The Current Case of Quinolones: Synthetic Approaches and Antibacterial Activity

19 Pages·2016·2.32 MB·English

molecules
Review
The Current Case of Quinolones: Synthetic
Approaches and Antibacterial Activity
AbdulNaeem1,SyedLalBadshah1,2,*,MairmanMuska1,NasirAhmad2andKhalidKhan2
1 NationalCenterofExcellenceinPhysicalChemistry,UniversityofPeshawar,Peshawar,
KhyberPukhtoonkhwa25120,Pakistan;[email protected](A.N.);[email protected](M.M.)
2 DepartmentofChemistry,IslamiaCollegeUniversityPeshawar,Peshawar,KhyberPukhtoonkhwa25120,
Pakistan;[email protected](N.A.);[email protected](K.K.)
* Correspondence:[email protected];Tel.:[phone]
AcademicEditor:PeterJ.Rutledge
Received:23December2015;Accepted:15February2016;Published:28March2016
Abstract: Quinolones are broad-spectrum synthetic antibacterial drugs first obtained during the
synthesisofchloroquine.Nalidixicacid,theprototypeofquinolones,firstbecameavailableforclinical
consumptionin1962andwasusedmainlyforurinarytractinfectionscausedbyEscherichiacoliand
otherpathogenicGram-negativebacteria.Recently,significantworkhasbeencarriedouttosynthesize
novelquinoloneanalogueswithenhancedactivityandpotentialusageforthetreatmentofdifferent
bacterialdiseases. Thesenovelanaloguesaremadebysubstitutionatdifferentsites—thevariation
attheC-6andC-8positionsgivesmoreeffectivedrugs. SubstitutionofafluorineatomattheC-6
positionproducesfluroquinolones,whichaccountforalargeproportionofthequinolonesinclinical
use.Amongothers,substitutionofpiperazineormethylpiperazine,pyrrolidinylandpiperidinylrings
alsoyieldseffectiveanalogues. Atotaloftwentysixanaloguesarereportedinthisreview. Thetargets
ofquinolonesaretwobacterialenzymesoftheclassIItopoisomerasefamily, namelygyraseand
topoisomeraseIV.Quinolonesincreasetheconcentrationofdrug-enzyme-DNAcleavagecomplexes
andconvertthemintocellulartoxins;asaresulttheyarebactericidal. Highbioavailability,relative
lowtoxicityandfavorablepharmacokineticshaveresultedintheclinicalsuccessoffluoroquinolones
andquinolones. Duetothesesuperiorproperties,quinoloneshavebeenextensivelyutilizedandthis
increasedusagehasresultedinsomequinolone-resistantbacterialstrains. Bacteriabecomeresistant
toquinolonesbythreemechanisms: (1)mutationinthetargetsite(gyraseand/ortopoisomeraseIV)
ofquinolones;(2)plasmid-mediatedresistance;and(3)chromosome-mediatedquinoloneresistance.
In plasmid-mediated resistance, the efflux of quinolones is increased along with a decrease in
theinteractionofthedrugwithgyrase(topoisomeraseIV).Inthecaseofchromosome-mediated
quinoloneresistance,thereisadecreaseintheinfluxofthedrugintothecell.
Keywords: quinolones;analogues;gyrase;topoisomeraseIV;resistance
1. Introduction
In the early 20th century, infectious diseases were the most common cause of human illness
leadingtodeath,outofwhichbacterialinfectionsaccountedforaboutone-thirdoftheseinfections[1].
Inadditiontobacterialinfections,malariaalsohasanenormousimpactonglobalhumanhealth,with
over200millioncasesofmalariaandover600,000deathseachyear[2]. Whiledifferenttherapieswere
usedforthetreatmentofthesediseases,theintroductionofantibioticagentsopenednewavenuesfor
thetreatmentofbacterialinfections. Theinventionofantibioticssuchassulfonamide,andafterward
penicillinbyAlexanderFlemingin1928andsyntheticantibioticssuchasquinolonesweresomeofthe
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greatmilestonesofscience[3,4]. However,withprogressinthedevelopmentofantibioticshascome
increasingly widespread antibiotic-resistant pathogens, which represent an unprecedented health
increasingly widespread antibiotic-resistant pathogens, which represent an unprecedented health
issue[5].
issue [5].
Here,wefocusonanimportantclassofsyntheticantibioticsknownasquinolones,thatconstitute
Here, we focus on an important class of synthetic antibiotics known as quinolones, that constitute
an important class of biologically-active broad-spectrum antibacterial drugs [6]. The spectacular
an important class of biologically-active broad-spectrum antibacterial drugs [6]. The spectacular
discovery of nalidixic acid, which is chemically a naphthyridone and the prototype compound of
discovery of nalidixic acid, which is chemically a naphthyridone and the prototype compound of the
thequinolonesasabyproductinchloroquinesynthesis(Figure1)byLesherandcoworkersin1962
quinolones as a byproduct in chloroquine synthesis (Figure 1) by Lesher and coworkers in 1962
initiatedtheimprovementofquinolones[7,8]. Itispresentinanumberofbiologically-activenatural
initiated the improvement of quinolones [7,8]. It is present in a number of biologically-active natural
products. Because of its valuable medicinal activities, quinolones have attracted a lot of attention
products. Because of its valuable medicinal activities, quinolones have attracted a lot of attention in
in the field of medicinal and synthetic chemistry [9]. In the later 1960s, nalidixic acid came into
the field of medicinal and synthetic chemistry [9]. In the later 1960s, nalidixic acid came into clinical
clinical use for the cure of urinary tract infections caused by enteric bacteria [10]. Around the
use for the cure of urinary tract infections caused by enteric bacteria [10]. Around the 1970s, several
1970s, several new generations of quinolones, with oxolinic acid being the most prominent, had
new generations of quinolones, with oxolinic acid being the most prominent, had been synthesized
beensynthesizedandbecameavailableforclinicaluse[10–12]. Until1980,quinoloneswerealess-used
and became available for clinical use [10–12]. Until 1980, quinolones were a less-used class of
class of antibacterial agents and later a second generation of quinolones was developed. In the
antibacterial agents and later a second generation of quinolones was developed. In the quest for
questforpotentquinolones,itwasdiscoveredthatalterationwithdifferentgroupsatpositionsC-6
potent quinolones, it was discovered that alteration with different groups at positions C-6 and C-8
andC-8givesmoreeffectiveantibacterialanalogues[13]. Themostsignificantchangesinthebasic
gives more effective antibacterial analogues [13]. The most significant changes in the basic skeleton
skeletonofquinolonesarethesubstitutionoffluorineatC-6andakeyringsubstituentpiperazineor
of quinolones are the substitution of fluorine at C-6 and a key ring substituent piperazine or
methylpiperazine,pyrrolidinylandpiperidinyl. DuetotheinsertionoffluorineatC-6,mostclinically
methylpiperazine, pyrrolidinyl and piperidinyl. Due to the insertion of fluorine at C-6, most
usedquinolonesarefluoroquinolones(FQ)[14–16].
clinically used quinolones are fluoroquinolones (FQ) [14–16].
O O
OH
N N
Nalidixicacid
Figure 1. Chemical structure of nalidixic acid.
Figure1.Chemicalstructureofnalidixicacid.
Fluoroquinolones (formally called simply quinolones) are characterized as broad-spectrum
Fluoroquinolones (formally called simply quinolones) are characterized as broad-spectrum
antibacterial drugs active against both Gram positive and Gram negative bacteria. Besides
antibacterial drugs active against both Gram positive and Gram negative bacteria.
broad-spectrum activity, the success of fluoroquinolones can be attributed to their properties such as
Besides broad-spectrum activity, the success of fluoroquinolones can be attributed to their
good bioavailability after oral administration, relatively low toxicity and favorable pharmacokinetics
propertiessuchasgoodbioavailabilityafteroraladministration,relativelylowtoxicityandfavorable
[17]. Although adverse events still happen while utilizing fluoroquinolones, these are still some of
pharmacokinetics [17]. Although adverse events still happen while utilizing fluoroquinolones,
the major antimicrobial agents and a lot of work has gone into the structural evolution in the
thesearestillsomeofthemajorantimicrobialagentsandalotofworkhasgoneintothestructural
framework of fluoroquinolones to make novel analogues with improved potency. Fluoroquinolones
evolutionintheframeworkoffluoroquinolonestomakenovelanalogueswithimprovedpotency.
have been primarily utilized for the treatment of urinary tract infections (UTI), respiratory tract
Fluoroquinolones have been primarily utilized for the treatment of urinary tract infections (UTI),
infections, sexually transmitted diseases, gastrointestinal and abdominal infections, skin and soft
respiratorytractinfections,sexuallytransmitteddiseases,gastrointestinalandabdominalinfections,
tissue infections and infections of bone and joints [11,18]. Besides these functions, fluoroquinolones
skin and soft tissue infections and infections of bone and joints [11,18]. Besides these functions,
with broad spectrum activity have been widely utilized in veterinary medicine to treat bacterial
fluoroquinoloneswithbroadspectrumactivityhavebeenwidelyutilizedinveterinarymedicineto
infections in food-producing animals, aquaculture and pets. Many fluoroquinolones are available on
treatbacterialinfectionsinfood-producinganimals,aquacultureandpets. Manyfluoroquinolonesare
the market; however the use of these antibacterial agents highly depends on the animal species and
availableonthemarket;howevertheuseoftheseantibacterialagentshighlydependsontheanimal
their geographical distribution [18]. They have a wide range of medical application in livestock,
speciesandtheirgeographicaldistribution[18]. Theyhaveawiderangeofmedicalapplicationin
poultry, fish and domestic animal in the treatment and prevention of respiratory, enteric and
livestock,poultry,fishanddomesticanimalinthetreatmentandpreventionofrespiratory,entericand
complex urinary tract infections [19]. Some quinolones such as 6-chloro-7-methoxy-4(1H)-quinolones
complexurinarytractinfections[19]. Somequinolonessuchas6-chloro-7-methoxy-4(1H)-quinolones
have good antimalarial activities, with good activity against multiple stages of Plasmodium infection
havegoodantimalarialactivities,withgoodactivityagainstmultiplestagesofPlasmodiuminfection[2].
[2]. Antimalarial activity was also shown in (1H)-quinolone, and its tetrahydroacridine analogue, with
Antimalarialactivitywasalsoshownin(1H)-quinolone,anditstetrahydroacridineanalogue,with
substitution of various benzenoid ring features and aryl moieties [20].
substitutionofvariousbenzenoidringfeaturesandarylmoieties[20].
2. Recent Developments in the Synthesis of Quinolones
Quinolones are very important in medicinal chemistry as they have broad spectrum antibacterial
activity, and they acts as anticancer and antimalarial agents. A lot of work has been carried out on
the synthesis of quinolones to develop more effective and economical analogues. A number of
different methods are reported for the synthesis of quinolones. In general these, procedures involve
Molecules2016,21,268 3of19
2. RecentDevelopmentsintheSynthesisofQuinolones
Quinolonesareveryimportantinmedicinalchemistryastheyhavebroadspectrumantibacterial
activity, and they acts as anticancer and antimalarial agents. A lot of work has been carried out
onthesynthesisofquinolonestodevelopmoreeffectiveandeconomicalanalogues. Anumberof
Molecules 2016, 21, 268 3 of 18
differentmethodsarereportedforthesynthesisofquinolones. Ingeneralthese,proceduresinvolve
Molecules 2016, 21, 268 3 of 18
theutilizationofapreactivatedsubstrate,amultistepstrategyandharshreactionconditions,which
the utilization of a preactivated substrate, a multistep strategy and harsh reaction conditions, which
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ausnyndnm tuhonedmsiifizoeedddif kibeeydto akn eemtsoe(nStaecslh- f(eSrmecehe eo1m)x.iedT 1ah)te.i vTaehd evin aatndetvramagneotloaegfcetuh loiasfr t mhMiesat hmnoneditchihso dtrhe iaastc ttihitoadnto ietb sdetnowoeset ernenoq tsu reiecrqeounthidreea rutyhs eea oumfsiean noeyfs
atarnnaydn tsuriatninmosniotmdioinefit eamdl ecktaeattlao clnyaetsast;l (yaSsncthd; aeinmtdoe c i1tc )uo. rcTschuuern sad duevnradmnetrial mdgeic loodfn ctdohinitsido mintiseo.tnhTsoh.d iTs ihsmi tshe mtahte oittdh docodae ncsa pnnro optd rroueqdcueuicareen atuh nmeu bumeserb eoorff
oaafnn aaynl otargaloungesusiteiionsn iv nme rveyetrahyli gchahitgayhliy eysldtie; la[d6n] d[.6 i]t. occurs under mild conditions. This method can produce a number
of analogues in very high yield [6].
O O Transitionmetalfree
TEMPO (2equiv)
O R' TKEOMtBPuO ( 2(2eeqquuiviv)) O R' DTirraencst istipo3n Cm-eHt a/ lsfpre3 eC-H coupling
R R' DKMOStBOu ((02.e0q5uMiv)) R R' BDrioreacdt ssupb3 sCtr-aHte / sscpo3 pCe-H coupling
R NH Ar DM80S0OC (,0 6.0h5rM) R NH Ar SBirmoapdle saunbds tmrailtde csocnodpietion
NH Ar 800C , 6hr NH Ar ESximceplllee natn ydie mldisld condition
20 examples
Excellent yields
u2p0to e 9x8a%mp yleiesld
upto 98% yield
Scheme 1. Metal-free oxidative intermolecular Mannich reaction for the synthesis of 2-arylquinone-
Scheme 1. Metal-free oxidative intermolecular Mannich reaction for the synthesis of
4S(c1hHe)m-oen e1s. Mfroemta ls-efrceoen odxairdya atimvein ienst earnmdo kleectounlaers M[6a].n nich reaction for the synthesis of 2-arylquinone-
2-arylquinone-4(1H)-onesfromsecondaryaminesandketones[6].
4(1H)-ones from secondary amines and ketones [6].
Kang and Hong performed alkynylation of 4-quinolones at three different positions for making
quinoKKloaannneggs aa annndda HlHooognnugges pp. eeInrrff oothrrmme efeiddrs aat llmkkyyennthyyollaadttii, ootnnh eooyff 44u--tqqiluuiziinnedooll ooTnnIPeeSss -aaEttB ttXhhrr e(eaeen dd aiifflffkeeyrreleanntttin ppgoo ssaiigttiieoonnntss) fftooor rd mmevaaekkliionnpgg
aqqnuu iiennfofoilclooiennneetss a aannndaa lslooitggeu-useeessl.e. IcIntnivt htehe Cefi 5fr iasrtslktm ymnetyehtlahotodiod,nt, h toehfy e4yu-q tuiultiiiznlieozdleodTn IeTPsI S(P-SSEc-BhEeXBmX(ae n (2a)an. l Ikanyl ktlhayteli anstegicnaoggn eadng stet)nrtatot)e dtgoey v daee lRvoupel(oaIIpn)
ceaafnfit aeclfiyefzinceitdean nCt d2a nssdietl ees-icstteei-vlseeec ltaeilvckteyivnCey5 Claa5tli koaylnkn ywynlaaystl iaaotcinohnoie fvo4ef -d4q- utqhiunrioonulooglnohen sNes(- Sp(cSyhcrheimmemiede2y 2)l .)g.I rnIontu thphee-ds seiercecoocntneddd s scttrrroaatsteesg-gcyyo uaa pRRliuun((gIIIIs))
tccoaa ttoaabllyytzzaeeindde CCd2 2u ssseeellefeucctlti ivvCee2 a-aallkklkyyynnnyyyllaalattiitooennd ww4a-aqssu aaiccnhhoiieleovvneeedds t,t hhwrroohuuiglgehh i NsNo--qppuyyirrniimmoliioddnyyells gg rwrooeuurppe-- dddiierreveccettleeoddp cecrdroo sstshs--rccooouuugpphllii nnCgg3ss
attoolk oyobnbtytaalaiinntieeoddn .u uTssheeeffuusell CtCh22r-e-aaell kkdyyifnnfeyyrlleaantttee ddro 44u--tqqeusu iionnfoo pllooronndeeuss,,c iwwnghh iiqlleeu iiinssooolqqouuniiennsoo allononanleeossg uwweeesrr eae rdde eesvviteeell ooseppleeeddct ittvhherr oomuueggthhho CCd3s3
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aanndd uusseeffuull ffoorr oobbttaaiinniinngg eeffffeeccttiivvee ddeerriivvaattiivveess [[2222]]..
SiiPr
3
SiiPr
3
O H O TIPS-EBX
TIPS-EBX
O TIP[SR-hE]BX H5 O [RTuIP] oSr- E[RBhX]
5
N R=[R ahlk]yl N 2 H R[R=u P] yorri m[Ridhy]l N
RN R= alkyl RN 2 H R= Pyrimidyl RN SiiPr3
R R R SiiPr
3
Scheme 2. Site selective C-H alkynylation of Quinolones [22].
Scheme 2. Site selective C-H alkynylation of Quinolones [22].
Scheme2.SiteselectiveC-HalkynylationofQuinolones[22].
Satio et al. synthesized chiral substituted 2,3-dihydro-4-quinolones in high yields using an
aza-MSaicthioa eelt aadl.d sityionnth eresiazcetdio nc h(iSrcahl esmube s3ti)t.u Ttehde 2a,d3-vdainhtyadgreo -o4f- qtuhiisn omloentheso din i sh itghhe eyniealndtsi ouseslinecgt ivaen
parzoad-MuSacicttiihooanee lto faa ldc.odmistyipononthu renesdaizsc etaidonndc h (siSorcamhleesm uobef st3thi)te.u Ttaenhdael 2oa,gd3u-vdeasinh tcyaadgnre o b-oe4f - pqtuhuirisinf oimeldoen tihenos dai nsiishn igtghlehe ryeenicearlnydstsitoausllseiilzneacgttiioavnne
saptzreaop-d.M uTcihcteiho acneh liorafa dlc d2o,im3ti-podnoihuryneddarcsot ia-o4nn-dq u(sSioncmhoeleom noeef s3t hc).aen Ta bnheae luoasgdeuvdea sfn otcraa gtnhe ebo epf rptehupirasirfimaetdieo tnhin oo daf osistinhtgehrlee u ersneecafrunylt siqotauslielnilzeoaclottiinovene
apsntreaopldo. ugTcuhteieso .cn Thhoirefa c2l o-2sm,u3b-pdsotiiuhtunytddersdo a2-4n,3-d-qdusioihnmyodlerooon-fe4s-tq hcueainna onblaeol nouegsseu hdea sflotc rma ntihtobese pispr aeunprdaifir aaertdeio uinns eoaffu soli atnhngetliret uurmseecofrruy als gtqaeulnliitnzso a[lt2oi3on]n.e
satneaplo.gTuhees.c Thhirea l2-2s,u3-bdstihituydterdo -24,3-q-duiihnyodloron-e4s-qcuainnobleonuesse dhaflot rmthiteospisr eapnadr aartieo unsoeffuol tahnetrituusmeofur laqguenintso [l2o3n]e.
analogues. The 2-substituted 2,3-dihydro-4-quinolones halt mitosis anXd are useful antitumor
O O
agents[23]. X
O O O O
Catalyst
PG freeN NaHmH22inReR bbeennCvzvz/ae/7evvtn0 na =e=0el yC 1/1s/ /C/tC1166HH1122 upto quanNHtNHitativReR yield XOOOPP OOOHH
PG free amine 700C uptou qpu taon 9ti4ta%tiv eee yield X= C6F5 X
up to 94% ee XC=a Cta6lFys5t
Catalyst
Scheme 3. Preparation of chiral 2-substituted 2,3-dihydro-4-quinolones through chiral phosphoric
aSccihde cmatea l3y.z Pedre ipnatrraa-tmionol eocfu clharir aazl a2--Msuicbhstaietul ateddd i2t,i3o-nd irheyacdtrioo-n4.- quinolones through chiral phosphoric
acid catalyzed intra-molecular aza-Michael addition reaction.
Molecules 2016, 21, 268 3 of 18
the utilization of a preactivated substrate, a multistep strategy and harsh reaction conditions, which
limit the compatibility and range of the functional groups involved in these reactions [9]. The use of
transition metal catalysts has also been utilized for the synthesis of quinolones and their analogues.
The catalytic activation of the C-H bond allows the synthesis of a remarkable variety of heterocyclic
compounds, including quinolones [21]. The following are some of the latest reported data on the
development of new methods for the synthesis of quinolones and their derivatives.
Hu et al. developed a novel method in which a broad range of 2-arylquinoline-4(1H)-ones were
synthesized by a metal-free oxidative intermolecular Mannich reaction between secondary amines
and unmodified ketones (Scheme 1). The advantage of this method is that it does not require the use of
any transition metal catalyst; and it occurs under mild conditions. This method can produce a number
of analogues in very high yield [6].
O O Transitionmetalfree
TEMPO (2equiv)
R' KOtBu (2equiv) R' Direct sp3 C-H / sp3 C-H coupling
R R Broad substrate scope
DMSO (0.05M)
NH Ar 800C , 6hr NH Ar Simple and mild condition
Excellent yields
20 examples
upto 98% yield
Scheme 1. Metal-free oxidative intermolecular Mannich reaction for the synthesis of 2-arylquinone-
4(1H)-ones from secondary amines and ketones [6].
Kang and Hong performed alkynylation of 4-quinolones at three different positions for making
quinolones analogues. In the first method, they utilized TIPS-EBX (an alkylating agent) to develop
an efficient and site-selective C5 alkynylation of 4-quinolones (Scheme 2). In the second strategy a Ru(II)
catalyzed C2 selective alkynylation was achieved through N-pyrimidyl group-directed cross-couplings
to obtained useful C2-alkynylated 4-quinolones, while isoquinolones were developed through C3
alkynylation. These three different routes of producing quinolones analogues are site selective methods
and useful for obtaining effective derivatives [22].
SiiPr3
O H O TIPS-EBX
TIPS-EBX
5
[Rh] [Ru] or [Rh]
N R= alkyl N 2 H R= Pyrimidyl N
R R R SiiPr3
Scheme 2. Site selective C-H alkynylation of Quinolones [22].
Satio et al. synthesized chiral substituted 2,3-dihydro-4-quinolones in high yields using an
aza-Michael addition reaction (Scheme 3). The advantage of this method is the enantioselective
production of compounds and some of the analogues can be purified in a single recrystallization
Molecusletsep20. 1T6h,2e1 c,h26ir8al 2,3-dihydro-4-quinolones can be used for the preparation of other useful quinolone4 of19
analogues. The 2-substituted 2,3-dihydro-4-quinolones halt mitosis and are useful antitumor agents [23].
X
O O
O O
Catalyst P
NH2 R benvz/evn =e 1/ /C16H12 NH R O OH
PG free amine 700C upto quantitative yield X
up to 94% ee X= C6F5
Catalyst
Scheme 3. Preparation of chiral 2-substituted 2,3-dihydro-4-quinolones through chiral phosphoric
Scheme3.Preparationofchiral2-substituted2,3-dihydro-4-quinolonesthroughchiralphosphoricacid
acid catalyzed intra-molecular aza-Michael addition reaction.
catalyzedintra-molecularaza-Michaeladditionreaction.

Molecules 2016, 21, 268 4 of 18
KuppusamyandKasisynthesizedenantiomericallyenriched2-aryl-2,3-dihydroquinolin-4(1H)-
ones(MinoleucuKpleust o2p0p196u9, s%2a1m, y2y6ie8 ladn)di nKaasoi nsyenpthoetssiyzendth eensaisntuiosminegripcaelrl-y6 -eAnrBicChDed( S2c-ahreyml-2e,34-)d.iThyhdisrosqyunitnhoelisnis-44m( 1oHef t1)h8- odis
ones (in up to 99% yield) in a one pot synthesis using per-6-ABCD (Scheme 4). This synthesis
veryusefulforobtainingenantiomeranaloguesofquinolones. Theyieldisveryhighanditisone-pot
methKoudp ips uvsearmy yu saenfudl Kfoars oi bstyaninthinesgi zeenda netnioanmtieorm anerailcoaglluye se norfi cqhueidn o2lo-anreysl-. 2T,3h-ed yihieylddr oisq vueinryol hini-g4h(1 aHn)d-
synthesiswhichoccursinasinglestepreactionwithreuseoftheexpensivecatalystafterseparation
oitn iess o n(ien- puopt styon t9h9e%si sy wiehldic) hi no cacu orsn ein p ao sti nsgylnet hsteespis r euascitniogn p werit-h6- rAeBuCseD o f( tShceh eemxpee n4s).i vTeh ciast aslyynstt haeftseisr
fromtheproduct. Thedisadvantageofthismethodisthatthelowtemperatureandlongreactiontime
mseeptahroadti oisn v ferorym u tsheefu plr foodr uocbtt. aTinhien dgi seandavnatinotmageer oanf athloisg umeest hofo dq uisin tohlaotn tehse. Tlohwe yteiemldp eisr avteurrye hanigdh laonndg
reactiirote niasc cotiononen-d ptiiotmito esn yrsneatahcreteisoians wbcoihtniccduhit mioocbncesu rrassro einm a a eb si[ti2 nc4gu]lm.e sbteerps ormeaec t[i2o4n] .w ith reuse of the expensive catalyst after
separation from the product. The disadvantage of this method is that the low temperature and long
O O
reaction time reaction conditions are a bit cumbersome [24].
O Per-6-ABCD
O + O
Ethanol , Water
NH R N R
2 O 1P5ehr-r6 ,- -A5B0CCD H
+
Ethanol , Water 20 examples
NH R N R
2 15hr , -50C ee up tHo 99%
20 examples
R= C6H5- , p-NO2C6H4-, p-CH3OC6H4-, cyclohexyl-, heterocycles-, etc
ee up to 99%
Scheme 4. Per-6-ABCD catalyzed asymmetric one-pot synthesis of 2-aryl-2,3-dihydro-4-quinolones
Scheme4.Per-6-ABRC=D Cc6aHt5a-l y, zpe-NdOa2sCy6mH4m-, ept-rCicHo3OneC-6pHo4t-,s cyynctlohheesxisyl-o, fh2e-taerroycly-2c,le3s-d-,i ehtyc dro-4-quinolones
using substituted aldehydes [24].
usingsubstitutedaldehydes[24].
Scheme 4. Per-6-ABCD catalyzed asymmetric one-pot synthesis of 2-aryl-2,3-dihydro-4-quinolones
uǺskinegr bsulabdshtit eutt eadl. aslydnethhyedseisz e[2d4 ]f.u nctionalized 4-quinolones from 2-iodoanilines and alkynes using
Åtwkoe rdbilfafedrhenett palr.ostoycnotlhs efsoirz ewdhfiuchn cmtioolnyabldiezneudm4 -hqeuxiancoalrobnoensylf rwomas 2u-sieodd oaas nai lisnoelisd asnoduraclek yofn eCsOu sing
two d(SifcfheeǺrmeknee tr5b)p.l arIdonh too encteo a lol.sf s tfyhonert hmweeshtizhiecodhd sfmu, tnhocelty irobenadaceltiinzoeundm c 4o-nqhdueiixtniaoocnloasnr ibensoc lnfuryodlme w m2-aiicosrdouowsaeanvdilei nahesesa aatinnsdgo laoildfk 1ys2no0e us° Cruc saeinnogdf CO
(Schettmwheeo c5dy)ic.flfIieznreedon ntp erpoordofuttochcte owlmsa sefo torhb owtadhisni,cehtdh meinro 2ely0a bcmdtieionnn uincm oh nhigdehxit ayicoiaenrlsdbo.i nnTcyhlleu wsdeaecsom nudisce rpdor woacsae vad eusrohele iidan tvsinoolugvreocsef t1ho2fe 0 Cu˝sOCe and
(oSfc hseenmseit i5v).e Insu obnset iotuf etnhtes m liekteh ondistr, oth- ea rneda cbtiroonm coo-ngdriotuiopnss, ibnucltu dthee m riecarcotwioanv eis h epaetrifnogr mofe 1d2 0a t° Cr oaonmd
thecyclizedproductwasobtainedin20mininhighyield. Thesecondprocedureinvolvestheuseof
ttheme cpyecrlaitzuerde .p Trohdisu scetc wonads mobettahinoded i si na l2so0 omnien- pino th siygnht hyeieslids .t hTahte o sceccuorns din p trwocoe rdeuarcet ioinnv sotlevpess. tIhne b uosthe
sensitivesubstituentslikenitro-andbromo-groups,butthereactionisperformedatroomtemperature.
ooff tsheen ssyitnivthe essuisb msteittuheondtss plaikllea dniuitmro -i sa unsde db aros ma oca-gtarloyuspt s[2, 5b].u t the reaction is performed at room
Thissecondmethodisalsoone-potsynthesisthatoccursintworeactionsteps. Inbothofthesynthesis
temperature. This second method is also one-pot synthesis that occurs in two reaction steps. In both
methodspalladiumisusedasacatalyst[25]. MethodA
of the synthesis methods palladium is used as a catalyst [25]. O
I
R1 + R2 Pd2(dba)3M ,e dthpopfd , AMo(CO)6 , Et2NH R2
H2NI MW , 1200C , 20min R1 ONH
R1 + R2 Pd2(dba)3 , dppf , Mo(CO)6 , Et2NH 13+20 entriesR2
H2N MW , 1200C , 20min R1 up NHto 85% yield
13+20 entries
Pd(OAc)2 up to 85% yield
{HP(tBu)3}BF4 O
MoP(dC(OO)A6c ,) 2Et3N Et2NH
{HPr(t,t B1u6)h3r}BF4 R1 O R2 rt, 5hr
Mo(CO)6 , Et3N H2N Et2NH
R2
rt, 16hr R1 rt, 5hr
HM2eNthod B
Method B
Scheme 5. Synthesis of 4-quinolones via palladium catalyzed carbonylative Sonogashira cross-coupling
Scheme5.Synthesisof4-quinolonesviapalladiumcatalyzedcarbonylativeSonogashira cross-coupling
reaction [25].
reaction[25].
Scheme 5. Synthesis of 4-quinolones via palladium catalyzed carbonylative Sonogashira cross-coupling
rMeaocntiaosnt y[2r5s]k. yi et al. developed a protocol for the synthesis of 3-aryl-4(1H)-quinolones from ethyl
acetoacetate (EAA) using hypervalent diaryliodonium salts under mild and metal-free conditions
(ScheMmoen a6s).t yTrhskisy im ete athl.o dde vhealos paeldso a bpereonto acoplp floierd t hfeo sr ytnhteh essyins tohfe 3s-ias ryolf- 4th(1eH a)-nqtuiminaollaorniaels cforommp oetuhnydl
aEcLeQto-a3c0e0t.a Tteh i(sE AcoAm) puosuinngd hisy apcetrivvael eangta idnisatr Pylliaosmdoondiiuumm fasalclitpsa urunmd earn md iPldla samnodd imumet avli-vfarxee a tc oanlld sittaiogness
(oSfc ihtse mlifee c6y)c. lTe hainsd m ise tihno tdh eh parse callisnoi cbael etens tainpgp lsietadg efo. rT hthe et osxyincitthye osifs thoifs tphreo dauntcitm isa lnaorita yl ecto rmeppoorutendd,
EbuLtQ t-h3e0 0p. rTehcliisn cicoaml dpaotuan pdr oisv aidcteisv eim apgaoirntasnt tP ilnasfmoromdiautmio nfa lccoipnacreurmni nangd e fPfilcaasmcyo.d Tiuhme vuisveafxu lante aslsl ostfa tgheiss
osyf nittsh leitfiecc ymceleth aondd iiss iitns pthreo dpurecct ltihnaicta ils t ehsigtihnlgy sdtaegsier.a Tbhlee, taosx miciatlya roiaf tihsi so nper oodf utchte i sd enaodt lyieestt rdeipsoeratseeds,,
bauffte cthtien gp rmecillliinoincsa lo df apteao pprleo vinid Aess iiam apnodr tAafnrti cian f[o2r6m]. ation concerning efficacy. The usefulness of this
synthetic method is its product that is highly desirable, as malaria is one of the deadliest diseases,
a ffecting millions of people in Asia and Africa [26].
Molecules2016,21,268 5of19
Monastyrskyietal. developedaprotocolforthesynthesisof3-aryl-4(1H)-quinolonesfromethyl
acetoacetate (EAA) using hypervalent diaryliodonium salts under mild and metal-free conditions
(Scheme6).ThismethodhasalsobeenappliedforthesynthesisoftheantimalarialcompoundELQ-300.
ThiscompoundisactiveagainstPlasmodiumfalciparumandPlasmodiumvivaxatallstagesofitslifecycle
andisinthepreclinicaltestingstage. Thetoxicityofthisproductisnotyetreported,butthepreclinical
dataprovidesimportantinformationconcerningefficacy. Theusefulnessofthissyntheticmethodisits
productthatishighlydesirable,asmalariaisoneofthedeadliestdiseases,affectingmillionsofpeople
inAsiaandAfrica[26].
Molecules 2016, 21, 268 5 of 18
Molecules 2016, 21, 268 5 of 18
O
O
O O COOEt R1
O Ar2IX COOEt O R1
BaAsre2I,X DMF Conrad-Limphac
COOEt R1 N
COOEt Base, DMF R1 Conrad-Limphac R2 HN
EAA R32-aryl-4H(1H)-quinolones
EAA 3-aryl-4(1H)-quinolones
Scheme 6. Metal free arylation of ethylacetoacetate with hypervalent diaryliodonium for the
Scheme6.Metalfreearylationofethylacetoacetatewithhypervalentdiaryliodoniumforthesynthesis
sSycnhtehmeseis 6o.f 3M-aertyall- 4f(r1eHe )-aqruyilnaotiloonn eos f[ 2e6t]h. ylacetoacetate with hypervalent diaryliodonium for the
of3-aryl-4(1H)-quinolones[26].
synthesis of 3-aryl-4(1H)-quinolones [26].
Wang et al. synthesized a wide variety of quinolones in a high yield in one step process using a
Wangetal. synthesizedawidevarietyofquinolonesinahighyieldinonestepprocessusing
mild WNa-nHg eatc atilv. saytinotnh/eHsiezcekd rae wacitdioen v amrieettyh oodf q(uSicnhoelmonee s7 i)n. aT hhiisg hp yroiecleds sin ionnveo lsvteesp pthroe cepsasl luasdiniugm a
a mild N-H activation/Heck reaction method (Scheme 7). This process involves the palladium
cmatialdly zNed-H-o xaidctaitvivatei oann/nHuelactkio nre oafc taicorny lammeitdheo dw it(hS cshtreaminee d7 )a.r yTnheiss. Tphriosc teescsh niniqvuoel vwesa s tmhea dpea plloasdsiiubmle
catalyzed-oxidativeannulationofacrylamidewithstrainedarynes. Thistechniquewasmadepossible
fcoart atlhyez efidrs-ot xtiimdaet iavse parnenvuiolautsio ant toefm apcrtsy lbaym oidthee wr ritehs esatrrachineerds raersyunletse.d T ihni slo twecehrn yiqieuled sw [a2s7 ]m. ade possible
forthefirsttimeaspreviousattemptsbyotherresearchersresultedinloweryields[27].
for the first time as previous attempts by other researchers resulted in lower yields [27].
TfO
TfO R3
TMS R3
TMS
CsF
O CsF O
Pd(OAc) (5 mol%)
R1 O OMe 2 R1 O OMe
R1 N OMe+ R3 PCdu((OOAAcc))22 ((52 emqouli%v)) R1 N OMe
R2 H HN + R3 DMCuS(OO/ADcio)2x a(2neeq =u i1v)/9 R2 N
H
R2 H DMSO/Dioxane = 1/9 R2
R3
R3
Scheme 7. Palladium catalyzed-oxidative annulation of acrylamide with strained arynes for the
sSycnhtehmeseis 7o.f Pqaulilnaodliounme s c[a2t7a]l.y zed-oxidative annulation of acrylamide with strained arynes for the
Scheme 7. Palladium catalyzed-oxidative annulation of acrylamide with strained arynes for the
synthesis of quinolones [27].
synthesisofquinolones[27].
Manikandan and Jeganmohan prepared 2-quinolones by Ru-catalyzed cyclization of anilides with
propiMolaanteisk aonrd aancr aynladt eJse gwanitmh ofhuarnth perr ecpoanrevde r2s-iqouni ninotloon 3e-sh baylo R-2u-q-cuaitnaolylozende sc yacnlidz a2ti-ocnh loofr oa-nqiuliidneosl ownieths
ManikandanandJeganmohanprepared2-quinolonesbyRu-catalyzedcyclizationofanilideswith
(pSrcohpeimolea t8e)s. Tohr ea 2cr-qyulaitneos lownieths pfruordthuecre dco tnhvroerusgiohn t hinist om 3e-chhaalnoi-s2m-q uairneo vloernye su saenfdu l 2f-ocrh tlhoero s-yqnutihneosloisn oefs
propiolatesoracrylateswithfurtherconversioninto3-halo-2-quinolonesand2-chloro-quinolones
o(Sthchere mquei n8)o. lTonhee 2d-eqruivinatoilvoense, sa npdro adruec pedre tpharroeudg ihn tehxisc emlleencht aynieisldm. Tarhee v mereyc huasnefisuml fso pr rtohpe ossyendt hfeosri sth oef
(Scheme8). The2-quinolonesproducedthroughthismechanismareveryusefulforthesynthesisof
aobthoevre qrueainctoiloonnse w deerreiv sattriovnegs,l ya nsudp aproe rpterdep bayr eedx pine reimxceenllteanl te yviiedledn. cTeh aen md edcehuatnerisiumms plarboeploinsged s tfuodr itehse,
otherquinolonederivatives,andarepreparedinexcellentyield. Themechanismsproposedforthe
saubgogvees rtienagc tieoanssy wiseorlea stitoronn ogfl yr seuacptpioonrt eindt berym eexdpieartiems ednutarli negv idsyenntchee asnisd. dTehuet ehraiulomge lnaabteeldin gp rsotudduicetss,
abovereactionswerestronglysupportedbyexperimentalevidenceanddeuteriumlabelingstudies,
msuagdgee tshtirnogu geha ssyu cihso slyantitohne soisf mreeatchtoiodns sitnitlle rnmeeedd itaot ebse dasusraiynegd sfyonr tthheesiirs .t oTxhicei tyh ainlo mgeonuastee dm opdroedlsu fcotrs
suggestingeasyisolationofreactionintermediatesduringsynthesis. Thehalogenatedproductsmade
tmheaidr ef uthturoreu gmhe dsuiccihn asly vnathluees i[s2 m8]e. thods still need to be assayed for their toxicity in mouse models for
throughsuchsynthesismethodsstillneedtobeassayedfortheirtoxicityinmousemodelsfortheir
their future medicinal value [28].
futuremedicinalvalue[281]-. Ru(II)AgSbF6
HN O 1C- u R(Ou(AIIc))A2g, SHb2FO6 HN Me HN O
HN O DCCu(EO, A1c1)020,C H,2 1O2hr HNO Me Ru(II)AgSbF6 HN O
R1 2- 3D0C%E H, C11l,0 103C0, 01C2,h 1r0hr R1 O RCROu(OII)HA,g iS-PbrFO6H R1 H
R1 2- 30% HClO, 13OO0RR0C44, 10hr R1 RRC211O33O000H0CC, ,,i -2C2P44OrhOhOrrHR3 R1 RR22 H
R2 COOR3
O H
N O
H NBS or NCS
N O
X NBASIB oNr NCS
R1 R2 X X=A IBBrN, Cl
R1 R2 X= Br, Cl
N Cl
POCl3
N Cl
R1 R2 POCl3
Scheme 8. Synthesis of 2-quinolones thrRou1gh ruRt2henium catalyzed cyclization of anilid es with
sSucbhsetmituet e8d. pSryonptihoelasitse so ofr 2a-cqruyilnatoelso n[2e8s] . through ruthenium catalyzed cyclization of anilides with
substituted propiolates or acrylates [28].
Molecules 2016, 21, 268 5 of 18
O
O COOEt O R1
Ar2IX
Base, DMF Conrad-Limphac
COOEt R1 N
R2 H
EAA 3-aryl-4(1H)-quinolones
Scheme 6. Metal free arylation of ethylacetoacetate with hypervalent diaryliodonium for the
synthesis of 3-aryl-4(1H)-quinolones [26].
Wang et al. synthesized a wide variety of quinolones in a high yield in one step process using a
mild N-H activation/Heck reaction method (Scheme 7). This process involves the palladium
catalyzed-oxidative annulation of acrylamide with strained arynes. This technique was made possible
for the first time as previous attempts by other researchers resulted in lower yields [27].
TfO
R3
TMS
CsF
O O
R1 OMe Pd(OAc)2 (5 mol%) R1 OMe
NH + R3 Cu(OAc)2 (2equiv) N
R2 H DMSO/Dioxane = 1/9 R2
R3
Scheme 7. Palladium catalyzed-oxidative annulation of acrylamide with strained arynes for the
synthesis of quinolones [27].
Manikandan and Jeganmohan prepared 2-quinolones by Ru-catalyzed cyclization of anilides with
propiolates or acrylates with further conversion into 3-halo-2-quinolones and 2-chloro-quinolones
(Scheme 8). The 2-quinolones produced through this mechanism are very useful for the synthesis of
other quinolone derivatives, and are prepared in excellent yield. The mechanisms proposed for the
above reactions were strongly supported by experimental evidence and deuterium labeling studies,
suggesting easy isolation of reaction intermediates during synthesis. The halogenated products
Molecules2016,21,268 6of19
made through such synthesis methods still need to be assayed for their toxicity in mouse models for
their future medicinal value [28].
1- Ru(II)AgSbF6
HN O Cu(OAc)2, H2O HN Me HN O
DCE, 1100C, 12hr Ru(II)AgSbF6
O
R1 2- 30% HCl, 13O0R0C4, 10hr R1 RC1O3O0H0C, ,i -2P4rOhrH R1 R2 H
R2 COOR3
O
H
N O
NBS or NCS
AIBN
R1 R2 X X= Br, Cl
N Cl
POCl3
R1 R2
Scheme 8. Synthesis of 2-quinolones through ruthenium catalyzed cyclization of anilides with
Scheme 8. Synthesis of 2-quinolones through ruthenium catalyzed cyclization of anilides with
substituted propiolates or acrylates [28].
substitutedpropiolatesoracrylates[28].

Suet et al. synthesized and evaluated bisaryl quinolones for biological activities against
P.falciparum[29]. Patelandhiscoworkerssynthesizedaseriesofnovelpyridoquinoloneanalogues
byintroducingsulfonamide,urea,thiourea,amine,amide,piperazineandβ-lactammoietiesinthe
pyridoquinolone molecule. These quinolones on the one hand inhibit gyrase and topoisomerase
IV of bacteria while the other attached groups are also inhibitors of specific metabolic pathways.
Thesemedicinalmoleculeshaveantibacterialandantifungalactivitiesandsomeofthemareeven
activeagainstdrugresistantMycobacteriumtuberculosisstrains. Howeverthereisaneedtotestthese
novelquinolonesinmammalsfortheirpotentialtoxicity[30–36]. Komarnickaetal. madephosphine
derivativesofsparfloxacininhighyieldbytreatingsparfloxacinwithmethoxy(diphenyl)phosphine.
The oxide derivative was made by treating the aminomethyl(diphenyl)phosphine analog of
sparfloxacinwith35%hydrogenperoxideinchloroformatroomtemperaturewithcontinuousstirring
for3h. Theaminomethyl(diphenyl)phosphineanalogofsparfloxacinshowedantibacterialactivityof
similarnaturetosparfloxacin,whiletheoxideformhadhighantitumoractivityagainstcancercell
lines[37]. Oneofthebeautifulmodificationsintheexistingquinoloneistheproductionofaseries
of 1,2,4-triazole-ciprofloxacin hybrid compounds that have potential antibacterial potency against
both Gram-positive as well as Gram-negative bacteria. These 1,2,4-triazole-ciprofloxacin hybrid
compounds were more active than ciprofloxacin against both vulnerable and quinolone resistant
bacteria. Suchpromisinghybridtriazoleanaloguesofotherquinolonecompoundsshouldalsobe
prepared and tested against both resistant and non-resistant bacterial strains that cause different
diseases. Inadditiontodeterminetheiractionagainstpathogenicbacteria,theyshouldalsobetested
forviralinfections,especiallyHIV[38]. Anumberofnewnaturalantibioticsarebeingdiscoveredthat
cantargetfluoroquinoloneresistantbacteria(FQR).Forexampledeoxynymbomycinscantargetthe
mutantbacterialDNAgyraseandcanbeusedagainstFQRbacteriabutthechancesofresistanceto
thisnewdrugarestillthere[39]. Similarly,theFQRNeisseriagonorrhoeaetypeIItopoisomerasecanbe
inhibitedbyanovelcompoundcalledspiropyrimidinetrioneAZD0914[40]soononehandwehave
thecontinuouslyevolvingresistantstrainstoquinolonesandotherantibacterialagents,butonthe
otherhandscientificcommunityisworkinghardtodesignandsynthesizenewdrugsfortheresistant
bacterialstrains.
3. AnaloguesofQuinolones
The first member of the quinolone family was nalidixic acid, which was synthesized as a
byproductinthesynthesisofchloroquine. Later,itwasmodifiedinordertoenhanceitsactivities.
OnemodificationwasthesubstitutionoffluorineattheC-6position,whichwasfoundtoprovidegood
antibacterialactivities. Moreover,substitutionofpiperazineormethylpiperazine,pyrrolidinyland
piperidinylmoietieswasalsodeterminedtoresultinincreasedantibacterialactivities. Followingare
theanaloguesofquinolonesavailableinthecommonliterature(Figure2)[15,16,41–48].
Molecules 2016, 21, 268 6 of 18
Suet et al. synthesized and evaluated bisaryl quinolones for biological activities against
P. falciparum [29]. Pateland his coworkers synthesized a series of novel pyridoquinolone analogues
by introducing sulfonamide, urea, thiourea, amine, amide, piperazine and β-lactam moieties in the
pyridoquinolone molecule. These quinolones on the one hand inhibit gyrase and topoisomerase IV
of bacteria while the other attached groups are also inhibitors of specific metabolic pathways. These
medicinal molecules have antibacterial and antifungal activities and some of them are even active
against drug resistant Mycobacterium tuberculosis strains. However there is a need to test these novel
quinolones in mammals for their potential toxicity [30–36]. Komarnicka et al. made phosphine
derivatives of sparfloxacin in high yield by treating sparfloxacin with methoxy(diphenyl)phosphine.
The oxide derivative was made by treating the aminomethyl(diphenyl)phosphine analog of
sparfloxacin with 35% hydrogen peroxide in chloroform at room temperature with continuous
stirring for 3 h. The aminomethyl(diphenyl)phosphine analog of sparfloxacin showed antibacterial
activity of similar nature to sparfloxacin, while the oxide form had high antitumor activity against
cancer cell lines [37]. One of the beautiful modifications in the existing quinolone is the production of
a series of 1,2,4-triazole-ciprofloxacin hybrid compounds that have potential antibacterial potency
against both Gram-positive as well as Gram-negative bacteria. These 1,2,4-triazole-ciprofloxacin
hybrid compounds were more active than ciprofloxacin against both vulnerable and quinolone
resistant bacteria. Such promising hybrid triazole analogues of other quinolone compounds should
also be prepared and tested against both resistant and non-resistant bacterial strains that cause
different diseases. In addition to determine their action against pathogenic bacteria, they should also
be tested for viral infections, especially HIV [38]. A number of new natural antibiotics are being
discovered that can target fluoroquinolone resistant bacteria (FQR). For example deoxynymbomycins
can target the mutant bacterial DNA gyrase and can be used against FQR bacteria but the chances
of resistance to this new drug are still there [39]. Similarly, the FQR Neisseria gonorrhoeae type II
topoisomerase can be inhibited by a novel compound called spiropyrimidinetrione AZD0914 [40] so on
one hand we have the continuously evolving resistant strains to quinolones and other antibacterial
agents, but on the other hand scientific community is working hard to design and synthesize new
drugs for the resistant bacterial strains.
3. Analogues of Quinolones
The first member of the quinolone family was nalidixic acid, which was synthesized as a
byproduct in the synthesis of chloroquine. Later, it was modified in order to enhance its activities.
One modification was the substitution of fluorine at the C-6 position, which was found to provide
good antibacterial activities. Moreover, substitution of piperazine or methyl piperazine, pyrrolidinyl
Molecules2016,21,268 7of19
and piperidinyl moieties was also determined to result in increased antibacterial activities. Following
are the analogues of quinolones available in the common literature (Figure 2) [15,16,41–48].
O O O O
O O
F
OH O OH
OH
N N O N N N
HN
Nalidixic acid Oxolinicacid Norfloxacin
O O
O O
F OH F
OH
N N
HN N N
N O
Molecules 2016, 21, 268C iprofloxacin Ofloxacin 7 of 18
O O O O
F F
OH OH
H
N N N N
N
O O
N H
H
Levofloxacin Moxifloxacin
O O
NH O O
2
F
F OH
OH
H N
2 N N
N N
O O
HN F N
Sparfloxacin 8-methoxyfloroquinolone
O O O O
F F
OH OH
HN N N N HN N N N
S N O
O
6-Fluoro-7-(3-methoxy-4-methylamino-pyrrolidin-1-yl)
-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-3-
Voreloxin carboxylicacid
O O
F
OH
F O O
HN
N N F
O OH
O
N N
HN F
5-Fluoro-6-(3-methoxy-4-methylamino-
pyrrolidin-1-yl)-3-oxo-3H-7-oxa-11b-aza-
benzo[de]anthracene-2-carboxylic acid Orbifloxacin
O O NH O O
2
F F
OH OH
N N N N
HN F HN O
Lomefloxacin Gatifloxacin
O O
O O
F
OH
OH O
N N N N
N
HN
O
H N
2
CHF
2
Garenofloxacin Gemifloxacin
Figure2.Cont.
Molecules2016,21,268 8of19
Molecules 2016, 21, 268 8 of 18
O O
F O O
OH
F
H N N N OH
F
H N N N
2 H
HN
F
Trovafloxacin Enoxacin
O O O O
F
OH F OH
H N
2
N N N
N
Enrofloxacin Pazufloxacin
O O
O O F
OH
F
OH
O
N N
O N N S Cl
O
N
H2N H
Prulifloxacin Besifloxacin
NH O O O O
2
O O F
F F OH OH
OH
HN N N N N
N N N
O Cl
O
H N
2 F
Balofloxacin Antofloxacin Sitafloxacin
O O
O O O O
F
F OH F OH OH
N N N N N
N N
Enrofloxacin Danofloxacin Flumequine
O O O O
F F
OH OH
NH O O
2
N N N N
F OH HN N
N N
N
O N
F F
Marbofloxacin Sarafloxacin Difloxacin
Figure 2. Common analogues of quinolones used for the treatment of different diseases.
Figure2.Commonanaloguesofquinolonesusedforthetreatmentofdifferentdiseases.
4. Clinical Use
4. ClinicalUse
There are a number of quinolone analogues used in clinical practice all over the world due to
tThheierr iencarreeasaedn aunmtibbaecrteorifalq ruainngoel oannde faanvaolroabglue epshaursmedacoinkincelitnicisc, awlhpilrea cthtiec eseaarlclho fvoerr ntehwe hwyborrildd due
to thneeirxt ignecnreeraastieodn qaunitnioblaocnteesr iisa olnrgaonignge. Aanmdonfag vthoer ambolest spuhitaarbmlea qcuoinkoinloenteicss c,anwdhidilaetetsh theast eaarer chhighfolyr new
prescribed are gatifloxacin, levofloxacin, ciprofloxacin. There are several quinolones that have more
hybridnextgenerationquinolonesisongoing. Amongthemostsuitablequinolonescandidatesthat
toxicity for the patients than usefulness, like halogenated quinolones, but such toxic analogues
are highly prescribed are gatifloxacin, levofloxacin, ciprofloxacin. There are several quinolones

that have more toxicity for the patients than usefulness, like halogenated quinolones, but such
toxic analogues should be used when no other option is available and the toxic damage is less
Molecules2016,21,268 9of19
ascomparedtothepathogenharm[49]. Thequinolonesarealsosuitablechoiceforlunginfectionslike
cysticfibrosis. Clinafloxaciniscytotoxic,butitcanbeusedagainstmulti-drugresistantBurkholderia
cepacia[49]. Pseudomonasaeruginosa-relatedrespiratorydiseasescanalsobetreatedbestwithanionic
fluroquinolones. InP.aeruginosabaseddiseaseslikecysticfibrosiswheretheyformathickbiofilmof
anionicmoleculessuchasrhamnolipidsandalginate,itisdifficultformostantibioticstopenetrate
andinhibitbacterialgrowth. Howeverthenegativelychargedfluoroquinoloneshavetheabilityto
crossthemucusandthushavebetterpharmacodynamicsduetotheirnegativelychargednature[50].
Somequinoloneslikeciprofloxacin,levofloxacin,moxifloxacin,ofloxacin,andgatifloxacinare
also approved by Federal Drug Administration (FDA) for pediatric use for different diseases like
conjunctivitis, otitis, sinusitis, respiratory tract infections, pneumonia, UTI and gastrointestinal
diseases[51]. Fluoroquinolonescanbeusedtocuretuberculosis(TB)asotheractiveagentsusedfor
treatmenttakesixmonthsormore, whileFQcanshorterthistimespan[52]. Thedevelopmentof
multi-drugresistanceinMycobacteriumtuberculosisstrainshasalreadyalarmedthemedicalcommunity
asthesestrainsarehighlyresistanttoantibiotics. Quinolonesalsosufferthesamefateasantibioticsas
severalstrainsofM.tuberculosisgeneratemutationsintheirDNAgyraseenzymeencodedbyGyrA
andGyrBgenes[53–55]. MutationsintheaminoacidsAla90andAsp94ofGyrAofseveralstrains
ofM.tuberculosisresultedinhighlevelsofresistancetolevofloxacin[56]. Thelevelofresistanceto
variousanaloguesofquinolonesisdifferentindifferentcountries[54,57–61].
Thequinolonescanalsobeusedtotreatdiseasesthatoccurasaresultofexcessiveproduction
of aldosterone. Some quinolone analogues can inhibit a group of mitochondrial cytochrome P450
(CYP)enzymesthatareinvolvedinaldosteronebiosynthesis. Thustheycanbeusedforthetreatment
ofheartrelateddiseaseslikehypertension,primaryaldosteronism,congestiveheartfailure,cardiac
fibrosis,ventricularremodelling,anddiabeticnephropathythatoccursduetohighlevelofaldosterone
production[62].
Besidetheantibacterialroleofquinolone,therearecertainquinolonyldiketoacidanaloguesthat
areactiveagainsthumanimmunodeficiencyvirus(HIV).Theyactagainstmultipleviralenzymes
thatincludereversetranscriptase,integraseandribonuclease. Theseagentsbindintheactivesiteof
integrase,ribonucleaseandreversetranscriptasewiththehelpofmagnesiumionwithacidicresidues
intheircatalyticsiteandinthatwaytheyhaltthefunctionoftheseenzymes[63–67]. Thesequinolonyl
diketoacidanaloguesaresynthesizedbyintroductionofvariousalkylatinggroupatthenitrogenatom
ofthequinolinonering[63]. Similarlythemonoandbifunctionalquinolinonyldiketoacidsarealso
potentinhibitorsofstrandtransferfunctionofHIVintegrase,whicharesynthesizedbytreatinganiline
withethylorthoformateandethylacetoacetate[65–67]. Theantitumoractivitiesofquinoloneswere
alsoinvestigatedbydifferentresearchgroups. AMannichbasecanbepreparedfromciprofloxacinand
kojicacidthatpossessesantitumoractivities. ThisMannichbaseanditscomplexwithcopperaretoxic
tocancerouscellsindifferentwaysthatincludeinhibitionofreplication,disruptionofpolarizationof
mitochondrialmembraneresultingintolossofATPactivityofcancerouscell[68]. Itisalsoreported
thatquinolonesactsagainstothertypesofcancerwhereitsmodeofactionissuggestedtobeinhibition
oftopoisomeraseII.
In veterinary medicine the quinolones are also prescribed due to their favorable
pharmacodynamicsandpharmacokinetics,especiallyforvarioustypesofdiseasesandwoundsin
dogsandcats. Thecommonlyprescribedfluoroquinolonesfordifferentdogandcatdiseasesincludes
ciprofloxacin,difloxacin,enrofloxacin,marbofloxacin,orbifloxacinandpradofloxacin[69,70].
5. TargetsofQuinolones
ThemaintargetsofquinolonesareDNAtopoisomerases. TheseenzymesareessentialforDNA
replication,transcription,recombinationandcondensedDNAremodeling,andfunctionbycarrying
outtransientsingle-anddouble-strandbreaks. ThetopoisomerasesmodulatethesupercoilingofDNA
toenableproperfunctionandinteractionwithproteins. Theseenzymesalsohaveafundamentalrole
inmostnucleicacidprocesses, likehelpingtocontrollevelsofDNAunder-andover-winding, as
Molecules2016,21,268 10of19
wellasremovingknotsandtanglesfrombacterialchromosomes[71–73]. Theenzymesthatcleave
just one strand of the DNA are called type I topoisomerases, and they are further divided into
type IA, based on the protein covalent linkage to 5’-phosphate, or type IB if the linkage is to 3’
phosphateoftheDNAstrand. ThetypeIItopoisomerasescleavebothstrandsofthedoublestranded
DNA concurrently. The binding and subsequent hydrolysis of ATP with type II topoisomerase
resultsinaconformationalchangesinDNA.Inmostofthebacteria,twodifferentbutstructurally
similartypeIItopoisomerasesarepresent,namely: gyraseandtopoisomerase-IV.Bothgyraseand
topoisomerase-IVareheterotetramericsubunits. ThegyrasehastwoeachGyrBandGyrAsubunits
whilethetopoisomerase-IVcontainstwosubunitseachofParEandParCsubunitsinGram-positive
bacteria. On the other hand GrlA and GrlB are the subunits of topoisomerase-IV in the case of
Gram-positivespecies [71,74–77]. Schoefflerand Bergerhave reviewed thestructure andfunction
ofthetypeIItopoisomerasemechanismingreatdetail,aswellastheroleoftheirATP-dependent
domains[76,78,79]. TheprocessesofligationandDNAcleavage,whichmakeupthecentralpartof
enzymefunction,useanon-canonicaltwo-metalionmechanism[80,81]. Gyraseandtopoisomerase-IV
make staggered cuts in DNA that are four base pairs apart and on opposite strands, leaving a 5’
overhang. Inthisprocess,acovalentbondisformedbetweenactivesitetyrosineresiduesandthe
newly generated 5’ DNA termini, in order to maintain a genomic integrity [16,71,74,75,77]. It is
noteworthythathumansalsohavetypeIIenzymes;topoisomeraseIIαandtopoisomeraseIIβwhich
havesignificantaminoacidsequencesimilaritytobacterialenzymes,butinhumans,thegenesthat
code for subunits A and B are fused, forming a single polypeptide chain. Thus, the human type
IIenzymesfunctionashomodimers. Duetothisdifference, theclinically-relevantquinolonescan
discriminatebetweenthehumanandbacterialtypeIItopoisomerases[16,71,82].
6. ModeofActionofQuinolones
Itwasfirstrecognizedin1977thatthebacterialenzymegyraseistheprimarytargetofquinolones.
Later,withthediscoveryoftopoisomerases,itwassuggestedthatthisenzymecouldalsobeatargetof
quinolones. AnalysisofEscherichiacolistrainscarryingdrug-resistancemutationsintheseenzymes
showed that quinolones inhibit gyrase and topoisomerase-IV as primary and secondary targets,
respectively[8]. Thereareseveralhigh-resolutionstructuresoftopoisomeraseindifferentcatalytic
modeswithDNA,whichhaveshownhowthetopoisomerasesmodifythetopologyofDNA[83–85].
Inarecentinvestigation,theinteractionofquinolonesandtypeIItopoisomeraseofhumanandbacteria
aremediatedbydifferenttypesofinteractions. Itwasshownthatthequinolonestargetthegyrase
andtopoisomerase-IVenzymesandinhibitbacterialgrowth[86]. Theseenzymeshavethepotentialto
fragmentthecellgenome,whichisessentialforcellsurvivalandreproduction. Quinolonesinhibit
cellgrowthanddivisionbyincreasingtheconcentrationofenzyme-DNAcleavagecomplexes[16,73].
Thusquinolonesarereferredtoastopoisomerasepoisonsastheyconvertgyraseandtopoisomerase
IVintocellulartoxins[87].
7. InteractionofQuinoloneswithTopoisomerases
Theinteractionofdrugswithproteinsplaysanimportantroleinstabilizingthecomplexes. Inthe
caseofGram-negativebacteria,quinolonesbindtogyrase,whileinGram-positivebacteria,thedrugs
preferentially bind to topoisomerase-IV [88,89]. The amino acids that are usually associated with
quinolone-resistanceareGyrA-Serine83andGyrA-aspartate87inE.coli[90–94]. Mutationofthese
twoaminoacidstoalanineresultsinresistancetoquinolones,whichshowedtheimportanceofthese
twoaminoacidsindrugbinding[95]. Consequently,itishasbeenassumedthatthesetwoaminoacids
playacrucialroleinmediatingquinolone-enzymeinteractions. Alargenumberofcrystallographic
studieshavebeenperformedtoexplainthequinolone-enzymeinteractions. Thesestructuresshowed
howthedrugsinteractwithboththeenzymeandDNAandhowthesedrugshaltthenormalprocess
ofDNAcleavageandreligation. Therearedifferencesintheinteractionofdrugswiththeenzyme
amongtheresolvedstructuresastheyvarywiththespeciesandthedrugused. Howevertheyare