will help you further memorize different uses and drug classes under Module 4 as well as their toxicities when you have mastered organic medicinal chemistry  IX. ANTI-NEOPLASTIC AGENTS SAR ANTINEOPLASTIC AGENTS: ALKYLATING AGENTS Class of drugs that are capable for forming covalent bonds. Major target: 7-position of Guanine (nucleophilic group present in DNA) Examples: Platinum compounds, Busulfan, Cyclophosphamide ANTINEOPLASTIC AGENTS: NITROGEN MUSTARDS Compounds that are chemically similar to sulfur mustards or mustard gas. Initial acid-base reaction is necessary to release the lone pairs of nitrogen. Examples: Mechlorethamine – di-alkylating agent that can alkylate two nucleophiles. ANTINEOPLASTIC AGENTS: MUST KNOWS