`
`SYNGENTA EXHIBIT 1007
`
`Syngenta v. FMC, PGR2020-00028
`
`SYNGENTA EXHIBIT 1007
`Syngenta v. FMC, PGR2020-00028
`
`

`

`~--------
`
`OXFORD
`
`UNIVERSITY PRESS
`
`Great Clarendon Street, Oxford, OX2 6DP,
`United Kingdom
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`Oxford University Press in the UK and in certain other countries
`
`© Graham L. Patrick 2017
`
`The moral rights of the author have been asserted
`
`Third edition 2005
`Fourth edition 2009
`Fifth edition 2013
`Impression: 1
`
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`ISBN 978-0-19-874969-l
`
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`Links to third party websites are provided by Oxford in good faith and
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`contained in any third party website referenced in this work.
`
`Oxford University Press makes no representation, express or implied, that the
`drug dosages in this book are correct. Readers must therefore always check
`the product information and data sheets provided by the manufacturers
`and the most recent codes of conduct and safety regulations. The authors
`and publishers do not accept responsibility or legal liability for any errors
`in the text or for the misuse or misapplication of material in this work.
`
`

`

`,he
`
`nical
`-61.
`
`ov., 20
`
`Id, April,
`
`NMR in
`211-9.
`
`, June,
`
`:ognosy.
`
`very.
`
`ass in
`86-96.
`
`ik, S. W.
`;: SAR by
`
`92-908.
`
`>rganic
`
`nes as
`nists:
`15,
`
`reen:
`is co very,
`
`,ctivities:
`-4.
`
`Drug design: opti
`interactions
`
`izing target
`
`In Chapter 12, we looked at the various methods of dis(cid:173)
`covering a lead compound. Once it has been discovered,
`the lead compound can be used as the starting point for
`drug design. There are various aims in drug design. The
`eventual drug should have a good selectivity and level
`of activity for its target, and have minimal side effects.
`It should be easily synthesized and chemically stable. Fi(cid:173)
`nally, it should be non-toxic and have acceptable phar(cid:173)
`macokinetic properties. In this chapter, we concentrate
`on design strategies that can be used to optimize the in(cid:173)
`teraction of the drug with its target in order to produce
`the desired pharmacological effect; in other words its
`pharmacodynamic properties. In Chapter 14, we look
`at the design strategies that can improve the drug's abil(cid:173)
`ity to reach its target and have an acceptable lifetime-in
`other words its pharmacokinetic properties. Although
`these topics are in separate chapters, it would be wrong
`to think that they are tackled separately during drug
`optimization. For example, it would be foolish to spend
`months or years perfecting a drug that interacts perfectly
`with its target, but has no chance of reaching that target
`because of adverse pharmacokinetic properties. Phar(cid:173)
`macodynamics and pharmacokinetics should have equal
`priority in influencing drug design strategies and deter(cid:173)
`mining which analogues are synthesized.
`
`13.1 Structure-activity
`relationships
`
`Once the structure of a lead compound is known, the
`medicinal chemist moves on to study its structure-activ(cid:173)
`ity relationships (SAR). The aim is to identify those parts
`of the molecule that are important to biological activity
`and those that are not. If it is possible to crystallize the
`target with the lead compound bound to the binding site,
`the crystal structure of the complex could be solved by X(cid:173)
`ray crystallography, then studied with molecular model(cid:173)
`ling software to identify important binding interactions.
`
`However, this is not possible if the target structure has
`not been identified or cannot be crystallized. It is then
`necessary to revert to the traditional method of synthe(cid:173)
`sizing a selected number of compounds that vary slightly
`from the original structure, then studying what effect
`that has on the biological activity.
`One can imagine the drug as a chemical knight going
`into battle with an affliction. The drug is armed with a
`variety of weapons and armour, but it may not be obvi(cid:173)
`ous which weapons are important to the drug's activity,
`or which armour is essential to its survival. We can only
`find this out by removing some of the weapons and ar(cid:173)
`mour to see if the drug is still effective. The weapons and
`armour involved are the various structural features in the
`drug that can either act as binding groups with the target
`binding site (section 1.3), or assist and protect the drug
`on its journey through the body (Chapter 14). Recog(cid:173)
`nizing functional groups and the sort of intermolecular
`bonds that they can form is important in understanding
`how a drug might bind to its target.
`Let us imagine that we have isolated a natural product
`with the structure shown in Fig. 13.1. We shall name it
`glipine. There are a variety of functional groups present
`in the structure, and the diagram shows the potential
`binding interactions that are possible with a target bind(cid:173)
`ing site.
`It is unlikely that all of these interactions take place, so
`we have to identify those that do. By synthesizing ana(cid:173)
`logues (such as the examples shown in Fig. 13.2) where
`one particular functional group of the molecule is re(cid:173)
`moved or altered, it is possible to find out which groups
`are essential and which are not. This involves testing all
`the analogues for biological activity and comparing them
`with the original compound. If an analogue shows a sig(cid:173)
`nificantly lowered activity, then the group that has been
`modified must have been important. If the activity re(cid:173)
`mains similar, then the group is not essential.
`The ease with which this task is carried out depends on
`how easily we can synthesize the necessary analogues. It
`may be possible to modify some lead compounds directly
`
`

`

`224 Chapter 13 Drug design: optimizing target interactions
`
`[2] Potential van der Waals binding groups
`
`Potential ionic binding groups
`Q Potential H-bonding groups
`
`FIGURE 13. 1 Glipine.
`
`Me
`
`Me
`
`Me
`
`FIGURE 13.2 Modifications of glipine.
`
`to the required analogues, whereas the analogues of other
`lead compounds may best be prepared by total synthesis.
`Let us consider the binding jnteractions that are possible
`for different functional groups, and the analogues that
`could be synthesized to establish whether they are involved
`in binding or not (see also section 1.3 and Appendix 7).
`
`13.1.1 Binding role of alcohols and phenols
`Alcohols and phenols are functional groups which are
`commonly present in drugs and are often involved in
`hydrogen bonding. The oxygen can act as a hydrogen
`bond acceptor, and the hydrogen can act as a hydrogen
`bond donor (Fig. 13.3). The directional preference for
`hydrogen bonding is indicated by the arrows in the fig(cid:173)
`ure, but it is important to realize that slight deviations
`are possible (section 1.3.2). One or all of these interac(cid:173)
`tions may be important in binding the drug to the bind(cid:173)
`ing site. Synthesizing a methyl ether or an ester analogue
`would be relevant in testing this, as it is highly likely that
`
`the hydrogen bonding would be disrupted in either ana(cid:173)
`logue. Let us consider the methyl ether first.
`There are two reasons why the ether might hinder or
`prevent the hydrogen bonding of the original alcohol or
`phenol. The obvious explanation is that the proton of the
`original hydroxyl group is involved as a hydrogen bond
`donor and, by removing it, the hydrogen bond is lost
`(Frames I and 2 in Fig. 13.4). However, suppose the oxy(cid:173)
`gen atom is acting as a hydrogen bond acceptor (Frame
`3, Fig. 13.4)? The oxygen is still present in the ether ana(cid:173)
`logue, so could it still take part in hydrogen bonding?
`Well, it may, but possibly not to the same extent. The
`extra bulk of the methyl group should hinder the close
`approach that was previously attainable and is likely to
`disrupt hydrogen bonding (Frame 4, Fig. 13.4). The hy(cid:173)
`drogen bonding may not be completely prevented, but
`we could reasonably expect it to be weakened.
`An ester analogue cannot act as a hydrogen bond do(cid:173)
`nor either. There is still the possibility of it acting as a
`hydrogen bond acceptor, but the extra bulk of the acyl
`
`H
`I
`(Ar)R-0:
`
`HBD
`
`I
`"i1 ~HBA
`
`HBA
`
`Alcohol or phenol
`
`CH3
`I
`(Ar)R-~:
`
`0
`\\
`C-CH
`I
`3
`(Ar)R-0:
`
`\. Methyl ether
`
`_____ Es_te_r_....,.)
`y
`Analogues
`
`FIGURE 13.3 Possible hydrogen bonding interactions for an alcohol or phenol.
`
`FIGURE 13.t
`alcohol/ph
`
`group is eve1
`and this too
`ing interacti
`electronic p1
`boxyl group
`neighbourin
`shown in Fi
`such an inte
`bond accept
`
`FIGURE 13.
`the hydn
`
`

`

`H-bond
`
`2
`
`' H
`
`®'a
`
`'
`
`Drug
`
`3
`
`H-bond
`
`.. /H
`
`0-H---~:O
`
`f .. · .. •.·.·.·.•··.:.:.· .•. ·.,.·.·.·
`
`Drug
`
`Analogue
`
`4
`
`Steric shield
`Me,
`0
`
`Aoalogoeo
`
`:rana-
`
`der or
`hol or
`of the
`bond
`is lost
`e oxy(cid:173)
`Frame
`r ana-
`1ding?
`t. The
`· close
`:ely to
`1e hy(cid:173)
`d, but
`
`td do(cid:173)
`g as a
`e acyl
`
`FIGURE 13.4 Possible hydrogen bond interactions for an
`alcohol/phenol in comparison with an ether analogue.
`
`group is even greater than the methyl group of the ether,
`and this too should hinder the original hydrogen bond(cid:173)
`ing interaction. There is also a difference between the
`electronic properties of an ester and an alcohol. The car(cid:173)
`boxyl group has a weak pull on the electrons from the
`neighbouring oxygen, giving the resonance structure
`shown in Fig. 13.5. Because the lone pair is involved in
`such an interaction, it will be less effective as a hydrogen
`bond acceptor. Of course, one could then argue that the
`
`Electronic factor
`
`Steric
`hindrance 0
`II
`H,c✓c~
`
`Analogue
`
`Steric factor
`
`Structure-activity relationships 225
`
`carbonyl oxygen is potentially a more effective hydrogen
`bond acceptor; however,-it is in a different position rela(cid:173)
`tive to the rest of the molecule and may be poorly po(cid:173)
`sitioned to form an effective hydrogen bond interaction
`with the target binding region.
`It is relatively easy to acetylate alcohols and phenols to
`their corresponding esters, and this was one of the early
`reactions that was carried out on natural products such
`as morphine (sections 24.3 and 24.5). Alcohols and phe(cid:173)
`nols can also be converted easily to ethers.
`In this section, we considered the OH group of alco(cid:173)
`hols and phenols. It should be remembered that the OH
`group of a phenol is linked to an aromatic ring, which
`can also be involved in intermolecular interactions (sec(cid:173)
`tion 13.1.2).
`
`13.1.2 Binding role of aromatic rings
`Aromatic rings are planar, hydrophobic structures, com(cid:173)
`monly involved in van der Waals interactions with flat
`hydrophobic regions of the binding site. An analogue
`containing a cyclohexane ring in place of the aromatic
`ring is less likely to bind so well, as the ring is no longer
`flat. The axial protons can interact weakly, but they also
`serve as buffers to keep the rest of the cyclohexane ring
`at a distance (Fig. 13.6). The binding region for the aro(cid:173)
`matic ring may also be a narrow slot rather than a planar
`surface. In that scenario, the cyclohexane ring would be
`incapable of fitting into it, because it is a bulkier structure.
`Although there are methods of converting aromat(cid:173)
`ic rings to cyclohexane rings, they are unlikely to be
`
`Aromatic ring
`R ---;;;; Q
`;;;,-
`. S S ~ >
`?
`
`~ood
`interaction
`
`Flat hydrophobic
`binding region
`
`R~ Cyclohexane
`
`r7 analogue
`H
`2
`
`H
`
`Poor
`interaction
`
`Flat hydrophobic
`binding region
`
`FIGURE 13.5 Factors by which an ester group can disrupt
`the hydrogen bonding of the original hydroxyl group.
`
`FIGURE 13.6 Binding comparison of an aromatic ring with
`a cyclohexyl ring.
`
`

`

`226 Chapter 13 Drug design: optimizing target interactions
`
`successful with most lead compounds, and so such ana(cid:173)
`logues would normally be prepared using a full synthesis.
`Aromatic rings could also interact with an aminium
`or quaternary ammonium ion through induced dipole
`interactions or hydrogen bonding (sections 1.3.4 and
`1.3.2). Such interactions would not be possible for the
`cyclohexyl analogue.
`
`13.1.3 Binding role of alkenes
`Like aromatic rings, alkenes are planar and hydrophobic,
`so they too can interact with hydrophobic regions of the
`binding site through van der Waals interactions. The ac(cid:173)
`tivity of the equivalent saturated analogue would be worth
`testing, since the saturated alkyl region is bullder and can(cid:173)
`not approach the relevant region of the binding site so
`closely (Fig. 13.7). Alkenes are generally easier to reduce
`than aromatic rings, so it may be possible to prepare the
`saturated analogue directly from the lead compound.
`
`13.1.4 The binding role of ketones and
`aldehydes
`A ketone group is not uncommon in many of the struc(cid:173)
`tures studied in medicinal chemistry. It is a planar group
`that can interact with a binding site through hydrogen
`bonding where the carbonyl oxygen acts as a hydrogen
`bond acceptor (Fig. 13.8). Two such interactions are pos(cid:173)
`sible, as two lone pairs of electrons are available on the
`carbonyl oxygen. The lone pairs are in sp2 hybridized
`orbitals which are in the same plane as the functional
`group. The carbonyl group also has a significant dipole
`
`moment and so a dipole-dipole interaction with the
`binding site is also possible.
`It is relatively easy to reduce a ketone to an alcohol
`and it may be possible to carry out this reaction directly
`on the lead compound. This significantly changes the
`geometry of the functional group from planar to tetra(cid:173)
`hedral. Such an alteration in geometry may well weaken
`any existing hydrogen bonding interactions and will cer(cid:173)
`tainly weaken any dipole-dipole interactions, as both the
`magnitude and orientation of the dipole moment will
`be altered (Fig. 13.9). If it was suspected that the oxygen
`present in the alcohol analogue might still be acting as
`a hydrogen bond acceptor, then the ether or ester ana(cid:173)
`logues could be studied, as described in section 13.1.1.
`Reactions are available that can reduce a ketone com(cid:173)
`pletely to an alkane and remove the oxygen, but they are
`unlikely to be practical for many of the lead compounds
`studied in medicinal chemistry.
`Aldehydes are less common in drugs because they are
`more reactive and are susceptible to metabolic oxidation
`to carboxylic acids. However, they could interact in the
`same way as ketones, and similar analogues could be
`studied.
`
`13.1.5 Binding role of amines
`Amines are extremely important functional groups in
`medicinal chemistry and are present in many drugs.
`They may be involved in hydrogen bonding, either as
`a hydrogen bond acceptor or a hydrogen bond donor
`(Fig. 13.10). The nitrogen atom has one lone pair of elec(cid:173)
`trons and can act as a hydrogen bond acceptor for one
`
`Flat
`R11,.c-c'-l!.\.B
`R,..... -
`--R
`
`Hydrophobic
`binding region
`
`Planar
`carbonyl
`R,,.c-o··
`R,...
`-
`.·
`' H-bond
`
`Tetrahedral alcohol
`0-H
`R,,.C/ R,...'
`
`H
`
`H
`'o
`. .
`Binding region
`
`0 .
`
`Binding region
`
`FIGURE 13. 7 Binding comparison of an alkene with an
`alkane.
`
`Carbonyl
`
`Alcohol
`
`Planar ~ HBA
`R,,.c-o··
`R,...
`-
`.·
`
`~HBA
`
`o+ o(cid:173)
`R,,.c-o
`R,...
`-
`-+--(cid:173)
`Dipole
`
`o+ o(cid:173)
`R,,.c-o
`R,...
`-
`-+--- Dipole-dipole
`~nteraction
`
`Binding region
`
`Binding region
`
`FIGURE 13.8 Binding interactions that are possible for a
`carbonyl group.
`
`FIGURE 13.9 Effect on binding interactions following the
`reduction of a ketone or aldehyde.
`
`R'
`~
`Tertiar
`
`FIGURE 1
`
`FIGURE 13.
`
`hydrogen I
`N-H groui;
`matic and:
`bond dono
`aromatic or
`In many
`interacts wi
`is ionized a
`However, it
`will form st
`ized (Fig. I:
`may take pl
`(Fig. 13.12).
`
`

`

`ith the
`
`alcohol
`:lirectly
`ges the
`) tetra(cid:173)
`weaken
`,ill cer(cid:173)
`oth the
`:nt will
`oxygen
`:ting as
`er ana-
`13.1.1.
`e com(cid:173)
`hey are
`Jounds
`
`hey are
`idation
`: in the
`mid be
`
`mps in
`drugs.
`ther as
`donor
`of elec(cid:173)
`for one
`
`R
`\
`R,,•N :¢:=iHBA
`R''
`Tertiary amine
`
`HBD
`
`\
`
`H
`\
`R"•N : ¢==I HBA
`R'
`Secondary amine
`
`HBD
`
`\
`HBD..,.y- R'
`
`H
`H,,.'N :¢==IHBA
`
`Primary amine
`FIGURE 13.10 Possible binding interactions for amines.
`
`HBD
`
`\
`
`HBD
`
`\
`H ,0
`H,,,N-H -
`' R
`FIGURE 13.11 Possible hydrogen bonding interactions for
`ionized amines.
`
`HBO,..,.-
`
`HBD
`
`hydrogen bond. Primary and secondary amines have
`N-H groups and can act as hydrogen bond donors. Aro(cid:173)
`matic and heteroaromatic amines act only as hydrogen
`bond donors, because the lone pair interacts with the
`aromatic or heteroaromatic ring.
`In many cases, the amine may be protonated when it
`interacts with its target binding site, which means that it
`is ionized and cannot act as a hydrogen bond acceptor.
`However, it can still act as a hydrogen bond donor and
`will form stronger hydrogen bonds than if it was not ion(cid:173)
`ized (Fig. 13.11). Alternatively, a strong ionic interaction
`may take place with a carboxylate ion in the binding site
`(Fig. 13.12).
`
`(o
`R
`\
`I/
`N-C
`/'" A
`\
`R'
`'-...Jf' CH3
`
`(cid:141) ,l(f-----1(cid:141)(cid:141)
`
`0 8
`R
`\
`I
`N=c
`/4'
`\
`R' IV
`CH3
`N unable to participate in a
`hydrogen bond or ionic bond
`
`Structure-activity relationships 227
`
`Binding site
`
`FIGURE 13.12 Ionic interaction between an ionized amine
`and a carboxylate ion (R = H, alkyl, or aryl).
`
`To test whether ionic or hydrogen bonding interac(cid:173)
`tions are taking place, an amide analogue could be stud(cid:173)
`ied. This will prevent the nitrogen acting as a hydrogen
`bond acceptor, as the nitrogen's lone pair will interact
`with the neighbouring carbonyl group (Fig. 13.13). This
`interaction also prevents protonation of the nitrogen
`and rules out the possibility of ionic interactions. You
`might argue that the right-hand structure in Fig. 13.13a
`has a positive charge on the nitrogen and could still take
`part in an ionic interaction. However, this resonance
`structure represents one extreme and is never present as
`a distinct entity. The amide group as a whole is neutral,
`and so lacks the net positive charge required for ionic
`bonding.
`It is relatively easy to form secondary and tertiary
`amides from primary and secondary amines respectively,
`and it may be possible to carry out this reaction directly
`on the lead compound. A tertiary amide lacks the N-H
`group of the original secondary amine and would test
`whether this is involved as a hydrogen bond donor. The
`secondary amide formed from a primary amine still has
`an N-H group present, but the steric bulk of the acyl
`group should hinder it acting as a hydrogen bond donor.
`Tertiary amines cannot be converted directly to
`amides, but if one of the alkyl groups is a methyl group, it
`is often possible to remove it with vinyloxycarbonyl chlo(cid:173)
`ride (VOC-Cl) to form a secondary amine, which could
`then be converted to the amide (Fig.13.14). This demeth(cid:173)
`ylation reaction is extremely useful and has been used to
`good effect in the synthesis of morphine analogues (see
`Box 24.2 for the reaction mechanism).
`
`0
`R
`\
`I/
`N-C
`\
`I
`R'
`CH3
`
`0
`R
`acyl
`11
`,
`group
`,N-\
`H
`CH3
`
`Tertiary amide Secondary amide
`
`ngthe
`
`FIGURE 13.13 (a) Interaction of the nitrogen lone pair with the neighbouring
`carbonyl group in amides. (b) Secondary and tertiary amides.
`
`(a)
`
`(b)
`
`

`

`228 Chapter 13 Drug design: optimizing target interactions
`
`VOC-CI
`
`R,
`N-Me
`I
`
`0
`R
`I;
`\
`N-C
`\
`I
`R'
`CH 3
`R'
`FIGURE 13.14 Demethylation of a tertiary amine and
`formation of a secondary amide.
`
`R
`CH 3COCI
`,
`N-H - - -(cid:141)
`I
`
`R'
`
`HBA
`
`\:t
`·o : ¢::J HBA
`
`R
`I;
`\
`N-C
`\
`I
`R'
`CH3
`
`HBA
`
`\:t
`·o: ¢::l HBA
`
`R
`\
`I/
`N-C
`\
`I
`H
`CH3
`
`I
`HBD
`
`Tertiary amide
`
`Secondary amide
`
`HBO
`
`\
`
`HBA
`\:t
`·o: ¢:::l HBA
`H
`\
`I/
`N-C
`\
`I
`H
`CH3
`
`I
`
`HBD
`
`Primary amide
`
`FIGURE 13.15 Possible hydrogen bonding interactions for
`amides.
`
`13.1.6 Binding role of amides
`
`Many of the lead compounds currently studied in medic(cid:173)
`inal chemistry are peptides or polypeptides consisting of
`amino acids linked together by peptide or amide bonds
`(section 2.1). Amides are likely to interact with binding
`sites through hydrogen bonding (Fig. 13.15). The carbon(cid:173)
`yl oxygen atom can act as a hydrogen bond acceptor and
`has the potential to form two hydrogen bonds. Both the
`lone pairs involved are in sp2 hybridized orbitals which
`are located in the same plane as the amide group. The
`
`nitrogen cannot act as a hydrogen bond acceptor because
`the lone pair interacts with the neighbouring carbonyl
`group (Fig. 13.13a). Primary and secondary amides have
`an N-H group, which allows the possibility of this group
`acting as a hydrogen bond donor.
`The most common type of amide in peptide lead com(cid:173)
`pounds is the secondary amide. Suitable analogues that
`could be prepared to test out possible binding interac(cid:173)
`tions are shown in Fig. 13.16. All the analogues, apart
`from the primary and secondary amines, could be used
`to check whether the amide is acting as a hydrogen bond
`donor. The alkenes and amines could be tested to see
`whether the amide is acting as a hydrogen bond accep(cid:173)
`tor. However, there are traps for the unwary. The amide
`group is planar and does not rotate because of its partial
`double bond character. The ketone, the secondary amine
`and the tertiary amine analogues have a single bond at
`the equivalent position which can rotate. This would alter
`the relative positions of any binding groups on either side
`of the amide group and lead to a loss of binding, even if
`the amide itself was not involved in binding. Therefore, a
`loss of activity would not necessarily mean that the amide
`is important as a binding group. With these groups, it
`would only be safe to say that the amide group is not es(cid:173)
`sential if activity is retained. Similarly, the primary amine
`and carboxylic acid may be found to have no activity, but
`this might be due to the loss of important binding groups
`in one half of the molecule. These particular analogues
`would only be worth considering if the amide group
`is peripheral to the molecule (e.g. R-NHCOMe or R(cid:173)
`CONHMe) and not part of the main skeleton.
`The alkene would be a particularly useful analogue to
`test because it is planar, cannot rotate, and cannot act as a
`hydrogen bond donor or hydrogen bond acceptor. How(cid:173)
`ever, the synthesis of this analogue may not be simple.
`In fact, it is likely that all the analogues described would
`have to be prepared using a full synthesis. Amides are
`relatively stable functional groups and, although several
`of the analogues described might be attainable directly
`from the lead compound, it is more likely that the lead
`
`H
`I
`R_...N,C,.,R
`II
`0
`Secondary
`amide
`
`Me
`I
`,.,R
`_...N,
`R
`C
`II
`0
`N-Methylated
`amide
`
`R~R
`
`Alkene
`
`H
`I
`R,...N........_,.....R
`
`Me
`I
`R_...N-......,.,.....R
`
`Secondary
`amine
`
`H
`I
`N
`'H
`
`R,...
`
`Primary
`amine
`
`N-Methylated
`tertiary
`amine
`
`HO, .,R
`C
`II
`0
`Carboxylic
`acid
`
`R_../"-.....C,.,R
`II
`0
`
`Ketone
`
`FIGURE 13. 16 Possible analogues to test the binding interactions of a secondary amide.
`
`A p-Lac
`
`~~ 0
`
`)
`
`OH
`
`Ser
`
`FIGURE 13.1
`
`compound
`required.
`Amides 1
`lactams. Th
`bonds as de
`and suffers :
`cal reaction
`covalent bo
`!ins which c
`acts as an a,
`terial enzyn
`site (Fig. 13
`
`13.1.7 Bin
`ammcmirn
`Quaternar:
`teract with
`(Fig. 13.18:
`interaction
`and any ar
`tively chaq
`
`FIGIJF
`
`

`

`cause
`)onyl
`have
`;roup
`
`com(cid:173)
`; that
`erac(cid:173)
`apart
`used
`bond
`) see
`xep(cid:173)
`mide
`1rtial
`mine
`1d at
`alter
`·side
`·en if
`lre, a
`mide
`JS, it
`,t es(cid:173)
`nine
`', but
`oups
`gues
`roup
`r R-
`
`1e to
`:as a
`Iow-
`1ple.
`ould
`; are
`reral
`~ctly
`lead
`
`A R-1
`
`0
`
`0
`
`f!GURIE 13.17 /3-Lactam ring acting as an acylating agent.
`
`compound would not survive the forcing conditions
`required.
`Amides which are within a ring system are called
`lactams. They, too, can form intermolecular hydrogen
`bonds as described above. However, if the ring is small
`and suffers ring strain, the lactam can undergo a chemi(cid:173)
`cal reaction with the target leading to the formation of a
`covalent bond. The best examples of this are the penicil(cid:173)
`lins which contain a four-membered /3-lactam ring. This
`acts as an acylating agent and irreversibly inhibits a bac(cid:173)
`terial enzyme by acylating a serine residue in the active
`site (Fig. 13.17) (section 19.5.1.4).
`
`13.1.7 Binding role of quaternary
`ammonium salts
`Quaternary ammonium salts are ionized and can in(cid:173)
`teract with carboxylate groups by ionic interactions
`(Fig. 13.18). Another possibility is an induced dipole
`interaction between the quaternary ammonium ion
`and any aromatic rings in the binding site. The posi(cid:173)
`tively charged nitrogen can distort the Jt electrons of
`
`DRUG I
`
`Ionic
`bonding
`
`Structure-activity relationships 229
`
`the aromatic ring such that a dipole is induced, whereby
`the face of the ring is slightly negative and the edges are
`slightly positive. This allows an interaction between the
`slightly negative faces of the aromatic rings and the posi(cid:173)
`tive charge of the quaternary ammonium ion. This is also
`known as a Jt-cation interaction.
`The importance of these interactions could be tested
`by synthesizing an analogue that has a tertiary amine
`group rather than the quaternary ammonium group.
`Of course, it is possible that such a group could ionize
`by becoming protonated, then interact in the same way.
`Converting the amine to an amide would prevent this
`possibility. The neurotransmitter acetylcholine has a
`quaternary ammonium group which is thought to bind
`to the binding site of its target receptor by ionic bonding
`and/or induced dipole interactions (section 22.5).
`
`13.1.8 Binding role of carboxylic acids
`The carboxylic acid group is reasonably common in
`drugs. It can act as a hydrogen bond acceptor or as a hy(cid:173)
`drogen bond donor (Fig. 13.19). Alternatively, it may ex(cid:173)
`ist as the carboxylate ion. This allows the possibility of an
`ionic interaction and/or a strong hydrogen bond where
`the carboxylate ion acts as a hydrogen bond acceptor. The
`carboxylate ion is also a good ligand for metal ion cofac(cid:173)
`tors present in several enzymes; for example zinc metal(cid:173)
`loproteinases (section 21.7.1 and Case study 2).
`In order to test the possibility of such interactions, an(cid:173)
`alogues such as esters, primary amides, primary alcohols,
`and ketones could be synthesized and tested (Fig. 13.20).
`None of these functional groups can ionize, so a loss of
`activity could imply that an ionic bond is important. The
`primary alcohol could shed light on whether the car(cid:173)
`bonyl oxygen is involved in hydrogen bonding, whereas
`the ester and ketone could indicate whether the hydroxyl
`group of the carboxylic acid is involved in hydrogen
`
`HBA
`
`~
`
`·o:¢::JHBA
`
`Induced
`dipole
`interactions
`
`Weak ~-H-HBD
`HBA
`'-v ..
`~
`Weak HBA
`
`Carboxylic acid
`
`,,
`
`0
`/•
`R-C'0
`0
`
`Ionic interaction
`and/or
`strong hydrogen bond acceptor
`
`Carboxylate ion
`
`FIGURE 13. 18 Possible binding interactions of a
`quaternary ammonium ion.
`
`FIGURE 13.19 Possible binding interactions for a
`carboxylic acid and carboxylate ion.
`
`

`

`230 Chapter 13 Drug design: optimizing target interactions
`·o,
`·o,
`R--{
`R--{
`:q_-H
`
`:q_-R'
`
`R\
`:q_-H
`Primary alcohol
`
`Carboxylic acid
`
`Ester
`
`Primary amide Ketone
`
`FIGURE 13.20 Analogues to test the binding interactions for a carboxylic acid.
`
`Analogues
`
`bonding. It may be possible to synthesize the ester and
`amide analogues directly from the lead compound, but
`the reduction of a carboxylic acid to a primary alcohol
`requires harsher conditions and this sort of analogue
`would normally be prepared by a full synthesis. The ke(cid:173)
`tone would also have to be prepared by a full synthesis.
`
`13.1.9 Binding role of esters
`
`An ester functional group has the potential to interact
`with a binding site as a hydrogen bond acceptor only
`(Fig. 13.21). The carbonyl oxygen is more likely to act
`as the hydrogen bond acceptor than the alkoxy oxygen
`(section 1.3.2), as it is sterically less hindered and has a
`greater electron density. The importance or otherwise of
`the carbonyl group could be judged by testing an equiva(cid:173)
`lent ether, which would require a full synthesis.
`Esters are susceptible to hydrolysis in vivo by meta(cid:173)
`bolic enzymes called esterases. This may pose a problem
`if the lead compound contains an ester that is important
`to binding, as it means the drug might have a short life(cid:173)
`time in vivo. Having said that, there are several drugs that
`do contain esters and are relatively stable to metabolism,
`
`HBA
`<:;:;
`R~b:¢::lHBA
`
`Weakq :q.- R'
`"\j
`HBA
`Weak
`HBA
`
`HBA
`
`FIGURE 13.:21 Possible binding interactions for an ester
`and an ether.
`
`thanks to electronic factors that stabilize the ester or ster(cid:173)
`ic factors that protect it.
`Esters that are susceptible to metabolic hydrolysis are
`sometimes used deliberately to mask a polar functional
`group such as a carboxylic acid, alcohol, or phenol in or(cid:173)
`der to achieve better absorption from the gastrointestinal
`tract. Once in the blood supply, the ester is hydrolysed
`to release the active drug. This is known as a prodrug
`strategy (section 14.6).
`Special mention should be made of the ester group
`in aspirin. Aspirin has an anti-inflammatory action
`resulting from its ability to inhibit an enzyme called
`cyclooxygenase (COX) which is required for prosta(cid:173)
`glandin synthesis. It is often stated that aspirin acts as
`an acylating agent, and that its acetyl group is covalently
`attached to a serine residue in the active site of COX
`(Fig. 13.22). However, this theory has been disputed
`and it is stated that aspirin acts, instead, as a prodrug to
`generate salicylic acid, which then inhibits the enzyme
`through non-covalent interactions.
`
`13.1.10 Binding rnle of alkyl and aryl halides
`Alkyl halides involving chlorine, bromine, or iodine
`tend to be chemically reactive, since the halide ion is a
`good leaving group. As a result, a drug containing an
`alkyl halide is likely to react with any nucleophilic group
`that it encounters and become permanently linked to
`that group by a covalent bond-an alkylation reaction
`(Fig. 13.23). This poses a problem, as the drug is likely
`to alkylate a large variety of macromolecules which have
`nucleophilic groups, especially amine groups in proteins
`and nucleic acids. It is possible to moderate the reactivity
`to some extent, but selectivity is still a problem and leads
`to severe side effects. These drugs are, therefore, reserved
`
`xoJ~
`
`V
`
`21()
`
`Acetylation
`
`Aspirin
`
`Salicylic acid
`
`FIGURE 13.22 The disputed theory of aspirin acting as an acylating agent.
`
`for life(cid:173)
`and 21.
`alkylati1
`easily b
`proton
`ferent e
`c:!CUle fo
`Aryl
`less of a
`ents an
`electror
`an influ
`ogen su
`in natm
`pockets
`be weak
`hydrogE
`erally p
`an ion(cid:173)
`import2
`binding
`Alipr
`substitu
`whethe1
`tivity of
`
`13.1.11
`
`The thi
`ford-bl
`several
`zinc coJ
`(section
`compm
`could b
`weaker
`Ane1
`accepto
`could b
`ing alky
`the gr01
`where t
`isostere
`affinity.
`The<
`poor hy
`
`

`

`~(:'f; }
`
`4.•.·.··.·.·.·.· •.••. · .. · ..• ·
`
`l i
`
`i
`l
`i
`I
`
`I
`
`Structure-activity relationships 231
`
`I"\
`X-R
`Alkyl halide
`
`Alkylation
`
`H
`R-N-Target
`
`+ X0
`
`Nucleophilic group
`
`Good leaving