1 Different Roles of Carboxylic Functions in Pharmaceuticals and Agrochemicals

12 Pages·2016·0.29 MB·English

1
1
DifferentRolesofCarboxylicFunctionsinPharmaceuticals
andAgrochemicals
ClemensLamberthandJürgenDinges
1.1
Introduction
Explaining the importance of carboxylic acid and its related derivatives in
medicine and crop protection is best achieved by examining the number
of endogenous processes and molecules that rely on the chemical nature of
this functional group. From amino acid conjugation via peptide synthesis to
proteins and posttranslational protein acylation to triglycerides, bile acids,
and prostanoids, it is evident that carboxylic acid, ester, and amide functions
contribute to the physiology of many living systems [1]. Not surprisingly then,
there exists an extensive number of active ingredients bearing such functions.
Roughly 25% of all commercialized pharmaceuticals contain a CO H group
2
[2]; a similar portion (25%) is reported to bear an amide [3]. A similar ratio
is true for agrochemicals; at least 40% of all marketed crop protection agents
bear a carboxylic function [4]. Several sets of criteria for the definition of the
preferred chemical composition leading to optimal bioavailability for active
ingredients, such as Lipinski’s “Rule of Five” for oral drugs [5], Astex’s “Rule of
Three” for fragment-based lead discovery [6], and Brigg’s “Rule of Three” for
agrochemicals [7], contain the need for the presence of hydrogen-bond donors
and hydrogen-bond acceptors for ideal drugs, a requirement that several car-
boxylicfunctionsfulfill.Thisbookchaptertriestohighlightthemostimportant
rolesthatcarboxylicfunctionsplayinpharmaceuticalsandagrochemicals.
1.2
Solubilizer
The introduction of carboxylic acid into a biologically active compound posi-
tively impacts the water solubility of the compound. Acids are generally highly
ionized at physiological pH values and therefore solvated to a greater degree
and display more favorable aqueous solubilities than neutral molecules of
similar lipophilicity do. In addition, the counterion influences solubility and
BioactiveCarboxylicCompoundClasses:PharmaceuticalsandAgrochemicals,FirstEdition.
EditedbyClemensLamberthandJürgenDinges.
©2016Wiley-VCHVerlagGmbH&Co.KGaA.Published2016byWiley-VCHVerlagGmbH&Co.KGaA.
2 1 DifferentRolesofCarboxylicFunctionsinPharmaceuticalsandAgrochemicals
physicochemical properties of active ingredients bearing a carboxylate [8]. The
presenceofchargesplaysasignificantroleinmodulatingsolubility,lipophilicity,
andthuscellpermeation.However,acidiccompoundsarealsooftenassociated
withpoorpermeabilitybecausetheyaremainlypresentinthedeprotonatedstate
in this pH range and cannot readily cross negatively charged lipid membranes
[2]. Such solubilizing effects are even more pronounced in the presence of two
ormoreionizedgroups,especiallyzwitterions.Forexample,becauseofthepH
gradient unique to the gastrointestinal tract, it is the piperazine moiety in the
quinoloneantibioticciprofloxacinthatgovernsthechargestatewithintheacidic
uppergastrointestinaltract(gastricregion).TheelevationofthepHvalueinthe
subsequentproximalintestineresultsinthezwitterionicstate2(Figure1.1)[1,9].
In crop protection, carboxylic acids are known for their pronounced phloem
mobility,whichincludesthebasipetalmovementofanactiveingredientfromthe
leavestotherootswithinaplant.
Further proof for the effect of carboxylic acid functions on the solubility of
pharmaceuticals is found in the history of antihistaminic drugs [10]. Several
first-generation derivatives, such as hydroxyzine (3), were rather lipophilic
compounds,whichwereabletocrosstheblood–brainbarrierandhadasedating
effect because they were no substrates for P-glycoproteins (P-gps). Owing to
the replacement of the hydroxyl function by a carboxylic acid, cetirizine (4),
a second-generation antihistaminic, is less lipophilic and therefore a P-gp
substratethatlimitstheCNSexposure(Figure1.2)[11,12].
O O O O
F F
OH O–
N N N N
H N+ H N+
2 2
1 2
Ciprofloxacin in the gastric Ciprofloxacin in the intestinal
environment (pH ≤ 3.5) environment (pH ≤ 7.0)
Figure1.1 Ionizationstateofciprofloxacininthegastrointestinaltract[1].
N N
N OH N OH
CI O CI O
3 4 O
Hydroxyzine Cetirizine
Figure1.2 Increasingsolubilityofantihistaminiccompoundsbycarboxylicacids.
1.3 Pharmacophore 3
1.3
Pharmacophore
A pharmacophore is the group of atoms and, therefore, also the ensemble of
stericandelectronicfeaturesofanactiveingredientensuringoptimummolecular
interactions with an enzyme and responsible for triggering or blocking its
biological response [13]. The acidity of carboxylic acids, combined with the
abilityofallcarboxylicacidderivativestoestablishrelativelystrongelectrostatic
interactions and single or bifurcated hydrogen-bond bridges with the protein
target, conferring both binding affinity and specificity to the drug–target
interaction,isthereasonthatcarboxylicacidfunctionsareoftenthekeydeter-
minant of pharmacophores [2]. Figure 1.3 shows only four examples of many
pharmaceuticals and agrochemicals that rely on the presence of a carboxylic
functionintheirpharmacophore.Theterminalcarboxylateofatorvastatin(5),a
bloodcholesterol-reducingblockbusterdrug,formsasaltbridgewithLysine735
of its target enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase [14].
The carbonyl oxygen atom of the carboxylic acid function in the nonsteroidal
anti-inflammatoryacidflurbiprofen(6)buildsahydrogen-bondbridgewiththe
phenol group of Tyrosine355 of cyclooxygenase-1 [15]. The broad-spectrum
activity of azoxystrobin (7), the world’s biggest selling fungicide, is due to the
interaction of the carbonyl oxygen atom of its ester function with an amine
proton of Glutamine272 in cytochrome bc1, the complex III of the respiratory
Lys735
O OH OH O N
H
OH
N N O–
H
O
F
F H Tyr355
O
5 6
Atorvastatin Flurbiprofen
CI CI CI
H
N
O
7 8
Azoxystrobin H Carpropamid
O
H
H Tyr30
O
Glu272
Figure1.3 Examplesforpharmacophoresofactiveingredientsbasedoncarboxylicacids,
esters,andamides.
4 1 DifferentRolesofCarboxylicFunctionsinPharmaceuticalsandAgrochemicals
chain in the mitochondria of the fungi [16]. The carbonyl oxygen of the amide
function of carpropamid (8), a melanin biosynthesis-inhibiting rice fungicide,
accepts a hydrogen bond from a water molecule coordinated to Tyrosine30 of
scytalonedehydratase[17].
1.4
Prodrug
Acarboxylicacidgroup,beingusuallyionizedinthephysiologicalpHrange,adds
to the hydrophilicity and polarity of the active ingredient. As a result, a large
number of biologically active carboxylic acids display unfavorable pharmacoki-
neticpropertiessuchaslowbioavailabilitybecauseoflimiteduptake.Thus,the
improvementofpharmacokineticpropertiescanbeachievedbytransferringthe
drugintoaprodrug.Aprodrugisacompoundthatitselfisnotbiologicallyactive,
butisconvertedbyenzymes,heat,moisture,orUVlightintoanintrinsicallyactive
derivative. Because of the ubiquitous availability of esterases and peptidases in
manyspecies,includinghuman,theinvivohydrolysisofestersandrelatedcar-
boxylicfunctionstothecorrespondingacidsisoneoftheclassicalprodrugcases
[18–23]. Such ester derivatives are called carrier prodrugs, because they often
facilitatetheadsorptionanddistributionofpharmaceuticalsoragrochemicalsto
thedesiredlocation,followedbyreleaseoftheactiveprinciplebycleavageofthe
carriergroupthroughahydrolyticreaction[19].Theethylesterinoseltamivir(9)
increasestheoralbioavailabilityinhumansfromlessthan5%forthecarboxylic
acidparent10to80%and,therefore,allowsthisanti-influenzaantiviralagentto
beadministeredorally[18,20,21].Esterprodrugsthatreleaseabiologicallyactive
alcoholspeciesinsteadofacarboxylicacid–containingdrugareknowntoalower
content.Thereasonforthismaybethattheimprovementofpharmacokineticfea-
turesisgenerallygreaterwhenmaskingthehighlypolarcarboxylateratherthan
thelesspolarhydroxylgroup[22].Animportantexampleistheantiherpesvirus
agentfamciclovir(11),whichdeliversinvivopenciclovir(12)byenzymaticester
cleavage and purine oxidation. The oral bioavailability of 4% for penciclovir is
increasedto75%forfamciclovir[20].Aspecialcaseofesterprodrugsarelactones,
whichareformedbyintramolecularcyclizationofhydroxylacidsandwhichlib-
erate this function after cleavage. An example is the reversible ring opening of
thelactonein3-hydroxy-3-methylglutaryl-CoAreductaseinhibitorlovastatin13
toitsβ-hydroxyacidopenform14[21,22].ThecarbothioicacidS-methylester
intheplantactivatoracibenzolar-S-methyl(15)[24]andthecarbonatefunction
intheinsecticidespirotetramat(17)[25]arefurtherexamplesofcarboxylicacid
derivatives,whichcanbeemployedascarrierprodrugs,andalsocarbamateshave
beenusedinthiscontext(Scheme1.1)[18,19].
Another kind of prodrugs are bioprecursors, which deliver the biologically
active compound via an in vivo transformation without the need to cleave a
carrier moiety. Also here, the formation of carboxylic acids seems to play an
important role. The angiotensin II receptor antagonist losartan (19), which
1.4 Prodrug 5
O O
O O
O O Carboxylesterase O OH
N N
H
N N
9 10
Oseltamivir Active principle
O
Carboxylesterase,
N N xanthine oxidase HN N
H2N N N O O H2N N N OH
11 12
Famciclovir O Penciclovir HO
O
O OH HO OH
O HO O
O O
O O
H H
Carboxylesterase
13 14
Lovastatin Active principle
O S O OH
S Carboxylesterase S
N N
N N
15 16
Acibenzolar-S-methyl Active principle
O
O
O O
O Carboxylesterase HO
HN N
O O
17 18
Spirotetramat Active principle
Scheme1.1 Someexamplesofester,carbonate,andcarbothioicS-esterprodrugs.
6 1 DifferentRolesofCarboxylicFunctionsinPharmaceuticalsandAgrochemicals
is used in antihypertensive medication, can be seen as bioprecursor prodrug,
becauseitsprimaryalcoholisoxidizedinvivobythecytochromeP450enzyme
CYP2C9 to the carboxylic acid 20, which represents the active principle [18,
19,21].Inaddition,theantithromboticdrugclopidogrel(21)ismetabolizedby
cytochrome P450 enzymes to its active form 22 containing a carboxylic acid
(Scheme1.2)[18,19].
CI CI
N N OH
OH H H
N N N N N N
O
N N CYP2C9 N N
19
Losartan 20
Active principle
O O O O
HO
N N
H CYPs H
O
S CI HS CI
21
22
Clopidogrel
Active principle
Scheme1.2 Losartan(19)andclopidogrel(21)asbioprecursorsofcarboxylicacid
derivatives.
1.5
BioisostericReplacement
We have seen so far that carboxylic functions are often important constituents
ofactiveingredients;however,thepresenceofsuchgroupscanalsoberespon-
sibleforsignificantdrawbacks,suchasmetabolicinstability,toxicity,andlimited
passivediffusionacrossmembranes.Toavoidsomeoftheseshortcomingswhile
retainingthedesiredattributesofthecarboxylicmoiety,itsreplacementbyacar-
boxylicbioisosteremightbeconsidered.Theconceptofbioisosterismisbasedon
thenotionthattheexchangeofsingleatomsorwholegroupsthatexhibitsimi-
larsize,shape,chargedistribution,andphysicochemicalpropertiescreatesanew
compoundwithsimilarbiologicalpropertiestotheparentactiveingredient[13].
Thesametypeofstrategycanalsobeappliedeffectivelyforotherpurposes,for
example,toincreasethepotencyorselectivityofabiologicallyactivecompoundor
1.5 BioisostericReplacement 7
tocreateownintellectualproperty.However,theoutcomeofanyisostericreplace-
mentcannotbereadilypredictedastheresultisgenerallyfoundtobedependent
onparticularpropertiesofthedruganditstarget.Asaresult,screeningofapanel
ofdifferentisosteresistypicallyrequired;themoreisosteresofonedefinedfunc-
tionalgroupareknown,thehigherthechancestofindonewithfullpreservation
orevenenhancementofthedesiredbiologicalactivity.Asamatteroffact,several
groupswithanisostericrelationshiptocarboxylicfunctionsareknown,especially
surrogates of carboxylic acids are really high in number [26, 27]. For example,
several organic heteroatom acids, such as phosphonic acids, phosphinic acids,
andsulfonicacids,areprovenreplacementsofcarboxylicacids,asdemonstrated
by the phosphonic acid phaclofen (24) and the sulfonic acid saclofen (25), two
γ-aminobutyricacid(GABA) antagonisticbioisosteresoftheGABA -agonistic
B B
antispasmodicdrugbaclofen(23)(Figure1.4)[26].
Anothergroupofwell-establishedbioisostericfunctionsofthecarboxylicacid
grouparecertainheterocycles,suchashydroxyisoxazole[28],hydroxyisothiazoles
[29],thiadiazolidinediones[30],oxadiazolones[31],andofcourseespeciallytetra-
zoles[32].Thetetrazolemoietyinlosartan(19)mimicsacarboxylicacidfunction.
3-Hydroxyisoxazolehasbeenextensivelyappliedascarboxylicacidbioisosterein
thecaseofGABAandglutamatesignalingdrugs,whichmimicGABAandglu-
tamic acid, two essential neurotransmitters in the mammalian central nervous
system[26,29].TheGABA agonistsmuscimol(27)andgaboxadol(28)areclose
A
analogsofGABA(26);theirhydroxyisoxazolemoietyresemblestheacidgroupof
26[26].Thenaturallyoccurringheterocyclicaminoacidibotenicacid(30)andits
syntheticanalogthioibotenicacid(31)arehydroxyisoxazoleandhydroxyisothia-
zolebioisosteresofglutamicacid(29),and,therefore,alsopotentglutamaterecep-
torligands[29].Thethiazolidinedioneintheantidiabeticdrugrosiglitazone(33)is
probablyrequiredascarboxylicacidsurrogate,becauseseveralothercompounds
with comparable activity against the targeted peroxisome proliferator-activated
receptor,suchasragaglitazar(32),bearanacidfunctioninthesameregionofthe
molecule(Figure1.5)[30].
Several bioisosteric groups of other carboxylic functions, such as esters and
amides,areclearlylinkedtorelatedacidsurrogates.Because5-substitutedtetra-
zoles are acid replacements, logically 1,5-disubstituted tetrazoles are effective
bioisosteresfortheamidebond[32].Inaddition,theabilityof1,2,4-oxadiazolesto
functionasheterocyclicsurrogateoftheamidebond[33]islinkedtotheknown
CI CI CI
O O OH O O
H2N OH H2N P OH H2N S OH
23 24 25
Baclofen Phaclofen Saclofen
Figure1.4 Baclofen(23)anditsbioisosteresphaclofen(24)andsaclofen(25)[26].
8 1 DifferentRolesofCarboxylicFunctionsinPharmaceuticalsandAgrochemicals
OH OH
O
H2N OH H2N O N N O N
H
26 27 28
γ-Aminobutyric acid (GABA) Muscimol Gaboxadol
OH OH
O O O O
N N
HO OH HO O HO S
NH NH NH
2 2 2
29 30 31
(S)-Glutamic acid Ibotenic acid Thioibotenic acid
O O
O OH NH
N O N N S
O O O
32 33
Ragaglitazar Rosiglitazone
Figure1.5 Heterocyclicbioisosteresofcarboxylicacidderivatives.
trackrecordofrelated1,2,4-oxadiazol-5-onesasgoodacidreplacement[31].As
2,2,2-trifluoroethan-1-olisahighlyviablecarboxylicacidbioisostere[26],itisno
surprisethatα-trifluoromethyl-substitutedaminescanmimicamides[34].
1.6
Scaffold
Amidesasstableandrelativelyneutralcarboxylicacidderivativesplayanimpor-
tantroleinprovidingathree-dimensionalscaffoldrequiredforoptimumbinding
oftheactiveingredienttothetargetenzymebylinkingelaboratedacidandamide
moietiestogether.Notonlythepotentialoftheamidegroupashydrogen-bond
donoraswellasacceptorisanadvantage,anotherreasonforthevastamountof
amidesamongpharmaceuticalsandagrochemicalsistheirstraightforwardsyn-
thetic accessibility from carboxylic acids, chlorides, or esters with appropriate
amines. The tyrosine kinase inhibitor imatinib (34) [35], the dopamine antago-
nistamisulpride(35)[36],thecellulosesynthaseinhibitormandipropamid(36)
[37],andthesuccinatedehydrogenaseinhibitor(SDHI)isopyrazam(37)[38]are
fourexamplesofmanypharmaceuticalsandagrochemicalsrelyingonanamide
bridge(Figure1.6).
References 9
N O O O
N
H H S N
N N N N N
H
O N H N O
2
34 35
Imatinib Amisulpride
F O
O
H
N O F N
N H
O N
O
36 37
Mandipropamid Isopyrazam
Figure1.6 Fouractiveingredients,whichrelyonanamidefunctionlinkingimportantparts
ofthemolecule.
1.7
Conclusion
Carboxylicacid–containingdrugs,suchasnonsteroidalanti-inflammatorydrugs
(NSAIDs),β-lactamantibiotics,andstatins,haverevolutionizedtheprogressin
themedicaltreatmentofpainanddiseasesinthetwentiethcentury.Thehistory
ofchemicalweedcontrolandthereforethestartofindustrialagriculturewould
be unimaginable without carboxylic acid herbicide classes such as auxin mim-
ics and sulfonylureas. Two out of the three currently most important fungicide
classes,theinhibitorsofcomplexIIandcomplexIIIofthefungalrespiratorychain
(SDHIsandquinoneoutsideinhibitor(QoI)s),arebasedoncarboxylicfunctions.
Allthesefactsareproofforthefundamentalimportanceofcarboxylicfunctions
forpharmaceuticalsandagrochemicals.
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