PST NTA Level 5

NTA Level 5 • Semester 1 • PST05106 Phenols of Pharmaceutical Importance Pharmaceutical Organic Chemistry • Source Session/Topic 19 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 19: Phenols of Pharmaceutical Importance. Total Session Time: 120 minutes Prerequisites • None Learning Tasks By the end of this session students are expected to be able to: • Define phenols • List phenols and their isomers • Explain nomenclature of phenols • Draw chemical structure of phenols • List chemical properties of phenols • Explain chemical reactions of phenols Resources Needed: • Flip charts, marker pens, and masking tape. • Black/white board and chalk/whiteboard markers. SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Presentation |Definition of Phenols | | | |Brainstorming | | |3 |15 minutes |Presentation |Phenols and their Isomers | |4 |15 minutes |Presentation |Nomenclature of Phenols | |5 |15 minutes |Presentation |Chemical Structure of Phenols | |6 |15 minutes |Presentation |Chemical Properties of Phenols | | | |Buzzing | | |7 |35 minutes |Presentation |Chemical Reactions involving Phenols| | | |Group | | | | |discussion | | |8 |05 minutes |Presentation |Key Points | |9 |05 minutes |Presentation |Evaluation | SESSION CONTENTS. STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Definition of Phenols (10 minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What are Phenols? | | | |ALLOW few students to respond. | | | |WRITE their responses on the flip chart/ board. | | | |CLARIFY and SUMMARISE by using the content below | • Phenols are organic compounds which contain a hydroxyl (—OH) group attached to a carbon atom in a benzene ring. • Their chemical behaviour is very distinct from that of alcohols, because they are not capable of undergoing the same oxidation reactions that alcohols participate it. • Also, unlike alcohols, phenols are weak acids, since the phenoxide anion generated by the loss of the hydroxyl proton is resonance-stabilized: [pic] [pic] • Phenol is the active ingredient in some treatments for sore throats and is found in several lozenges and throat sprays. • It is used in the manufacture of many other compounds, such as aspirin, and Bakelite. STEP 3: Phenols and their Isomers (10 minutes). • Cresol is a trivial name for the three isomeric methylphenols. ortho-Cresol [pic] • The structure shown above is ortho-cresol, or 2-methylphenol; the other isomers are shown below. 2,6 xylenol [pic] • The cresols are commonly used as solvents, in disinfectants and deodorizers, and in the manufacture of other compounds (for example, the BHA and BHT shown below). • Xylenol is a trivial name given to the six isomeric dimethylphenols. • The name is derived from xylene, which is the trivial name for the three isomeric dimethylbenzenes. • The structure shown above is 2,6-xylenol, or 2,6-dimethylphenol; the other isomers are shown below. [pic] • The xylenols are found in a number of pesticides and are also used in the manufacture of many other compounds. STEP 4: Nomenclature of Phenols (15 minutes). • Locate the position of hydroxyl group attached to the benzene ring. • Benzene rings attached to more than one hydroxyl groups are labeled with the Greek numerical prefixes such as di, tri, tetra to denote the number of similar hydroxyl groups attached to the benzene ring. • If two hydroxyl groups are attached to the adjacent carbon atoms of benzene ring, it is named as benzene1, 2-diol • In case of substituted phenols, we start locating the positions of the other function groups with respect to the position where the hydroxyl group is attached. For example, if a methyl group is attached at fourth carbon atom with respect to hydroxy group; compound is named as, 4-Methyl phenol. [pic] • Depending on the position of substituted functional group with respect to the hydroxyl group, words like ortho (when the functional group is attached to the adjacent carbon atom), para (when the functional group is attached to the third carbon atom from the hydroxyl group), meta (when the functional group is attached to the second carbon atom from the hydroxyl group) are also used for the nomenclature of phenols. • Compounds with two or more –OH groups have special names: [pic] • Certain groups, e.g., -COOH, -CHO, -SO3H, if present in the ring, take priority; the –OH group is then used as a modifying prefix: STEP 5: Chemical Structure of Phenols (15 minutes). • The simplest way to draw the structure of phenol is [pic] • There is an interaction between the delocalized electrons in the benzene ring and one of the lone pairs on the oxygen atom. • This has an important effect on both the properties of the ring and of the -OH group. • One of the lone pairs on the oxygen overlaps with the delocalized ring electron system [pic] Giving a structure rather like this [pic] • The donation of the oxygen's lone pair into the ring system increases the electron density around the ring. That makes the ring much more reactive than it is in benzene itself. That is explored in another page in this phenol section. • It also helps to make the -OH group's hydrogen a lot more acidic than it is in alcohols. That will also be explored elsewhere in this section. STEP 6: Chemical Properties of Phenols (15 minutes). |Activity: Buzzing (5minutes) | | | |ASK students to pair up and buzz on the following question for 5 | |minutes. | | | |What are the chemical properties of Phenols? | | | |ALLOW pairs to respond on the question. | | | |WRITE their response

NTA Level 5 • Semester 1 • PST05106 Aryl Halides of Pharmaceutical Importance Pharmaceutical Organic Chemistry • Source Session/Topic 20 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 20: Aryl Halides of Pharmaceutical Importance. Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: • Define aryl halides • Explain nomenclature of aryl halides • Draw chemical structure of aryl halides • List chemical properties of aryl halides • Explain chemical reactions of aryl halides Resources Needed: • Flip charts, marker pens, and masking tape • Black/white board and chalk/whiteboard markers SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Brainstorming |Definition of Aryl Halides | | | |Presentation | | |3 |15 minutes |Presentation |Nomenclature of Aryl Halides | |4 |15 minutes |Presentation |Chemical Structure of Aryl Halides | |5 |20 minutes |Buzzing |Chemical Properties of Aryl Halides | | | |Presentation | | |6 |45 minutes |Group |Chemical Reactions involving Aryl | | | |discussion |Halides | | | |Presentation | | |7 |05 minutes |Presentation |Key Points | |8 |05 minutes |Presentation |Evaluation | SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes). READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Definition of Aryl Halides (10 minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What are Phenols? | | | |ALLOW few students to respond. | | | |WRITE their responses on the flip chart/ board. | | | |CLARIFY and SUMMARISE by using the content below | Aryl halides are the compounds that contain halogen atom directly attached to the benzene ring. They have general formula ArX. [pic] Any halogen compound that contains a benzene ring is not classified as aryl halide. e.g. Benzyl chloride is not an aryl halide but is a substituted alkyl halide. STEP 3: Nomenclature of Aryl Halides (15 minutes). • Functional group suffix = -halobenzene Functional group prefix = halo- Numbering of the ring begins at the halogen-substituted carbon and proceeds in the direction of the next substituted carbon that possesses the lower number. • Mono-substituted aryl halides are characterized using the prefix ortho (o- ), meta (m-) or para (p-) depending on the placement of the substituent from the halogen or the halogen from a higher priority functional group: 1,2-, 1,3- or 1,4- respectively. | | | | |1-chloro-2-ethylbenze|1-chloro-3-ethylbenze|1-chloro-4-ethylbenze| |ne |ne |ne | |or |or |or | |o-ethylchlorobenzene |m-ethylchlorobenzene |p-ethylchlorobenzene | STEP 4: Chemical Structure of Aryl Halides (15 minutes). • An aryl halide is classified by its distinct bonding of a halogen directly to a benzene ring. o From a structural standpoint, one of the more important things to realize is the trend in bond lengths of the four aryl halides. • Since the trend for atomic size goes F < Cl < Br < I, (meaning fluorine is smaller than chlorine, which is smaller than bromine, etc.) it's probably not surprising that in terms of bond length, the observation is as follows: |[pic] | |Bond lengths (given in picometers) of the four | |aryl halides | • The bond lengths here are measured in picometers, which is a small unit of measurement used because we are talking about chemical bonds on a microscopic scale. • Notice that as we go from fluorine, to chlorine, to bromine, to iodine, the bond lengths get longer and longer. • That is because as the size of the halogen gets bigger, the bond has to elongate to make room for the larger atom that's bonded to the benzene ring. STEP 5: Chemical Properties of Aryl Halides (20 minutes). |Activity: Buzzing (5minutes) | | | |ASK students to pair up and buzz on the following question for 5 | |minutes. | | | |What are the chemical properties of Aryl Halides? | | | |ALLOW pairs to respond on the question | | | |WRITE their response on the flip chart/board | | | |CLARIFY and SUMMARIZE by using the content below | Reactivity of Aryl halides • In haloalkane, the carbon atom attached to halogen is sp3 hybridised while in case of haloarene, the carbon atom attached to halogen is sp2- hybridised. [pic] • The sp2 hybridized carbon with a greater s-character is more electronegative and can hold the electron pair of C—X bond more tightly than sp3 -hybridized carbon in haloalkane with less s- character. • Thus, C—X bond length in halo alkane is shorter than those present in haloarene. • Since it is difficult to break a shorter bond than a longer bond, therefore, haloarenes are less reactive than haloalkanes towards nucleophilic substitution reaction. • Unlike alkyl halides, aryl halides are less reactive towards Nucleophilic substitution reactions, this can be attributed to their electron release via resonance [pic] • Structures III, IV and V stabilise chlorobenzene molecule and give a double bond character to the carbon-chlorine bond. • Now because of this the carbon-chlorine bond has more strength and hence aryl halides are more stable towards Nucleophilic substitution reactions. • In Alkyl halides the carbon atom attached to halogen is sp3 hybridized and in aryl halides it is sp2, hybridized, as sp2 hybridized carbon is more electronegative it does not permit the chlorine atom to get displaced with the bonded pair of electrons. Nucleophilic Substitution Reactions of Aryl Halides • Aryl halides undergo Nucleophilic substitution reactions when a strong Electron withdrawing group is present on the benzene ring. • Electron withdrawing groups activate the benzene ring towards nucleophilic substitution in aryl halides whereas Electron donating groups deactivate the ring. Elimination – Addition Mechanism • In the absence of an electron withdrawing group, nucleophilic substitution

NTA Level 5 • Semester 1 • PST05106 Amines of Pharmaceutical Importance Pharmaceutical Organic Chemistry • Source Session/Topic 21 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 21: Amines of Pharmaceutical Importance. Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: • Define Amines • Explain nomenclature of amines • Draw chemical structure of amines • List chemical properties of amines • Explain chemical reactions of amines Resources Needed: • Flip charts, marker pens, and masking tape • Black/white board and chalk/whiteboard markers SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Brainstorming |Definition of Amines | | | |Presentation | | |3 |15 minutes |Presentation |Nomenclature of Amines | |4 |15 minutes |Presentation |Chemical Structure of Amines | |5 |20 minutes |Buzzing |Chemical Properties of Amines | | | |Presentation | | |6 |45 minutes |Group |Chemical Reactions involving Amines | | | |discussion | | | | |Presentation | | |7 |05 minutes |Presentation |Key Points | |8 |05 minutes |Presentation |Evaluation | SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Definition of Amines (10 minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What are Amines? | | | |ALLOW few students to respond | | | |WRITE their responses on the flip chart/ board | | | |CLARIFY and SUMMARISE by using the content below | • Amines are organic derivatives of ammonia NH3 with one or more alkyl or aryl groups bonded to the nitrogen atom. • Amines contain a nitrogen atom with a lone pair of electrons; basic & nucleophilic. • Amines are present widely throughout both plants & animals. • As a class amine include some of the most important biological compounds. • Amines serve many functions in living organisms such as bioregulation, neurotransmission, and defense against predators. Examples of some biologically active amines [pic] [pic] [pic] [pic] [pic] STEP 3: Nomenclature of Amines (15 minutes). • The IUPAC nomenclature for amines is similar to that for alcohols. • The longest continuous chain of the carbon atoms determines the root name. • The -e ending in the alkane name is changed to -amine, and a number shows the position of the amino group along the chain. • Other substituents on the carbon chain are given numbers, and the prefix N- is used for each substituent on nitrogen. Examples [pic] Common Names • Common names of amines are formed from the names of the alkyl groups bonded to nitrogen, followed by the suffix –amine • The pefixes di-, tri and tetra- are used to describe two, three, or four identical substituents Examples [pic] [pic] • In naming amines with more complicated structures, the -NH2 group is called the amino group. • The amino group is treated like any other substituent, with a number or other symbol indicating its position on the ring or carbon chain. Examples [pic] [pic] • Aromatic and heterocyclic amines are generally known by historical names. • For example, phenylamine is called aniline, and its derivatives are named as derivatives of aniline. [pic] [pic] Heterocyclic amines • Compounds in which the nitrogen atom occurs as part of a ring. • The heterocyclic nitrogen atom is always numbered as position 1. Examples [pic] STEP 4: Chemical Structure of Amines (15 minutes). • The basic chemical structure is that of ammonia (NH3) with the key atom being the central nitrogen atom. • The basic ammonia structure is changed when the hydrogen atoms are replaced by alkyl groups to form amines. • There are primary, secondary and tertiary amines. |[pic] | | |Secondary amine | | | | | | [pic] Primary amine [pic] Tertiary amine • The naming of amines is pretty straightforward. Primary amines are called things like methylamine (CH3-NH2) and ethylamine (CH3-CH2-NH2). • Simple secondary and tertiary amines are also easy to name. Dimethylamine is CH3-NH-CH3 and trimethylamine is CH3-N(CH3)-CH3. • Larger amines have names beginning with amino. For example, CH3-CH(NH) -CH2-CH2-CH3 is called 2-aminopentane. STEP 5: Chemical Properties of Amines (15 minutes). |Activity: Buzzing (5minutes) | | | |ASK students to pair up and buzz on the following question for 5 | |minutes. | | | |What are the chemical properties of Amines? | | | |ALLOW pairs to respond on the question. | | | |WRITE their response on the flip chart/board. | | | |CLARIFY and SUMMARIZE by using the content below | • They react with acids to form acid-base salts • They react with electrophiles in polar reactions • Amines are stronger bases than alcohols, ethers or water • Kb (basicity constant) – used to measure the base strength of an amine • Simple methylated amines are prepared by reaction of NH3 with CH3OH in the presence of alumina catalyst. STEP 6: Chemical Reactions involving Amines (45 minutes) |Activity: Small Group Discussion (20 minutes) | | | |DIVIDE students into small groups | | | |ASK students to discuss in groups on the following questions | |What are the chemical reactions involving Amines? | | | |[pic]REFER Students to Book | | | |ALLOW students to discuss for 15 minutes | | | |ALLOW each group to present for 5 minutes | | | |CLARIFY and SUMMARIZE by using the contents below | Due to the unshared electron pair, amines can act as both bases and nucleophiles. • Reaction with acids When reacted with acids, amines donate electrons to form ammonium salts. [pic] • Reaction with acid halides o Acid halides react with amines to form substituted amides. [pic] o Aldehydes

NTA Level 5 • Semester 1 • PST05106 Amides of Pharmaceutical Importance Pharmaceutical Organic Chemistry • Source Session/Topic 22 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 22: Amides of Pharmaceutical Importance. Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: • Define Amides • Explain nomenclature of amides • Draw chemical structure of amides • List chemical properties of amides • Explain chemical reactions of amides Resources Needed: • Flip charts, marker pens, and masking tape. • Black/white board and chalk/whiteboard markers. SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Brainstorming |Definition of Amides | | | |Presentation | | |3 |15 minutes |Presentation |Nomenclature of Amides | |4 |15 minutes |Presentation |Chemical Structure of Amides | |5 |20 minutes |Buzzing |Chemical Properties of Amides | | | |Presentation | | |6 |45 minutes |Group |Chemical Reactions involving Amides | | | |discussion | | | | |Presentation | | |7 |05 minutes |Presentation |Key Points | |8 |05 minutes |Presentation |Evaluation | SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify. ASK students if they have any questions before continuing. STEP 2: Definition of Amides (10 minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What are Amides? | | | |ALLOW few students to respond | | | |WRITE their responses on the flip chart/ board | | | |CLARIFY and SUMMARISE by using the content below | • Amides are usually regarded as derivatives of carboxylic acids in which the hydroxyl group has been replaced by an amine or ammonia. • The lone pair of electrons on the nitrogen is delocalized into the carbonyl, thus forming a partial double bond between N and the carbonyl carbon. • So, amides contain the -CONH2 group. STEP 3: Nomenclature of Amides (15 minutes). • Primary amides are named by changing the name of the acid by dropping the -oic acid or -ic acid endings and adding -amide. • The carbonyl carbon is given the #1 location number. • It is not necessary to include the location number in the name because it is assumed that the functional group will be on the end of the parent chain. [pic] [pic] [pic] methanamide or formamide (left), ethanamide or acetamide (center) , benzamide (right). [pic] • Secondary amides are named by using an upper-case N to designate that the alkyl group is on the nitrogen atom. • Alkyl groups attached to the nitrogen are named as substituents. • The letter N is used to indicate they are attached to the nitrogen. [pic] Tertiary amides are named in the same way as secondary amides, but with two N's [pic] STEP 4: Chemical Structure of Amides (15 minutes). • The amide functional group has a nitrogen atom attached to a carbonyl carbon atom. • If the two remaining bonds on the nitrogen atom are attached to hydrogen atoms, the compound is a simple amide. • If one or both of the two remaining bonds on the atom are attached to alkyl or aryl groups, the compound is a substituted amide. [pic] • The carbonyl carbon-to-nitrogen bond is called an amide linkage. • This bond is quite stable and is found in the repeating units of protein molecules, where it is called a peptide linkage. • Simple amides are named as derivatives of carboxylic acids. • The -ic ending of the common name or the -oic ending of the International Union of Pure and Applied Chemistry (IUPAC) name of the carboxylic acid is replaced with the suffix –amide [pic] STEP 5: Chemical Properties of Amides (20 minutes). |Activity: Buzzing (5minutes) | | | |ASK students to pair up and buzz on the following question for 5 | |minutes. | | | |What are the chemical properties of Amides? | | | |ALLOW pairs to respond on the question. | | | |WRITE their response on the flip chart/board. | | | |CLARIFY and SUMMARIZE by using the content below | • Amphoteric Character. o Amides are very weak bases. o This is due to the fact that the lone pair of electrons on nitrogen atom is involved in resonance with carbonyl group. o This is due to the contribution of resonating structure II as shown below; [pic] o Thus, electron pair of nitrogen is not easily available for protonation. o Consequently, the basic character is considerably decreased. o However, under suitable conditions amides can also exhibit a feeble acidic character. • Basic character. o In accordance with resonating structure I already shown, it is evident that nitrogen atom of amide molecule has a lone pair of electrons. o Therefore, it can act as a base. o For example, acetamide (as base) reacts with hydrochloric acid (an acid) to form a salt. o CH3 CONH2 + HCl à CH3 CONH2 HCl • Acidic character. o In accordance with resonating structure II shown earlier, it is clear that the development of positive character on nitrogen atom facilitates the release of proton. o Thus, amide can act as acid. o For example, acetamide (as acid) reacts with mercuric oxide (a base) to form mercury salt and water. o 2CH3 COHN2 + HgO → (CH3 CONH)2 Hg + H2O • Hydrolysis. o On boiling with dilute acid or alkali, amides rapidly undergo hydrolysis. o For example: [pic] STEP 6: Chemical Reactions involving Amides (45 minutes). |Activity: Small Group Discussion (20 minutes). | | | |DIVIDE students into small groups. | | | |ASK students to discuss in groups on the following questions. | |What are the chemical reactions involving Amides? | | | |[pic]REFER Students

NTA Level 5 • Semester 1 • PST05106 Introduction to Heterocyclic Compounds Pharmaceutical Organic Chemistry • Source Session/Topic 23 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 23: Introduction to Heterocyclic Compounds. Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: • Define heterocyclic compounds • Classify heterocyclic compounds • Explain nomenclature of heterocyclic compounds • Draw chemical structure of heterocyclic compounds Resources Needed: • Flip charts, marker pens, and masking tape. • Black/white board and chalk/whiteboard markers. SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Brainstorming |Definition of Heterocyclic Compounds| | | |Presentation | | |3 |25 minutes |Presentation |Classification of Heterocyclic | | | | |Compounds | |4 |30 minutes |Presentation |Nomenclature of Heterocyclic | | | | |Compounds | |5 |30 minutes |Presentation |Chemical Structure of Heterocyclic | | | | |Compounds | |6 |10 minutes |Presentation |Key Points | |7 |10 minutes |Presentation |Evaluation | SESSION CONTENTS. STEP 1: Presentation of Session Title and Learning Tasks (5 minutes). READ or ASK students to read the learning tasks and clarify. ASK students if they have any questions before continuing. STEP 2: Definition of Heterocyclic Compounds (10minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What are Heterocyclic compounds? | | | |ALLOW few students to respond. | | | |WRITE their responses on the flip chart/ board. | | | |CLARIFY and SUMMARISE by using the content below | • Heterocyclic compound, also called heterocycle, any of a major class of organic chemical compounds characterized by the fact that some or all of the atoms in their molecules are joined in rings containing at least one atom of an element other than carbon (C). • The cyclic part (from Greek kyklos, meaning “circle”) of heterocyclic indicates that at least one ring structure is present in such a compound, while the prefix hetero- (from Greek heteros, meaning “other” or “different”) refers to the noncarbon atoms, or heteroatoms, in the ring. • Heterocyclic compounds include many of the biochemical material essential to life. For example, nucleic acids, pigments, vitamins, and antibiotics. STEP 3: Classification of Heterocyclic Compounds (25 minutes). • Classification of heterocyclic compounds depends on ring size because heterocyclic rings of a given size has many common features. • Therefore, heterocyclic compounds can be classified as: o Three-membered rings o four-membered rings o Five-membered rings o six-membered rings o Seven-membered rings • Three-membered rings o The three-membered ring heterocycles containing single atoms of nitrogen, oxygen, and sulfur—aziridine, oxirane (or ethylene oxide), and thiirane, respectively—and their derivatives can all be prepared by nucleophilic reactions, of the type shown. o Thus, aziridine is formed by heating β-aminoethyl hydrogen sulfate with a base (in this case Y is −OSO3H). [pic] • Four-membered rings o Azetidine, oxetane, and thietane—four-membered rings containing, respectively, one nitrogen, oxygen, or sulfur atom—are prepared by nucleophilic displacement reactions similar to those used to prepare the corresponding three-membered rings. [pic] • Five-membered rings with one heteroatom o The parent aromatic compounds of this family—pyrrole, furan, and thiophene—have the structures shown. [pic] o The saturated derivatives are called pyrrolidine, tetrahydrofuran, and thiophane, respectively. o The bicyclic compounds made of a pyrrole, furan, or thiophene ring fused to a benzene ring are called indole (or isoindole), benzofuran, and benzothiophene, respectively. • Six-membered rings with one heteroatom o The nomenclature used for the various monocyclic nitrogen-containing six-membered ring compounds is given below. o Positions on the ring are shown for pyridine, Arabic numerals being preferred to Greek letters, although both systems are used. o The pyridones are aromatic compounds because of contributions to the resonance hybrid from charged resonance forms such as that shown for 4- pyridone. [pic] STEP 4: Nomenclature of Heterocyclic Compounds (30 minutes). • Many heterocycles, especially amines, were identified early on, and received trivial names which are still preferred. • Some monocyclic compounds of this kind are shown in the following chart, with the common (trivial) name in bold and a systematic name based on the Hantzsch-Widman system given beneath it in blue. [pic] • An easy to remember, but limited, nomenclature system makes use of an elemental prefix for the heteroatom followed by the appropriate carbocyclic name. • A short list of some common prefixes is given in the following table, priority order increasing from right to left. • Examples of this nomenclature are: ethylene oxide = oxacyclopropane, furan = oxacyclopenta-2,4-diene, pyridine = azabenzene, and morpholine = 1-oxa-4-azacyclohexane. |Element|oxygen|sulfu|seleniu|nitroge|phosphorou|silic|boron| | | |r |m |n |s |on | | |Valence|II |II |II |III |III |IV |III | |Prefix |Oxa |Thia |Selena |Aza |Phospha |Sila |Bora | | | | | | | | | | • The Hantzsch-Widman system provides a more systematic method of naming heterocyclic compounds that is not dependent on prior carbocyclic names. • It makes use of the same hetero atom prefix defined above (dropping the final "a"), followed by a suffix designating ring size and saturation. • As outlined in the following table, each suffix consists of a ring size root (blue) and an ending intended to designate the degree of unsaturation in the ring. • In this respect, it is important to recognize that the saturated suffix applies only to completely saturated ring systems, and the unsaturated suffix applies to rings incorporating the maximum number of non-cumulated double bonds. • Systems having a lesser degree of unsaturation require an appropriate prefix, such as "dihydro"or "tetrahydro". |Ring Size |3 |4 |5 |6 |7 |8 |9 |10 | |Suffix | | | | | | | | | | |iren|ete |ole |ine |epine|ocine|onine|ecine| |Unsaturated|e |etan|olan|inane|epane|ocane|onane|ecane| | Saturated|iran|e |e | | | | | | | |e | | | | | | | |

NTA Level 5 • Semester 1 • PST05106 Chemical Reactions of Heterocyclic Compounds Pharmaceutical Organic Chemistry • Source Session/Topic 24 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 24: Chemical Reactions of Heterocyclic Compounds. Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: • List chemical properties of heterocyclic compounds • Explain chemical reactions of heterocyclic compounds Resources Needed: • Flip charts, marker pens, and masking tape • Black/white board and chalk/whiteboard markers SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |35 minutes |Brainstorming |Chemical Properties of Heterocyclic | | | |Presentation |Compounds | |3 |60 minutes |Group |Chemical Reactions involving | | | |discussion |Heterocyclic Compounds | | | |Presentation | | |4 |10 minutes |Presentation |Key Points | |5 |10 minutes |Presentation |Evaluation | SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify. ASK students if they have any questions before continuing. STEP 2: Chemical Properties of Heterocyclic Compounds (35 minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What are the chemical properties of heterocyclic compounds? | | | |ALLOW few students to respond. | | | |WRITE their responses on the flip chart/ board. | | | |CLARIFY and SUMMARISE by using the table below | |Chemical Name |Chemical properties | |2-AMINOPYRIDINE |The substance decomposes on burning | | |producing toxic gases and vapours | | |including nitrous oxides | | |Reacts with strong oxidants causing | | |fire and explosion hazard | | |The substance is a strong base that | | |is soluble in water | |3,6-DICHLOROPICOLINIC ACID |The substance decomposes on burning | | |producing toxic and corrosive gases | | |Reacts with bases forming salts | | |Solutions of them are corrosive to | | |aluminum, iron, and tin | |2-MERCAPTOBENZOTHIAZOLE |On combustion, forms toxic gases | | |(carbon monoxide and sulphur | | |compounds) | | |The substance decomposes on heating | | |and on burning producing toxic and | | |irritating fumes (sulphur and | | |nitrogen oxides) | | |Reacts with acids with the formation | | |of highly toxic fumes of sulphur | | |compounds | | |Reacts with acids or acid fumes | | |producing toxic fumes (sulphur | | |compounds) | |2-MERCAPTOBENZOTHIAZOLE |On combustion, forms toxic gases: | |DISULPHIDE |carbon, sulphur and nitrogen oxides | | |Reacts with strong oxidants and acids| | |The substance decomposes on heating | |2-METHYLPYRIDINE |producing toxic fumes (nitrogen | | |oxides) | | |Reacts with oxidants and strong acids| | | | | |Attacks copper and its alloys | |3-METHYLPYRIDINE |The substance decomposes on heating | | |producing toxic fumes (nitrogen | | |oxides) | | |Reacts with oxidants and strong acids| |4-METHYLPYRIDINE |The substance decomposes on heating | | |producing toxic fumes (nitrogen | | |oxides) | | |Reacts with oxidants and strong acids| |1-METHYL-2-PYRROLIDONE |The substance decomposes on heating | | |above 315 °C producing toxic fumes | | |Reacts with strong acids | | |Attacks aluminium | |MORPHOLINE |The substance decomposes on heating | | |producing toxic fumes (nitrogen | | |oxides) | | |The substance is a weak base | | |Reacts with strong oxidants causing | | |fire hazard | | |Attacks copper and its compounds | |PHENOTHIAZINE |The substance decomposes on heating | | |and on burning producing toxic and | | |irritating fumes including nitrogen | | |oxides and sulphur oxides | |PHENYLENEPYRENE |Upon heating, toxic fumes are formed | |PIPERIDINE |The substance decomposes on heating | | |and on burning producing toxic gases | | |such as nitrogen oxides | | |The substance is a medium strong base| | | | | |Reacts violently with oxidants | |PYRIDINE |On combustion, forms toxic fumes | | |(amines) | | |The substance decomposes on heating | | |or on burning producing toxic fumes | | |(nitrogen oxides and hydrogen | | |cyanide) | | |Reacts violently with strong oxidants| | |and strong acids | |2-PYRROLIDINONE |The substance decomposes on heating | | |producing toxic fumes | | |Reacts with strong acids cf | | |• methylpyrrolidone Attacks aluminium| |QUINOLINE |The substance decomposes on heating | | |and on burning producing toxic fumes | | |of nitrogen oxides | | |Reacts with strong oxidants and | | |maleine anhydride | |TETRAHYDROTHIOPHENE |On combustion, forms toxic fumes | | |• Reacts violently with strong | | |oxidants and nitric acid • Attacks | | |rubber | |THIOPHENE |The substance decomposes on heating | | |and on burning producing toxic and | | |irritating fumes (sulphur oxides) | | |• Reacts violently with oxidizing | | |materials, including fuming nitric | | |acid | STEP 3: Chemical Reactions involving Heterocyclic Compounds (60 minutes). |Activity: Small Group Discussion (20 minutes) | | | |DIVIDE students into small groups | | | |ASK students to discuss in groups on the following questions | |What are the chemical reactions involving heterocyclic compounds? | | | |[pic]REFER Students to Book | | | |ALLOW students to discuss for 15 minutes | | | |ALLOW each group to present for 5 minutes | | | |CLARIFY and SUMMARIZE by using the contents below | Three-Membered Rings • Oxiranes (epoxides) are the most commonly encountered three-membered heterocycles. Epoxides are easily prepared by reaction of alkenes with peracids, usually with good stereospecificity. • Because of the high angle strain of the three-membered ring, epoxides are more reactive that unstrained ethers. • Addition reactions proceeding by electrophilic or nucleophilic opening of the ring constitute the most general reaction class. • Example 1 in the following diagram shows one such transformation, which is interesting

NTA Level 5 • Semester 1 • PST05106 Introduction to Structure – Activity Relationship of Drugs Pharmaceutical Organic Chemistry • Source Session/Topic 25 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 25: Introduction to Structure – Activity Relationship of Drugs. Total Session Time: 60 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: • Define structure-activity relationship • Explain the importance of structure-activity relationship in pharmacy Resources Needed: • Flip charts, marker pens, and masking tape • Black/white board and chalk/whiteboard markers SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Brainstorming |Definition of structure – activity | | | |Presentation |relationship | |2 |30 minutes |Group |Importance of structure – activity | | | |discussion |relationship in pharmacy | | | |Presentation | | |4 |05 minutes |Presentation |Key Points | | 5 |10 minutes |Presentation |Evaluation | SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Definition of Structure – Activity Relationship (10 minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What is structure- activity relationship? | | | |ALLOW few students to respond. | | | |WRITE their responses on the flip chart/ board. | | | |CLARIFY and SUMMARISE by using the table below | Structure Activity Relationship (SAR): • A structure activity relationship relates features of a chemical structure to a property, effect, or biological activity associated with that chemical. • SAR is the subject which brings about the awareness of the relationships between the chemistry of a particular compound or group of compounds and their interaction with the body hence activity. STEP 3: Importance of Structure – Activity Relationship in Pharmacy (30 minutes). |Activity: Small Group Discussion (15 minutes) | | | |DIVIDE students into small groups. | | | |ASK students to discuss in groups on the following questions. | |What is the importance of structure- activity relationship in Pharmacy?| | | |[pic]REFER Students to Book | | | |ALLOW students to discuss for 10 minutes. | | | |ALLOW each group to present for 5 minutes. | | | |CLARIFY and SUMMARIZE by using the contents below | • SAR enables the determination of the chemical groups responsible for evoking a target biological effect in the organism. • It allows modification of the effect or the potency of a bioactive compound (typically a drug) by changing its chemical structure • Medicinal chemists use the techniques of chemical synthesis to insert new chemical groups into the biomedical compound and test the modifications for their biological effects. STEP 4: Key Points (05 minutes). • The structure–activity relationship (SAR) is the relationship between the chemical or 3D structure of a molecule and its biological activity. • SAR enables the determination of the chemical groups responsible for evoking a target biological effect in the organism. • It allows modification of the effect or the potency of a bioactive compound (typically a drug) by changing its chemical structure. • Medicinal chemists use the techniques of chemical synthesis to insert new chemical groups into the biomedical compound and test the modifications for their biological effects. STEP 5: Evaluation (10 minutes) • What is Structure-activity relationship? • What is the importance of SAR in pharmacy? References Ternay, A.L (1976). Contemporary Organic Chemistry. Philadelphia, United States: W.B. Saunders Co. Morrison R.T and Boyd R N (1997). Organic Chemistry (6th Ed.). New Delhi, India: Prentice Hall of India Graham Solomon et al (2014). Organic Chemistry (11th Ed.). New Jeysey, United States: John Willey and Sons. Nadendla R. R. (2005). Principles of Pharmaceutical Organic Chemistry. New Delhi, India: MacMillan Publishers Bruice Y (2013). Organic Chemistry (7th ed.). New York, United States: Prentice Hall Pearson. Delgado J. N. Et al (1998). Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry (10th Ed.). Calfornia, United States: Lippincott Williams Bhassin S.K, Gupta R. (2013). Pharmaceutical organic chemistry (E-book Kindle edition). New Delhi, India: Elsevier Publishing Services ← Previous TopicNext Topic →View all Pharmaceutical Organic Chemistry topicsOpen Complete Full Notes PDF / OFFLINE NOTES Unataka kutumiwa notes hizi kupitia WhatsApp?Kwa notes zilizopangiliwa vizuri kwa kusoma offline au PDF, bonyeza kitufe hapa chini. Ujumbe wenye Level, Semester, Module na Topic utaandaliwa moja kwa moja.TUMIWA NOTES WHATSAPP WhatsApp: 255620339260

NTA Level 5 • Semester 1 • PST05106 Structure – Activity Relationship of Penicillins Pharmaceutical Organic Chemistry • Source Session/Topic 26 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 26: Structure – Activity Relationship of Penicillins. Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: • Define Penicillins • Explain Chemical structure of penicillins • Explain the structure – activity relationship of penicillins Resources Needed: • Flip charts, marker pens, and masking tape • Black/white board and chalk/whiteboard markers SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Brainstorming |Definition of Penicillins | | | |Presentation | | |3 |40 minutes |Presentation |Chemical Structure of Penicilins | |4 |45 minutes |Group |Structure – Activity Relationship of| | | |discussion |Penicillins | | | |Presentation | | |5 |10 minutes |Presentation |Key Points | | 6 |10 minutes |Presentation |Evaluation | SESSION CONTENTS. STEP 1: Presentation of Session Title and Learning Tasks (5 minutes). READ or ASK students to read the learning tasks and clarify. ASK students if they have any questions before continuing. STEP 2: Definition of Penicillins (10 minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What are penicillins? | | | |ALLOW few students to respond | | | |WRITE their responses on the flip chart/ board | | | |CLARIFY and SUMMARISE by using the table below | • There are two major classes of antibacterial agents which act by inhibiting ell wall synthesis. • Penicillins are a group of β-lactam antibiotics consisting of natural penicillins and semisynthetic penicillins. • Penicillin inhibit peptidoglycan synthesis in bacteria and the drugs are mainly active against gram (+) ve bacteria. STEP 3: Chemical Structure of Penicillins (40 minutes). Fig. 24.1 General Chemical structure of penicillin [pic] G.L Patrick, an introduction to medical chemistry. • Penicillin contains a highly unstable-looking bicyclic system consisting of a four membered β-lactam ring fused to a five-membered thiazolidine ring. • The skeleton of the molecule suggests that it is derived from the amino acids cysteine and valine. According to biogenesis, antibiotics can be derived from various natural substances like β-lactam antibiotics from cysteine and valine amino acids. [pic] Penicillin appears to be derived from cysteine and valine [pic] Side chain varies according to carboxylic acids presents in fermentation medium. [pic] • All penicillin has the same β-lactam-thiazolidine general structure that contains three chiral centers. • Therefore, theoretically this structure could present eight optically active forms. • However, the natural isomer, presumably the only one with biological activity, has the stereochemistry of 3S:5R:6R. (According to BP & USP 2S:5R:6R). [pic] Penicillin analogues [pic] STEP 4: Structure – Activity relationship of Penicillins (45 minutes). |Activity: Small Group Discussion (20 minutes) | | | |DIVIDE students into small manageable groups. | | | |ASK students to discuss on the following question. | |What is the importance of structure activity relationship of | |Penicillins? | | | |ALLOW students to discuss for 15 minutes. | | | |ALLOW few groups to present and the rest to add points not mentioned. | | | |CLARIFY and SUMMARIZE by using the contents below | A large number of penicillin analogues have been synthesized and studied. The results of these studies have demonstrated following features are important for penicillins activity. • The strained β-lactam ring is essential. • The bicyclic system is important. • The acidic functional group (free carboxylic acid) is essential. • The acylamino (amide) side-chain is essential. • The stereochemistry of the bicyclic ring with respect to the acylamino side-chain is important. • The acyl side-chain (R) can varies. Very little variation is possible in penicillin nucleus. Structure activity relationships of penicillin [pic] The acid sensitivity of penicillin. There are three reasons for the acid sensitivity of penicillin. • Ring strain o The bicyclic system in penicillin consists of a four-membered ring and a five membered ring. o As a result, penicillins suffers large angle and torsional strains. o Acid-catalyzed ring opening relieves these strains by breaking open the more highlystrained four-memberedβ-lactam ring. [pic] [pic] Ring opening • A highly reactive β-lactam carbonyl group o The carbonyl group in the β-lactam ring is highly susceptible to nucleophiles and it does not behave like a normal tertiary amide which is usually quite resistant to nucleophilic attack. o A normal tertiary amide is far less susceptible to nucleophiles since the resonance structures reduce the electrophilic character of the carbonyl group. o The β-lactam nitrogen is unable to show such effect. o To show the similar effect like tertiary amide, penicillin had to obtain astrained flat structure, which is highly unstable. o As a result, the lone pair is localized on the nitrogen atom and the carbonyl group is far more electrophilic than a tertiary amide. [pic] • Influence of the acyl side-chain o Figure above demonstrates how the neighboring acyl group canactively participate in a mechanism to open up the lactam ring. o Thus,penicillin Ghas a self-destruct mechanism built into its structure. [pic] Influence of the acyl side chain on acid sentivity [pic] STEP 5: Key Points (10 minutes). • Penicillin refers to any of several antibiotics produced naturally by molds of genus Penicillium and also semi-synthetically, having a bactericidal action on many susceptible Gram positive and Gram- negative bacteria. negative cocciand bacilli, some also being effective against certain sp irochetes. • The term "penam" is used to describe the common core skeleton of a member of the penicillins which has the molecular formula R- C9H11N2O4S, where R is the variable side chain that differentiates the penicillins from one another. • SAR of penicillins has enabled development of acid resistant drugs such as ampicillin, improving their spectrum of activity and bioavailability (amoxicillin),

NTA Level 5 • Semester 1 • PST05106 Structure – Activity Relationship of Cephalosporins Pharmaceutical Organic Chemistry • Source Session/Topic 27 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 27: Structure – Activity Relationship of Cephalosporins. Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: • Define Cephalosporins • Explain Chemical structure of cephalosporins • Explain the structure – activity relationship of cephalosporins Resources Needed: • Flip charts, marker pens, and masking tape. • Black/white board and chalk/whiteboard markers. SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Brainstorming |Definition of Cephalosporins | | | |Presentation | | |3 |40 minutes |Presentation |Chemical Structure of Cephalosporins| |4 |45 minutes | Group |Structure – Activity Relationship of| | | |discussion |Cephalosporins | | | |Presentation | | |5 |10 minutes |Presentation |Key Points | | 6 |10 minutes |Presentation |Evaluation | SESSION CONTENTS. STEP 1: Presentation of Session Title and Learning Tasks (5 minutes). READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Definition of Cephalosporins (10 minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What are Cephalosporins? | | | |ALLOW few students to respond | | | |WRITE their responses on the flip chart/ board | | | |CLARIFY and SUMMARISE by using the table below | • Cephalosporins are Antibacterial agents which inhibit bacterial cell wall synthesis. • Cephalosporins are the second group of β-lactam antibiotic family to be discovered after penicillin, which showed broad spectrum of action against Staphylococcus aureus, Vibrio cholerae, and B. anthracis, but moderate antibacterial activity was isolated from the fermentation broth of a strain of A. chrysogenum • Cephalosporins are bactericidal antibiotics, chemically closely related to penicillins, and have the same mode of action, disrupting the synthesis of the peptidoglycan layer of bacterial cell walls of bacteria, causing their death. STEP 3: Chemical Structure of Cephalosporins (40 minutes). • Cephalosporin is a β-lactam antibiotic that inhibits bacterial cell wall synthesis. • In 1948 Dr. Abraham first isolated cephalosporin C from a fungus Cephalosporium acremonium. • Cephalosporins have broader gram –ve coverage than penicillin yet no one of the cephalosporins is active against MRSA and enterococci. Basic structure of cephalosporin is 7-aminocephalosporanic acid [pic] Structural classification of cephalosparins [pic] [pic] STEP 4: Structure – Activity relationship of Cephalosporins (45 minutes). |Activity: Small Group Discussion (20 minutes) | | | |DIVIDE students into small manageable groups. | | | |ASK students to discuss on the following question | |What is the importance of SAR of Cephalosporins? | | | |ALLOW students to discuss for 15 minutes. | | | |ALLOW few groups to present and the rest to add points not mentioned. | | | |CLARIFY and SUMMARIZE by using the contents below | Many analogues of Cephalosporin C have been made and the structure-activity relationship (SAR) conclusions are as follows • The β-lactam ring is essential • A free carboxyl group is needed at position 4. • The bicyclic system is essential • The stereochemistry of the side-groups and the rings is important These are very close to penicillin and there are only a limited number of place where modifications can be made. Those places are: • Variations of the 7-acylamino side chain • Variations of the 3-acetoxymethyl side chain • Extra substitution at carbon 7. [pic] Positions which can be varied Beta-Lactam Ring: • Required for PBP reactivity and antibacterial activity • Reactivity reduced compared to the penicillins • Compare mechanism of action, resistance, pharmacodynamics, etc to penicillins 2-Carboxyl Group: • Acidic: Salt formation, product formulation • Prodrug formation • Elimination profile: Renal X-Substituent: • Cephalosporins and cephamycins • Determines, in part, resistance to beta-lactamase inactivation 3- Substituent (R3) • Chemical/acid stability/instability • Metabolic stability/instability • Minimal impact on antibacterial activity • Protein binding and half-life: Heterocycles • Adverse Reaction and Drug Interaction • Some role in cephalosporin classification (generation) 7-Substituent (R7) • Incorporated by semi synthesis: Variable structures • Impact on spectrum of activity (beta-lactamases, PBP affinity, etc.) • Significant role in activity and classification by generation Cephalosporin analogues [pic] • Different cephalosporins are developed by changing the moieties attached at the 3 and/or 7 positions of the 7-ACA. • Usually, substituents at C-3 (R2) modify the overall pharmacokinetic properties, whereas those at C-7 (R1) alter the antibacterial spectrum. • R1 – the substituents at this position effects β-lactamase resistance and its activity against Gram –ve and/or Gram +ve bacteria (its spectrum). • R2 –these substituents primarily affect the pharmacokinetics: the oral activity, the extent of metabolism, and the duration of action. • Electron withdrawing group at this position provide resonance structure and thus increase stability of the structure. • Carboxylic acid group –necessary for activity, this functional group mimics the carboxylic acid group of alanine when binding the enzyme active site. [pic] STEP 5: Key Points (10 minutes) • The cephalosporins are a class of β-lactam antibiotics originally derived from the fungus Acremonium, which was previously known as "Cephalosporium". • Cephalosporins have broder gram –ve coverage than penicillin yet no one of the cephalosporins is active against MRSA and enterococci. Basic structure of cephalosporin is 7-aminocephalosporanic acid. • Important parameters for the SAR of Cephalosporins which are used to modify its activity includes beta lactam ring, 2-Carboxyl Group, X- Substituent,3- Substituent (R3) and 7- substituent (R7). STEP 6: Evaluation (10 minutes) • What are Cephalosporins? • Draw general chemical structure of cephalosporins. • What is the importance of structure – activity relationship of cephalosporins? References. Ternay, A.L (1976). Contemporary Organic Chemistry. Philadelphia, United States: W.B. Saunders Co. Morrison R.T and Boyd R N (1997). Organic Chemistry (6th Ed.). New

NTA Level 5 • Semester 1 • PST05106 Structure – Activity Relationship of Quinolones Pharmaceutical Organic Chemistry • Source Session/Topic 28 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 28: Structure – Activity Relationship of Quinolones. Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: • Define Quinolones • Explain Chemical structure of Quinolones • Explain the structure – activity relationship of Quinolones Resources Needed: • Flip charts, marker pens, and masking tape. • Black/white board and chalk/whiteboard markers. SESSION OVERVIEW |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Brainstorming |Definition of Quinolones. | | | |Presentation | | |3 |40 minutes |Presentation |Chemical Structure of | | | | |Quinolones. | |4 |45 minutes | Group |Structure – Activity | | | |discussion |Relationship of Quinolones. | | | |Presentation | | |5 |10 minutes |Presentation |Key Points | | 6 |10 minutes |Presentation |Evaluation | SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Definition of Quinolones (10 minutes). |Activity: Brainstorming (5 minutes) | | | |Ask students to brainstorm on the following question: | | | |What are Quinolones? | | | |ALLOW few students to respond | | | |WRITE their responses on the flip chart/ board | | | |CLARIFY and SUMMARISE by using the table below | • The Quinolones (fluoroquinolones) are broad-spectrum antibiotics with particular activity against gram-negative organisms, especially Pseudomonas aeruginosa. • The fluoroquinolones are bactericidal antibiotics that act by specifically targeting DNA gyrase. o Fluoroquinolones can be classified as; o First-generation drugs (e.g., nalidixic acid) o Second-generation quinolones (e.g., ciprofloxacin) o Third-generation drugs (e.g., levofloxacin) o Fourth-generation quinolone drugs (e.g., trovafloxacin) STEP 3: Chemical Structure of Quinolones (40 minutes). The following are chemical structure of quinolones; [pic] STEP 4: Structure – Activity relationship of Quinolones (45 minutes). |Activity: Small Group Discussion (20 minutes) | | | |DIVIDE students into small manageable groups. | | | |ASK students to discuss on the following question | |What is the importance of SAR of fluoroquinolones? | | | |ALLOW students to discuss for 15 minutes. | | | |ALLOW few groups to present and the rest to add points not mentioned. | | | |CLARIFY and SUMMARIZE by using the contents below | [pic] Structure of quinolone • Structure of the quinolone molecule, using the accepted numbering scheme for positions on the molecule. • An R indicates possible sites for structural modification. • Molecules at positions marked by a dashed box can also be changed; however, the most commonly used structure is shown. Position 1. • This position is part of the enzyme-DNA binding complex and has a hydrophobic interaction with the major grove of DNA. • A cyclopropyl substituent is now considered the most potent modification here, followed by addition of a 2,4-difluorophenyl. • Most other substituents, including one with only the wrong stearic position ((R)-ofloxacin) can presumably lower the number of molecules capable of binding to the enzyme-DNA pocket, and therefore reduce potency. • Interestingly, ofloxacin has a tricyclic ring structure with a CH3 attached to the asymmetric C-3 position on the oxazine ring, thus connecting positions 1 and 8 with a fused ring. • Although this has been a useful alternative to the cyclopropyl substituent, the S- isomer exhibits twice the order of magnitude of activity as the R- isomer, which seems to be determined by the number of molecules that can be assembled, or stacked, in the enzyme-DNA complex binding pocket. • Even the potency of the purified S- isomer fused ring is less than that of the cyclopropyl substituent, suggesting the difficulty of improving upon this latter modification. Position 2. • This location is very close to the site for DNA gyrase (or topoisomerase IV) binding so it is believed that any added bulk inhibits access and results in a lower level of microbiological activity. • Only sulfur, incorporated into a small ring, has been able to replace hydrogen at the R-2 position. • To accomplish this, researchers reconfigured positions 3 and 4. Positions 3 and 4. • These two positions on the quinolone nucleus are considered critical for binding to cleaved or perturbed DNA, and no useful substitutions have yet been reported. • Therefore, the 3-carboxylate and 4-carbonyl groups are considered essential for antimicrobial activity. Oxoquinolizines. • This is a new addition to the quinolone class, in which nitrogen replaces the carbon between ring carbons C-4 and C-5. • Making this alteration renumbers the other positions so that 5- becomes 6- , 6- becomes 7-, 7- becomes 8-, and 8- becomes position 9. • This substitution enhances the in vitro and in vivo (mouse protection) activity against gram-positive cocci, including methicillin-resistant S. aureus (MRSA) that are resistant to ciprofloxacin. Position 5. • Substituents at this position of the basic quinolone nucleus appear to have the capacity to alter overall stearic configuration (planar structure) of the molecule, which is how changes here are thought to affect activity. • Modestly sized additions, such as an amino, hydroxyl, or methyl group can markedly increase in vitro activity against gram-positive bacteria, as well as enhance potency against Toxoplasma gondii. • Also, it was found that the methyl group enhances action against gram- positive but not against gram-negative bacteria. Position 6. The addition of a fluorine molecule here markedly improved antimicrobial activity compared to the original quinolone agents and gave rise to the now widely used and clinically successful fluoroquinolone compounds. Position 7. • This position is considered to be one that directly interacts with DNA gyrase, or topoisomerase IV. The optimal substituents at this position have been found to