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What is the primary objective of medicinal chemistry ? Which disciplines are involved ?

What is the primary objective of medicinal chemistry ? Which disciplines are involved ?. The primary objective of medicinal chemistry is the design and discovery of new compounds that are suitable for use as drugs .

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What is the primary objective of medicinal chemistry ? Which disciplines are involved ?

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  1. What is theprimaryobjective of medicinalchemistry ? Whichdisciplinesareinvolved ? Theprimaryobjective of medicinalchemistry is thedesignanddiscovery of newcompoundsthataresuitableforuse as drugs. Thisprocessinvolves a team of workersfrom a widerange of disciplinessuch as pharmacy, medicineandotherrelatedareasmainly: analyticalchemistry, organicchemistry, pharmaceuticalchemistry, biochemistry, biology, pharmacology, drugmetabolismandtoxicology, mathematics, andcomputing,

  2. Inourlectures, wewillconcentrate on thefollowing main titles: • Researchareas of medicinalchemistry • Factorsaffectingbiologicalactivity of drugs • Drugaction • Functionalgroups (theirnomenclature, properties, reactions) • Heterocyclics (theirnomenclatureandproperties) • Stability of organiccompounds • Metabolism of organiccompounds • (aims, goodandbadaspects, metabolicphases, in vitroand in vivoexperiments, metabonates) • Pro-drugs • Structure-activityrelationships • Clinicaldrugdevelopmentprocesses Terminology of medicinalchemistrywill be given in all of thelectures

  3. Main researchareas of medicinalchemistry • Drugsynthesis • Structureidentification • Drugmetabolismstudies • Chemicalbasis of drugbioactivation • Pharmacologicalactivityscreening

  4. Sources of drugs Originallydrugsandleadswerederivedfromnaturalsources. Thesenaturalsourcesarestillimportantsources of leadcompoundsandnewdrugs, howeverthemajority of leadcompoundsarenowdiscovered in thelaboratoryusing a variety of sources, such as local folk remedies (ethnopharmacology), investigationsintothebiochemistry of thepathology of diseasestatesandhigh-throughputscreening of compoundcollections, databasesandotherliteraturesources of organiccompounds.

  5. FACTORS ACTING ON THE BIOLOGICAL ACTIVITY OF A DRUG MOLECULE I- PHYSICO-CHEMICAL PROPERTIES OF DRUGS -Solubility -Acid–Base Properties, Ionization, -pKa, pH, logP (oil/waterpartitioncoefficient) II-CHEMICAL PROPERTIES OF DRUGS -Chemicalbonds -FunctionalGroups -Heterocyclicrings -Stereoisomerism

  6. Solubility A degree of lipidsolubility is requiredtopassthroughmembranes but if it is toohigh, it is trapped in themembraneandbecomeineffective. Fortransportationwatersolubility is required.

  7. Acidbaseproperties Functionalgroupsdetermineandconferacidityandbasicity on a molecule. Human body is 70- 75% watermeaningthatwearedealingwith a dilutesolutionifwehave a drugmolecule of 200 M.A. and a dose of 20 mg

  8. pH solution 1 – 3.5 gastricjuice 5.3 intestine 6.4 saliva 7.4 blood We can determinetheionisationandabsorption site.

  9. Chemicalproperties Chemicalbonds Ifcovalentbondsoccurbetweendrugandreceptor, it is strongandproduceirreversiblelongerpharmacologicaleffects. İfionicbondoccur, it is weakerand has reversibleshorterpharmacologicaleffects.

  10. Properties of functionalgroupsdetermineactivity, solubilityetc. Thesewill be shownlater in detail.

  11. Stereochemistry Three dimensionalstructures in spacemayaffectthepharmacologicalactivity. Theisomersmayinteractwithreceptors in differentways. Racemicmixtures (enantiomers) haveasymmetriccarbonatoms (chiralcenter), differentpharmacologicaleffects, metabolismandtoxicity but samechemicalproperties.

  12. Receptor In order for drug molecules to exhibit their pharmacologic activity, they must interact with a biologic target, typically an enzyme, nucleic acid, or excitable membrane or other biopolymer(RECEPTOR). These interactions occur between the functional groups found in the drug molecule and those found within each biologic target.

  13. LeadCompound A compound of knownpharmacologicalactivity, theleadrelatedcompound is calledanalogue. Pharmacophorgroup Themoietyinteractingwithreceptorandresponsiblefrombiologicaleffect. Bioisosters Groupshavingsimilarpharmacophorestoeliminatesideeffects. C=S C=O ; SH, OH, NH2 ; ;

  14. Somedesirableproperties of leadsandanalogues • Bioavailability (a fraction of thedose of a drugthat is found in general circulation) • A moleculemasslessthan 500 • A calculatedvalue of log P lessthan 5 • lessthan ten hydrogenbondacceptorgroups (eg. –O- and –N- etc.) • lessthanfivehydrogenbonddonorgroups (e.g. NH and OH, etc.)

  15. Wewillnow be revievingfunctionalgroupsused in medicinalchemistry. Functionalgroupshaveratherthan C and H in themoleculeandtheyproduce a Chemical, pharmacological, ortoxicologicaleffect in thedrugformula. ALCOHOLS Anyhydroxyl (OH) moietylinkedtothesaturated C atom formsalcohols. Theseare generally polar groups. Alcohols can be used as solventsand as mostlysynthetic intermediates (SIM). Primaryalcoholshave 2, secondaryalcohols 1 andtertiaryalcoholshaveno H atoms. Alcoholsarenamedwiththe name of total hydrocarbonename plus-ole endingor alkyl name plusalcoholending: CH3-OH methanolormethylalcohol ; C2H5-OH ethanolorethylalcohol

  16. primarysecondarytertiary Primaryalcohols can be oxidizedtothecorrespondingaldehydesandketones but tertiaryalcohols not.

  17. (O) (O) aldehydecarboxylicacid Primaryalcohol secondaryalcohol tertiaryalcohol

  18. Esterification of alcoholwithcarboxylicacid is alsoimportant andproduces an ester functionalgroup: R-OH + R-COOH -> R-COOR + H2O PHENOLS Phenolshave OH groupslinkedtoaromatic ring.

  19. ETHERSTheoxygenebridge has twocarbonmoiety in ethers (symmetricalorasymmetrical) R-O-R or R-O-R1 Ether is a veryinertandnon-polar functionalgroup. Etherscan be used as solvents. Theiranestheticproperty is known. Ring ethersareknown as epoxydesandthesearegenerallytoxicchemicals. Ethyleneoxide Tetrahydrofurane (THF)

  20. Ethersarenamed as follows: Groupslinkedto –O- arealphebeticallyindicated: CH3-O-C2H5ethylmethylether C2H5-O-C2H5diethylether C6H5-O-C2H5ethylphenylether

  21. ALDEHYDES and KETONES Carbonylgropu at theend of carbonsystem is aldehyde, ifthecarbonylgroup is in themiddle, it is ketone: R-CHO (aldehyde) R-CO-R (ketone) Aldehydesaremorereactivethanketones. Theiroxidationproducescarboxylicacids (look at formerslides) Ketones can not be oxidizedsothey can be somehowinertandused as solvents (ie. acetone) One of themostimportantcommonreactions of carbonylgroup is imine formationwhich is rathertoxicgroup: C=O + H2N-R -> C=N-R + H2O (This is a reversiblereactionand it goeseasilybacktothecorrespondingcompounds byhydrolysis)

  22. Ketones can be namedbyindicatingfirstthegrouplinkedtocarbonylgroupalphebetically: CH3-CO-CH2-CH3 CH3-CO-CH3 EthylmethylketoneDimethylketone (ACETONE) C2H5-CO-C6H5 ethylphenylketone

  23. Fornamingaldehydes, weshouldknowthenames of carboxylicacids (pleaserefertocarboxylicacidslater). Aldehydes can not be preferred as soventsbecause of theirlabilityagainstoxidationandotherreactions. Bothaldehydesandketonesareused as SIM

  24. Ring ketonesareindicatedby-oneending Theirsubstitent name is oxo cyclohexanone 2-oxopentane

  25. CARBOXYLIC ACIDS andTHEIR DERIVATIVES -COOH (carboxylgroup = carbonyl + hydroxyl) Thisgroupformsa carboxylicacidmoietyand it is a polar andreactivegroup: H-COOH metanoicacid (formicacid) CH3-COOH etanoicacid(aceticacid) CH3-CH2-COOH propanoicacid(propionicacid) CH3-CH2-CH2-COOH butananoicacid(butyricacid) CH3-CH2-CH2-CH2-COOH pentanoicacid(valericacid) C6H5-COOH (benzoicacid) (pyridine-3-carboxylic acidor3-carboxypyridine)

  26. Correspondingaldehydesarenamedbyeliminatingicacidandinsertingaldehydesuffixes:Correspondingaldehydesarenamedbyeliminatingicacidandinsertingaldehydesuffixes: H-CHO (formaldehyde) CH3-CHO (acetaldehyde) CH3-CH2-CHO (propionaldehyde) CH3-CH2-CH2-CHO (butyaldehyde) CH3-CH2-CH2-CH2-CHO (valeraldehyde) C6H5-CHO (benzaldehyde) (pyridine-3-carbaldehyde or 3-formylpyridine)

  27. Importantreactions of carboxylicacids: (fromaceticacid)

  28. Whyarewepreparingcarboxylicacidderivatives: • Topurifycarboxylicacids (salts) • Toincreaseand/ordecreasethepolarity (salts, amides, esters) • Toprepareprodrugs (salts, amides, esters) (Acidgroup is generally not suitablefor oral route)

  29. Ring estersareknown as «lactones»: Ring amidesareknown as «lactames»: Diamidesfromdiacidesarecalled «imides»:

  30. Importantdiacids*: Oxalicacid (n = 0) Malonicacid (n = 1) Succinicacid (n = 2) Glutaricacid (n = 3) Adipicacid (n = 4) Pimelicacid (n = 5) *thesenameswill be requiredfortheimportantdrugmoleculeslater in pharmaceuticalchemistry Tomemorizethembear in mindthefollowingwords: oh mysuchgoodapplepie

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