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Medicinal Chemistry I Lecture 14 Quick Review A chiral center is defined as an atom in a molecule that is bonded to four different chemical species, allowing for optical isomerism. How can we determine the configuration of a compound? □find the chiral center. □determine the priority of the functional groups according to their atomic number. □set the group with the lowest priority backward. □start counting from the group with the first priority to the 2nd then 3rd . □If you are counting clock wise then the configuration is R, if you are counting anti clock wise then the configuration is S. R: clock wise. S: anti-clock wise. Diastereomers: are very similar compounds but are not mirror images. Diastereomers types: □Cis and trans □ compounds with more than one chiral center. How many isomers does a compound with more than one chiral center have? number of isomers=2n n: number of chiral centers. e.g. Suppose a compound has three chiral center, how many diastereomers we have? number of diastereomers=23 =8 If we have a compound with two chiral centers, then the possible diastereomers are: S,S R,R R,S S,R S,S and R,R are enantiomers R,S and S,R are enantiomers R,R and R,S are diastereomers Diastereomers have different physical properties so we can use this in separation and purification of enantiomers,, HOW?!! Suppose we have a mixture of R and S enantiomers. To separate them we may use an optically active molecule with known stereochemistry –for example we will call it R'- now we will obtain R,R' and S,R'. 1 R,R' and S,R' are diastereomers with different physical properties so their separation is easier than separation of enantiomers. We can separate them by physical methods depending on the difference in: Solubility, melting point ,boiling point. After separation break the bond between S-R' and R-R'. Now we have separate pure enantiomers. The figure above may help in clarifying the idea. Enantiomers have similar chemical and almost similar physical properties. Diastereomers have similar chemical properties but different physical properties. Examples on diastereomers: -Ephedrine Example on a compound with more than one chiral center. -Tartaric acid In Tartaric acid: S,S and R,R are enantiomers R,S and S,R are enantiomers R,R and R,S are diastereomers There is an exceptional case in compounds with more than one chiral center: R,S and S,R are supposed to be enantiomers but in some cases like in tartaric acid they are meso-compounds. meso-compounds means that mirror images compounds are identical, it happens when we have a plane of symmetry in the compound. ))هم نفس الجزيء بس بنطلع عليه من جهتين مختلفتين -pseudoephedrine So in this case instead of having 4 isomers we have 3 isomers. Chirality is a result of asymmetry. For example It's no way to find a plane of symmetry in our hands !! Plane of symmetry cancels chirality. Threonine is an amino acid. -They have different biological activity 2 In Threonine; First chiral center has hydroxyl and methyl. Second chiral center has amino and carboxyl. S,S and R,R are enantiomers R,S and S,R are enantiomers R,R and R,S are diastereomers S,S and R,S are diastereomers No plane of symmetry; No mesocompounds. Study Amino acids for the midterm exam. Geometric isomers E,Z isomers -If the highest priority substitutions -on two carbons- are on the same direction then we call the compound Z. -If the highest priority substitutions on two carbons are on the opposite direction then we call the compound E. Cis-trans system is used when we have two identical functional groups. E, Z system is used when we have two different functional groups. Priority is according to the atomic number. Examples Tamoxifen Z isomer has anti estrogenic activity "antagonist' E isomer has estrogenic activity "agonist' E isomer has lower affinity than Z isomer to the receptor. Our role as medicinal chemists is to convert a starting molecule with low activity, unwanted physical properties and side effects to a DRUG. We aim to increase the biological activity, increase affinity to the target receptor, improve physiochemical properties, reduce the side effects, etc.. We will concentrate on methodologies that we can employ to convert a lead compound into drug: Conformational restriction; fixation or freezing of a certain conformer. *methods used in conformational restriction: -single bond to double bond. -addition of a bulky group. -non-aromatic ring to aromatic ring. Acetylcholine Has muscarinic and nicotinic effect. Starting from acetylcholine structure and its muscarinic activity, how can we deign a drug with anti-muscarinic properties?!! 2 1 Acetylcholine displays muscarinic activity when it is in the staggered conformation. Staggered: in the opposite direction. We should fix the compound on the staggered conformation; to preserve its affinity toward the receptor. We fix staggered conformation by converting the single bond (where the arrow points) to double bond (trans conformation) To design an antagonist we should guarantee that the drug will interact and fit with the receptor but without activating the receptor. So we will change some functional groups to another that is similar in size. 3 Suggestion: -Chloride group on carbonyl groupoxygen number 2- to form acyl chloride; size is close but we will have more reactive compound which means more side effects not acceptable. of chloride to the nitrogen will actually form salt. -Add oxygen to the nitrogen group to form nitro group not acceptable; because nitro group is electron deficient while amino group is electron donating. -The compound is positively chargedno absorption, so we may remove a methyl group linked to nitrogen (in other words convert the quaternary amine to tertiary amine). -We need to reserve the ionization status of the nitrogen. -acetylcholine is easily metabolized in liver because it has an ester group, so we can: change the ester group to carboxyl group not acceptable because the resulted charge is problematic. replace oxygen number 1 to methyl group to result in ketone acceptable; ketone group is metabolized in a lower extent. -convert methyl group linked to nitrogen to ethyl group possible, but it still have agonist activity. -ester group is important because it forms hydrogen bonds, so we need to replace it with another functional group that forms hydrogen bonds but in the same time less susceptible to metabolism. -N= C (cyano-group) not acceptable; very small in size and we will lose ionic binding. -we may form enol, but in fact compounds and their enol forms are in equilibrium in solution. -convert the nitrogen to amidepossible. -We may add benzene ring possible, but it will change the size so it will affect the compound's fitness with the receptor. -aniline ringpossible. -We may transform the nitrogen to a cyclic structure instead of the three methylsacceptable. Substitute N(CH3) with this ring -nitrogen to sulfurnot acceptable; different interaction with the receptor. Enol form -convert to ether group, by removing oxygen number 2 (ethers are more resistant to metabolism). -Add chloride to the nitrogen groupnot acceptable because addition The above discussion is called isosteric substitution, which is the second method to modify structures. Instead of discussing similarities between molecules isosteric substitution discusses similarities between functional groups. 4 both of them occupy the same 3D space and form the same interactions. In medicinal chemistry we use the Isomers: similar compounds. Isosteres: similar functional groups; similar in their chemical, physical and electronic properties. *We are concerned with: -Size -Type of electronic interaction. -Solubility. -pka, etc.. Before start modifying our drug, we should study the functional groups of the receptor. There are functional groups important for activity and functional groups important for the affinity. When we want to design an antagonist we shouldn't change functional groups responsible for affinity, we should modify functional groups responsible for activity. In case of agonist we should focus on increasing both activity and affinity. Pharmacophore is the functional groups responsible for activity, their dimensional position, their relationships and distance between them. Just like saying that I want in position X a H-bond forming group and in position Y that is 90˚ from position X I want an ionic group and in a third site I want hydrophobic bond. It is important to know the pharmacophore before starting random changes in the structure. We start with a lead and end with a drug; the structure of the drug may be very different from that of the lead BUT biological substrate to design an inhibiter, for example the neuraminidase inhibitor "tamiflu" is designed from sialic acid. To be able to change the chemistry without changing interaction we should understand different properties of different functional groups. That’s why isosteric and bioisosteric terms have emerged. The first definition of these terms was in 1999, isosteric means that some molecules with different atoms but with similar electron distribution and similar size have similar physical properties. An example: CO2 and NO2. have similar 3D structure, similar density, solubility and electronic properties of the outer surface of the molecule. Isosteres Functional groups or substituents have similar size, volume and electronic distribution. Note here we do not talk about molecules, we talk about functional groups. Example: CH3 can be replaced by NH2 -Similar size -NH2 form hydrogen bond but CH3 do not. -NH2 is ionizable. So depending on our need we can replace them. -OH ad NH2 5 -Both form H-bond -NH2 is ionizable while OH is not, so if I want to design a drug that crosses BBB we replace –NH2 with –OH. -Fluoride and chloride are more resistant to metabolism. So may be used in sustained release drugs. -Chloride forms H-bonds. -amino and hydroxyl groups are metabolized easily. Nitrogen to form amide or with be replaced with CH2. To sum up, we can substitute a certain group with an equivalent group to change physical properties while preserving 3D size and affinity. -Oxygen of the ester -in the middle of the structure- can be replaced with Good Luck Done By: Banan Oqilan 6