molecules

Review CinnolineReview Scaffold—A Molecular Heart of Medicinal Chemistry?Cinnoline Sca ffold—A Molecular Heart of Medicinal Chemistry? Marta Szumilak1,* and Andrzej Stanczak 2 Marta1 Department Szumilak of Hospital1,* and Pharmacy, Andrzej Faculty Stanczak of Phar2 macy, Medical University of Lodz, 1 Muszynskiego Street, 90-151 Lodz, Poland 1 Department of Hospital Pharmacy, Faculty of Pharmacy, Medical University of Lodz, 1 Muszynskiego Street, 2 Department of Applied Pharmacy, Faculty of Pharmacy, Medical University of Lodz, 1 Muszynskiego 90-151 Lodz, Poland Street, 90-151 Lodz, Poland; [email protected] 2 Department of Applied Pharmacy, Faculty of Pharmacy, Medical University of Lodz, 1 Muszynskiego Street, * Correspondence: [email protected]; Tel.: +48 426-779-252 90-151 Lodz, Poland; [email protected] Academic* Correspondence: Editor: Josef [email protected]; Jampilek Tel.: +48 426-779-252 Received: 31 May 2019; Accepted: 16 June 2019; Published: date


Academic Editor: Josef Jampilek
 Received: 31 May 2019; Accepted: 16 June 2019; Published: 18 June 2019 Abstract: The cinnoline nucleus is a very important bicyclic heterocycle that is used as the structural subunitAbstract: ofThe many cinnoline compounds nucleus with is a veryinteresting important pharmaceutical bicyclic heterocycle properties. that isCinnoline used as the derivatives structural exhibitsubunit broad of many spectrum compounds of pharmacological with interesting activities pharmaceutical such as antibacterial, properties. antifungal, Cinnoline antimalarial, derivatives anti-inflammatory,exhibit broad spectrum analgesic, of pharmacological anxiolytic and activities antitumor such asactivities. antibacterial, Some antifungal, of them antimalarial,are under evaluationanti-inflammatory, in clinical analgesic, trials. anxiolyticIn the present and antitumor review, we activities. have compiled Some of them studies are underfocused evaluation on the biologicalin clinical trials.properties In the of present cinno review,line derivatives we have compiledconducted studies by many focused research on the biologicalgroups worldwide properties betweenof cinnoline 2005 derivatives and 2019. Comprehensive conducted by many and target research oriented groups information worldwide clearly between indicate 2005 and that 2019. the developmentComprehensive of cinnoline and target based oriented mole informationcules constitute clearly a significant indicate that contribution the development to the identification of cinnoline ofbased lead moleculescompounds constitute with optimized a significant pharma contributioncodynamic to and the pharmacokinetic identification of properties. lead compounds with optimized pharmacodynamic and pharmacokinetic properties. Keywords: cinnoline; biological activity; heterocyclic compounds Keywords: cinnoline; biological activity; heterocyclic compounds

1. Introduction 1. Introduction Cinnoline (1,2-benzodiazine) 1, depicted in Figure 1, is present in many compounds of considerableCinnoline pharmacological (1,2-benzodiazine) and1 ,chemical depicted importance in Figure1, is [1]. present It is six-membered in many compounds ring system of considerable with two nitrogenpharmacological atoms, an and isosteric chemical relati importanceve to either [1]. quinoline It is six-membered or isoquinoline ring system and isomeric with two with nitrogen phthalazine atoms, [1,2].an isosteric relative to either quinoline or isoquinoline and isomeric with phthalazine [1,2].

N N 1

Figure 1. Structure of the cinnoline ring system. Figure 1. Structure of the cinnoline ring system. Synthesis of cinnoline and its derivatives has been extensively discussed in many papers [2–9]. UntilSynthesis 2011, no compoundsof cinnoline containing and its der theivatives cinnoline has been ring systemextensively were di foundscussed in nature. in many The papers first natural [2–9]. Untilcinnoline 2011, derivative no compounds 2-furanmethanol-(5 containing the 11)-1,3-cyclopentadiene-[5,4-cinnoline ring system were cfound]-1H-cinnoline in nature.2 (FigureThe first2) 0→ naturalwas isolated cinnoline from derivatCichoriumive endivia2-furanmethanol-(5when investigating′→11)-1,3-cyclopentadiene-[5,4- the in vitro and in vivoc]-1hepatoprotectiveH-cinnoline 2 (Figureproperties 2) ofwasCichorium isolated endivia fromL. extractCichorium (CEE) endivia [10]. Syntheticwhen investigating molecules bearing the in a cinnolinevitro and framework in vivo hepatoprotectiveare extensively studied properties due toof theirCichorium various endivia biological L. extract activities (CEE) depending [10]. Synthetic on the molecules nature and bearing position a cinnolineof their substituents. framework Inare addition, extensively they studied are often due designed to their asvarious analogs biological of previously activities obtained depending quinoline on theorisoquinoline nature and derivativesposition of [11their–14 ].substituents. In addition, they are often designed as analogs of previously obtained quinoline or isoquinoline derivatives [11–14].

Molecules 2019, 24, x; doi: www.mdpi.com/journal/molecules

Molecules 2019, 24, 2271; doi:10.3390/molecules24122271 www.mdpi.com/journal/molecules Molecules 2019, 24, x 2 of 25 Molecules 2019, 24, x 2 of 25 Molecules 2019, 24, 2271 2 of 25 Molecules 2019, 24, x 2 of 25 O O OH O OH N OH N N N H N 2 NH 2 H 2 Figure 2. Structure of 2-furanmethanol-(5′→11)-1,3-cyclopentadiene-[5,4- c]-1H-cinnoline. Figure 2. Structure of 2-furanmethanol-(5′→11)-1,3-cyclopentadiene-[5,4-c]-1H-cinnoline. Figure 2. Structure of 2-furanmethanol-(50 11)-1,3-cyclopentadiene-[5,4-c]-1H-cinnoline. Figure 2. Structure of 2-furanmethanol-(5′→→11)-1,3-cyclopentadiene-[5,4-c]-1H-cinnoline. Cinnoline, together with other bicyclic scaffolds, is the subject of our special interest as the Cinnoline,Cinnoline, togethertogether withwith other other bicyclicbicyclic scascaffolds,ffolds, isis thethe subjectsubject ofof ourour specialspecial interestinterest asas thethe terminal moiety of symmetrical compounds designed in agreement with the bisintercalators’ terminalterminalCinnoline, moiety moiety together of symmetricalof symmetrical with other compounds compounds bicyclic designed scaffolds, designed in agreementis thein subjectagreement with of the ourwith bisintercalators’ special the bisintercalators’interest structural as the structural requirements [15,16]. Our previous review describing the biological properties of cinnoline terminalstructural moiety requirements of symmetrical [15,16]. Ou compoundsr previous review designed describing in agreement the biological with propertiesthe bisintercalators’ of cinnoline requirementsderivatives included [15,16]. Ourpapers previous and reviewpatents describing published the until biological 2004 [1]. properties Herein, of we cinnoline aimed derivatives to review structuralderivatives requirements included papers [15,16]. and Ou r patentsprevious publishe review ddescribing until 2004 the [1]. biological Herein, properties we aimed of cinnolineto review includeddocuments papers published and patents from published2005 to 2019, until focusing 2004 [1]. on Herein, the compounds we aimed tobearing review a documentscinnoline nucleus, published in derivativesdocuments includedpublished papers from 2005 and to patents 2019, focusing publishe ond theuntil compounds 2004 [1]. Herein,bearing awe cinnoline aimed nucleus,to review in fromparticular 2005 towith 2019, respect focusing to their on thebiological compounds activity bearing and potential a cinnoline therapeutic nucleus, inuse. particular with respect documentstoparticular their biological withpublished respect activity from to andtheir 2005 potential biological to 2019, therapeutic focusing activity onand use. the potential compounds therapeutic bearing use. a cinnoline nucleus, in particular with respect to their biological activity and potential therapeutic use. 2. Biological Activity of Cinnoline Derivatives 2.2. BiologicalBiological ActivityActivity ofof CinnolineCinnoline DerivativesDerivatives 2. Biological Activity of Cinnoline Derivatives 2.1. Antimicrobial Activity 2.1.2.1. AntimicrobialAntimicrobial ActivityActivity 2.1. AntimicrobialInfectious diseases Activity constitute a growing therapeutic challenge worldwide due to the developing InfectiousInfectious diseases diseases constitute constitute a a growinggrowing therapeutictherapeutic challengechallenge worldwideworldwide due due toto thethe developingdeveloping resistance of pathogens to known drugs [17,18]. As a consequence, there is an urgent need to design resistanceresistanceInfectious of of pathogenspathogens diseases constitute to to known known drugsa dr growingugs [17 [17,18].,18 therap]. AsAseutic aa consequence,consequence, challenge worldwide therethere isis anan due urgenturgent to the needneed developing toto designdesign new compounds with improved activity against drug-sensitive as well as drug-resistant pathogens. resistancenewnew compoundscompounds of pathogens withwith improvedto known activitydrugs [17,18]. against As drug-sensitivedrug-s a consequence,ensitive as as ther welle as is andr drug-resistantug-resistant urgent need pathogens. to design Cinnoline derivatives were widely studied as antimicrobial agents [1]. Cinoxacin 3 (Figure 3) is a newCinnolineCinnoline compounds derivatives derivatives with were improved were widely widely activity studied studied asagainst antimicrobial as antimicrobial drug-sensitive agents agents [1as]. well Cinoxacin [1]. as Cinoxacindrug-resistant3 (Figure 33 (Figure) is pathogens. a common 3) is a common drug used in urinary tract infections [19]. Since it has a high phototoxicity index, Vargas et Cinnolinedrugcommon used drug inderivatives urinary used tractin were urinary infections widely tract [ 19studied infections]. Since as it [19]. hasantimicrobial a Since high phototoxicityit has agents a high [1]. index,phototoxicity Cinoxacin Vargas 3 et index, (Figure al. synthesized Vargas 3) is aet al. synthesized the naphthyl ester of cinoxacin 4 (Figure 3) in order to evaluate its possible application commontheal. synthesized naphthyl drug ester used the of naphth in cinoxacin urinaryyl ester tract4 (Figure of infections cinoxacin3) in order [19]. 4 (Figure toSince evaluate 3) it in has order its a high possible to evaluate phototoxicity application its possible index, in antibacterial application Vargas et in antibacterial phototherapy. The ester derivative of cinoxacin 4 exhibited comparable photostability al.phototherapy.in synthesized antibacterial Thethe phototherapy. naphth ester derivativeyl ester Th ofe ofester cinoxacin cinoxacin derivative 44 (Figureexhibited of cinoxacin 3) in comparable order 4 exhibited to evaluate photostability comparable its possible and photostability antibacterialapplication and antibacterial activity against E. coli to the parent drug but enhanced antibacterial activity upon inactivityand antibacterial antibacterial against phototherapy.E. coliactivityto the against parent The drugesterE. coli butderivative to enhancedthe parent of cinoxacin antibacterial drug but 4 enhancedexhibited activity upon comparableantibacterial irradiation photostability activity [20]. upon irradiation [20]. andirradiation antibacterial [20]. activity against E. coli to the parent drug but enhanced antibacterial activity upon O O irradiation [20]. O O O O O O O O O O OH O O O OH O O O O N O OH O N N N O O O N N N N O N O N N O N

3 4 3 4 3 Figure 3. Cinoxacin and its naphthyl ester4 derivative. Figure 3. Cinoxacin and its naphthyl ester derivative. Figure 3. Cinoxacin and its naphthyl ester derivative. Depicted in Figure4,Figure 6-hydroxycinnolines 3. Cinoxacin and wereits naphthyl synthesized ester derivative. and tested for in vitro antifungal Depicted in Figure 4, 6-hydroxycinnolines were synthesized and tested for in vitro antifungal activityDepicted against inCandida Figureand 4, 6-hydroxycinnolinesAspergillus species. It waswere elucidatedsynthesized that and most tested of the for obtained in vitro compounds antifungal activity against Candida and Aspergillus species. It was elucidated that most of the obtained exhibitedactivityDepicted against potent in Figure antifungalCandida 4, 6-hydroxycinnolinesand activity Aspergillus against species.C. kruseiwere It ,synthesized C.was neoformans elucidated and, and tested thatA. nigerformost in, withvitroof the theantifungal obtained highest compounds exhibited potent antifungal activity against C. krusei, C. neoformans, and A. niger, with the activityactivitycompounds towardsagainst exhibited C.Candida neoformans potent and antifungal [Aspergillus21]. activity species. against It was C. kruseielucidated, C. neoformans that most, and of A. theniger obtained, with the highest activity towards C. neoformans [21]. compoundshighest activity exhibited towards potent C. antifungal activity against C. krusei, C. neoformans, and A. niger, with the highest activity towards C. neoformans [21]. O O R OO R = Cl; arylthio R = Cl; arylthio R O O HO R NHR2 = Cl; arylthio OH NH2 HO NH N 2 N N N N N 5 5 Figure 4. General structure5 of 6-hydroxycinnoline derivatives. FigureFigure 4.4. GeneralGeneral structurestructure ofof 6-hydroxycinnoline 6-hydroxycinnolinederivatives. derivatives. Figure 4. General structure of 6-hydroxycinnoline derivatives.

Molecules 2019, 24, 2271 3 of 25 Molecules 2019, 24, x 3 of 25 Molecules 2019, 24, x 3 of 25 CinnolineCinnoline derivatives derivatives bearing bearing sulphonamide sulphonamide moiety moiety 66 (Figure(Figure 55)) werewere synthesizedsynthesized asas potentialpotential Cinnoline derivatives bearing sulphonamide moiety 6 (Figure 5) were synthesized as potential antimicrobialantimicrobial and and antifungal antifungal agents. agents. Evaluation Evaluation of of their their activity activity against against a a panel panel of of bacteria strains antimicrobial and antifungal agents. Evaluation of their activity against a panel of bacteria strains includingincluding P.P. aeruginosa, aeruginosa, E. E. coli, coli, B. B. subtilis, subtilis, S. S.aureus aureus andand fungi fungi C. C.albicans albicans andand A. nigerA. niger revealedrevealed that thatthe including P. aeruginosa, E. coli, B. subtilis, S. aureus and fungi C. albicans and A. niger revealed that the combinationthe combination of two of two active active moieties moieties in inone one molecule molecule resulted resulted in in significant significant activity activity improvement. improvement. combination of two active moieties in one molecule resulted in significant activity improvement. HalogenHalogen substituted substituted derivatives derivatives showed showed potent potent acti activityvity at at lesser lesser concentrations concentrations with with approximately approximately Halogen substituted derivatives showed potent activity at lesser concentrations with approximately thethe same same zone zone of of inhibition inhibition as as the the reference reference drug [22]. [22]. the same zone of inhibition as the reference drug [22]. H2N R = o-nitro; p-chloro; o-methyl; p-nitro; p-bromo; H N 2 3,4-dinitro;R = o-nitro; m-chloro; p-chloro; o-flouro, o-methyl; 2,3-dichloro p-nitro; p-bromo; O 3,4-dinitro; m-chloro; o-flouro, 2,3-dichloro O S S NH O O NH O O

NH2 R NH2 R N N N N 6 6 FigureFigure 5. 5. CinnolinesCinnolines bearing bearing a a sulphonamide sulphonamide moiety moiety wi withth antibacterial antibacterial and and antifungal antifungal activity. activity. Figure 5. Cinnolines bearing a sulphonamide moiety with antibacterial and antifungal activity. Some new cinnoline based chalcones 7 and cinnoline based pyrazoline derivatives 8 (Figure6) Some new cinnoline based chalcones 7 and cinnoline based pyrazoline derivatives 8 (Figure 6) were evaluatedSome new forcinnoline their antibacterial based chalcones activity 7 and against cinnolineB. subtilis based, E. pyrazoline coli, S. aureus derivativesand K.pneumoniae 8 (Figure 6), were evaluated for their antibacterial activity against B. subtilis, E. coli, S. aureus and K. pneumoniae, antifungalwere evaluated activity for against their antibacterialA. flavus, F. oxysporum activity against, A. niger B.and subtilisT. viridae, E. coliand, S. insecticidal aureus and activity K. pneumoniae against , antifungal activity against A. flavus, F. oxysporum, A. niger and T. viridae and insecticidal activity Periplanetaantifungal americanaactivity against. The mostA. flavus potent, F. testedoxysporum compounds, A. niger were and 4-Cl-,T. viridae 2-NO and2-, 4-NOinsecticidal2-substituted activity against Periplaneta americana. The most potent tested compounds were 4-Cl-, 2-NO2-, 4-NO2- cinnolineagainst Periplaneta based chalcones americana as well. The as 3-Cl-,most 2-NOpotent2- andtested 4-OH-substituted compounds were cinnoline 4-Cl-, based 2-NO pyrazolines.2-, 4-NO2- substituted cinnoline based chalcones as well as 3-Cl-, 2-NO2- and 4-OH-substituted cinnoline based Insubstituted addition, allcinnoline chloro-substituted based chalco derivativesnes as well of as series 3-Cl-,7 2-NOand hydroxy-substituted2- and 4-OH-substituted derivatives cinnoline of seriesbased pyrazolines. In addition, all chloro-substituted derivatives of series 7 and hydroxy-substituted 8pyrazolines.exhibited better In addition, insecticidal all activity chloro-substituted in comparison derivatives to the standard of series drug 7 [ 23and]. hydroxy-substituted derivatives of series 8 exhibited better insecticidal activity in comparison to the standard drug [23]. derivatives of series 8 exhibited better insecticidal activity in comparison to the standard drug [23]. H H O N N O N N R R R N R N N N N N N 7 N 8 7 8 R = NO2; Cl; Br; OH; OCH3; N(CH3)2 R = NO ; Cl; Br; OH; OCH ; N(CH ) 2 3 3 2 Figure 6. General structures of cinnoline based chalcones and cinnoline based pyrazoline derivatives. Figure 6. General structures of cinnoline based chalcones and cinnoline based pyrazoline Figure 6. General structures of cinnoline based chalcones and cinnoline based pyrazoline In the search for potent antibacterialderivatives. and antimalarial drugs, Unnissa and co-workers derivatives. synthesized pyrazole based cinnoline derivatives 9 (Figure7). All compounds demonstrated significantIn the antitubercularsearch for potent and antifungalantibacterial activity. and antimalarial Compound drugs,10 4-methyl-3-[5-(4-hydroxy-3- Unnissa and co-workers In the search for potent antibacterial and antimalarial drugs, Unnissa and co-workers synthesizedmethoxyphenyl)-4,5-dihydro-1 pyrazole based cinnolineH-pyrazol-3-yl]cinnoline-6-sulphonamide derivatives 9 (Figure 7). All compounds (Figure7) wasdemonstrated found to synthesized pyrazole based cinnoline derivatives 9 (Figure 7). All compounds demonstrated significantbe the most antitubercular potent with promising and antifungal activity againstactivity. resistantCompound strains 10 of 4-methyl-3-[5-(4-hydroxy-3-M. tuberculosis and various significant antitubercular and antifungal activity. Compound 10 4-methyl-3-[5-(4-hydroxy-3- methoxyphenyl)-4,5-dihydro-1pathogenic fungi [24], as well asH-pyrazol-3-yl]cinnoline-6-sulphonamide against protozoan parasite P. falciparum [ 25(Figure]. 7) was found to be methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl]cinnoline-6-sulphonamide (Figure 7) was found to be the most potent with promising activity against resistant strains of M. tuberculosis and various the most potent with promising activity against resistant strains of M. tuberculosis and various pathogenic fungi [24], as well as against protozoan parasite P. falciparum [25]. pathogenic fungi [24], as well as against protozoan parasite P. falciparum [25].

Molecules 2019, 24, x 4 of 25 Molecules 2019, 24, 2271 4 of 25 Molecules 2019, 24, x 4 of 25 O OH O OH R R = NO ; Cl; F; OH; OCH ; CH=CH CH 2 3 2 3 R R = NO2; Cl; F; OH; OCH3; CH=CH2CH3 O H2N NH O SO H2N NH H2N N NH SO OS H2N N NH N N OS O N N N N O N N N 910N 910 Figure 7. General structure of pyrazole based cinnoline-6-sulphonamides. Figure 7. General structure of pyrazole based cinnoline-6-sulphonamides. Figure 7. General structure of pyrazole based cinnoline-6-sulphonamides. Parasuraman et al.al. described 7-substituted 4-aminocinnoline-3-carboxamide4-aminocinnoline-3-carboxamide derivatives that wereParasuraman evaluatedevaluated againstagainst et al. adescribeda panelpanel ofof 7-substituted GramGram++ andand GramGram4-aminocinnoline-3-carboxamide− bacteria.bacteria. All the synthesized derivatives compounds that − wereexhibited evaluated moderate against to good a panel antibacterialantibacterial of Gram+ activity.activity and Gram. The − MICbacteria. (Minimal All the inhibitory synthesized concentration) compounds of exhibitedtested compounds moderate against to good V. antibacterialcholera, E. coli, activity B. substills, . The B. MIC linct linctus, (Minimalus, M. luteus, inhibitory S. au aureus,reus, concentration) K. pneumoniae, of testedCorynebacterium compoundsand and againstS. S. albus albus V.was cholera, was found found E. to coli, be to inB. the besubstills, rangein the ofB. range 6.25–25linctus, of µ M.6.25–25g/ mL.luteus, The μ S.g/mL. most aureus, activeThe K. pneumoniae,most compounds, active Corynebacterium11compounds,and 12 (Figure 11 andand8), demonstrated12 S. (Figure albus was 8), largerdemonstrated found or to approximately be largerin the or range theapproximately same of 6.25–25 zone of the inhibitionμg/mL. same zoneThe as theofmost inhibition reference active compounds,drugas the ciprofloxacin. reference 11 and drug 12 In ciprofloxacin. addition,(Figure 8), the demonstrated synthesizedIn addition ,larger compoundsthe synthesized or approximately exhibited compound moderate the ssame exhibited tozone good ofmoderate antifungalinhibition to asactivitygood the antifungalreference against A. drugactivity fumigatus, ciprofloxacin. against S. griseus, A. fumigatus, In addition A. niger, S. ,A.griseus, the parasitus, synthesized A. ni C.ger, albicans A. compound parasitus,and M. sC. exhibited ruber albicans, with andmoderate the M. zone ruber to of, goodinhibitionwith theantifungal zone between of activity inhibition 8–27 against mm. between MIC A. fumigatus, values 8–27 weremm. S. MIC foundgriseus, values to A. be ni inwereger, the A. found range parasitus, to of 6.25–25be C. in albicans theµ grange/mL and [of26 M. ].6.25–25 ruber, withμg/mL the [26]. zone of inhibition between 8–27 mm. MIC values were found to be in the range of 6.25–25

μg/mL [26]. N NH2

N NH2 N N NH2 O Cl NH2 O R = NH2 O Cl R = R N NH2 O NH N OH R N NH N OH OH 11, 12 OH 11, 12 Figure 8. Selected 4-aminocinnoline-3-carboxamide derivatives with antibacterial and antifungal activity. Figure 8. Selected 4-aminocinnoline-3-carboxamide derivatives with antibacterial and antifungal FigureSaxenaactivity. 8. andSelected co-workers 4-aminocinnoline-3-carboxamide obtained a series of deri substitutedvatives with 4-( antibacterialp-aminopiperazine)cinnoline-3- and antifungal carboxamideactivity. derivatives 13 (Figure9). The in vitro antimicrobial screening against G+ B. subtilis Saxena and co-workers obtained a series of substituted 4-(p-aminopiperazine)cinnoline-3- and S. aureus and G E. coli and P. aeruginosa revealed the MIC of the synthesized compounds in the range carboxamide derivatives− 13 (Figure 9). The in vitro antimicrobial screening against G+ B. subtilis and of 12.5–50Saxenaµg /andmL, whereasco-workers the zoneobtained of inhibition a series was of between substituted 6–29 mm. 4-(pA.-aminopiperazine)cinnoline-3- niger and C. albicans were used S. aureus and G− E. coli and P. aeruginosa revealed the MIC of the synthesized compounds in the range carboxamidefor evaluation derivatives of the antifungal 13 (Figure activity. 9). The The in MIC vitro of theantimicrobial tested compounds screening was against found G+ to beB. insubtilis the range and of 12.5–50 μg/mL, whereas the zone of inhibition was between 6–29 mm. A. niger and C. albicans were S.of aureus 12.5–50 andµg /GmL,− E. whereas coli and theP. aeruginosa zone of inhibition revealed was the betweenMIC of the 8–25 synthesized mm. The mostcompounds potent antimicrobial in the range used for evaluation of the antifungal activity. The MIC of the tested compounds was found to be in ofagents 12.5–50 in comparison μg/mL, whereas to standard the zone drugs of wereinhibition 6-chloro, was 7-chloro between and 6–29 7-bromo mm. A. substituted niger and derivativesC. albicans were [27]. usedthe range for evaluation of 12.5–50 of μ g/mL,the antifungal whereas activity.the zone Th ofe inhibition MIC of the was tested between compounds 8–25 mm. was The found most to potent be in theantimicrobial range of 12.5–50 agents μ g/mL,in comparison whereas the to zone standa of inhibitionrd drugs waswere between 6-chloro, 8–25 7-chloro mm. The and most 7-bromo potent antimicrobialsubstituted derivatives agents in [27]. comparison to standard drugs were 6-chloro, 7-chloro and 7-bromo substituted derivatives [27].

MoleculesMolecules2019 2019, 24,, 24 2271, x 5 of5 of25 25 Molecules 2019, 24, x 5 of 25

H H N N R = 6-chloro; 8-chloro; 7-chloro; 6-bromo; O N NH R8-bromo; = 6-chloro; 2,4,6-tribromo; 8-chloro; 7-bromo 7-chloro; 6-bromo; O N H NH 8-bromo; 2,4,6-tribromo; 7-bromo H NH2

R NH2 N R N N N 13 13 Figure 9. General structure of 4-(p-aminopiperazine)cinnoline-3-carboxamide derivatives. Figure 9. General structure of 4-(p-aminopiperazine)cinnoline-3-carboxamide derivatives. Figure 9. General structure of 4-(p-aminopiperazine)cinnoline-3-carboxamide derivatives. As a continuation of previous studies, they obtained a new series of cinnoline-3-carboxamide As a continuation of previous studies, they obtained a new series of cinnoline-3-carboxamide derivatives with five-membered (thiophene 14, furan 15, pyrazole 16, imidazole 17) or six-membered derivativesAs a continuation with five-membered of previous (thiophene studies,14 they, furan obtained15, pyrazole a new 16series, imidazole of cinnoline-3-carboxamide17) or six-membered heterocycle (piperazine 18) substitutions at the 4-amino group of cinnoline core (Figure 10). heterocyclederivatives with (piperazine five-membered18) substitutions (thiophene at14, thefuran 4-amino 15, pyrazole group 16, of imidazole cinnoline 17) core or six-membered (Figure 10). heterocycleCompounds (piperazine were evaluated 18) substitutions for antibacterial, at the antifungal 4-amino andgroup anti-inflammatory of cinnoline core activity. (Figure They 10). Compoundsexhibited wereantibacterial evaluated activity for antibacterial, against B. subtilis, antifungal S. aureus, and anti-inflammatory E. coli and P. aeruginosa. activity. However, They exhibited the antibacterialCompounds activitywere evaluated against B. for subtilis, antibacterial, S. aureus, antifungal E. coli and P.and aeruginosa. anti-inflammatoryHowever, theactivity. potency They of exhibitedpotency antibacterial of tested compounds activity againstdiffered B. depending subtilis, S. on aureus, the substituent E. coli and at P.th eaeruginosa. cinnoline nucleus.However, The the testedmost compounds potent compounds differed in depending comparison on to the the substituent standard drug at the norfloxacin cinnoline we nucleus.re 6-chloro The substituted most potent potency of tested compounds differed depending on the substituent at the cinnoline nucleus. The compoundscompounds. in comparisonAntifungal activity to the standardagainst C. drugalbicans norfloxacin and A. niger were was 6-chloro observed substituted for all series, compounds. but the most potent compounds in comparison to the standard drug norfloxacin were 6-chloro substituted Antifungalmost potent activity antifungal against agentsC. albicans were theand 7-chloroA. niger substitutedwas observed cinnoline for allthiophene series, butderivative the most and potent the compounds. Antifungal activity against C. albicans and A. niger was observed for all series, but the antifungal6-chloro agentssubstituted were cinnoline the 7-chloro furan substitutedderivative. In cinnoline all five series, thiophene haloge derivativen substituted and compounds the 6-chloro most potent antifungal agents were the 7-chloro substituted cinnoline thiophene derivative and the substitutedwere found cinnoline to be the furan most derivative. active, followed In all five by series,methyl halogen substituted substituted and nitr compoundso substituted were derivatives found to 6-chloro substituted cinnoline furan derivative. In all five series, halogen substituted compounds be the[28]. most active, followed by methyl substituted and nitro substituted derivatives [28]. were found to be the most active, followed by methyl substituted and nitro substituted derivatives

[28]. S O R = 8-nitro; 6-nitro; 6-chloro; 6-bromo; O O S NH O NH 6,7-dinitro; 8-methyl; 7-chloro; 8-flouro, 7,8-dichloro; 7-nitro R = 8-nitro; 6-nitro; 6-chloro; 6-bromo; O NH2 O NH26,7-dinitro; 8-methyl; 7-chloro; 8-flouro, R NH R NH N N 7,8-dichloro; 7-nitro N N NH2 NH2 15 R 14 R H N N N NHN N N N 15 14 H O O N O NH NH N NH NH N H N NH NH2 NH2 2 O O O R R NH R N NH NH N N N H N N N NH NH NH2 2 18 2 R 16 R 17 R N N N N N N FigureFigure 10. 10. StructureStructure of 4-aminocinnoline-3-carboxamides of 4-aminocinnoline-3-carboxamides substituted substitutedwith five- or withsix-membered five- or six-membered heterocycles. 17 18 heterocycles.16

LookingFigureLooking 10. for Structure for potent potent antitubercularof antitubercular 4-aminocinnoline-3-carboxamides compounds, compounds, DawadiDawadi substituted et al. obtained with five-analogues analogues or six-membered of of nucleoside nucleoside antibioticsantibioticsheterocycles. where where the the salicyl-sulfamate salicyl-sulfamate moiety moiety waswas replacedreplaced by a a cinnolinone-3-sulphonamide cinnolinone-3-sulphonamide group. group. TheThe most most active active compound compound19 (Figure 19 (Figure 11) demonstrated11) demonstrated low nanomolarlow nanomolar mycobacterial mycobacterial salicylate salicylate ligase (MbtA)ligaseLooking inhibition (MbtA) for inhibitionpotent and exhibited antitubercular and exhibited very good compounds, very antimycobacterial good Daantimycobacterialwadi activityet al. obtained under activity iron-deficientanalogues under iron-deficient of conditionsnucleoside (MICantibioticsconditions= 2.3 µwhereM) (MIC by the blocking= 2.3 salicyl-sulfamate μM) productionby blocking moiety ofproduction siderophores was replacedof siderophores in whole by a cinnolinone-3-sulphonamideM. in tuberculosiswhole M. tuberculosiscells [29]. cells group.[29]. The most active compound 19 (Figure 11) demonstrated low nanomolar mycobacterial salicylate ligase (MbtA) inhibition and exhibited very good antimycobacterial activity under iron-deficient conditions (MIC = 2.3 μM) by blocking production of siderophores in whole M. tuberculosis cells [29].

Molecules 2019, 24, x 6 of 25 Molecules 2019, 24, 2271 6 of 25 Molecules 2019, 24, x 6 of 25 NH Molecules 2019, 24, x 2 6 of 25

N NH2 O N NH2 O O N O S N NN O ONH N N O O O S O N - N S NH N F N NH O N N O - N F N - N F N OH OH 19 OH OH 19 OH OH Figure 11. Cinnoline nucleoside analog19 acting as a siderophore biosynthesis inhibitor. Figure 11. Cinnoline nucleoside analog acting as a siderophore biosynthesis inhibitor. Figure 11. Cinnoline nucleoside analog acting as a siderophore biosynthesis inhibitor. The cinnolineFigure 11.ring Cinnoline system nucleoside was also analog used acting in designingas a siderophore compounds biosynthesis active inhibitor. against tropical The cinnoline ring system was also used in designing compounds active against tropical protozoan protozoan infections. Devine and co-workers synthesized a panel of compounds with different infections.TheThe cinnoline Devinecinnoline andring ring co-workerssystem system waswas synthesized alsoalso usedused ainin panel designing of compounds compoundscompounds with activeactive diff erentagainst against heterocyclic tropical tropical heterocyclic scaffolds (quinoline, isoquinoline, cinnoline, phthalazine, 3-cyanoquinoline). Cinnoline scaprotozoanprotozoanffolds (quinoline, infections. infections. isoquinoline, Devine Devine and and cinnoline, co-workersco-workers phthalazine, sysynthesized 3-cyanoquinoline). aa panelpanel ofof compoundscompounds Cinnoline with with derivativedifferent different derivative 20 (Figure 12) displayed potent proliferation inhibition for L. major and P. falciparum (Half 20heterocyclic(Figureheterocyclic 12 scaffolds) displayedscaffolds (quinoline, (quinoline, potent proliferation isoquinoline, isoquinoline, inhibition cinnoline,cinnoline, for phthalazine,L. major and 3-cyanoquinoline). 3-cyanoquinoline).P. falciparum (Half Cinnoline Cinnoline maximal maximal effective concentration EC50 value = 0.24 μM and 0.003 μM, respectively). In addition, the ederivativeffectivederivative concentration 20 20 (Figure (Figure 12) EC12) displayed displayedvalue = potent potent0.24 µ Mproliferation proliferation and 0.003 µinhibitionM, respectively). forfor L. L. major major In and addition, and P. P. falciparum falciparum the cinnoline (Half (Half cinnoline derivative exhibited50 increased potency against amastigotes (0.24 μM) but with a significant derivativemaximalmaximal effective exhibited effective concentration increasedconcentration potency EC EC5050 value againstvalue == amastigotes 0.240.24 μM and (0.24 0.0030.003µ M) μμM,M, but respectively). respectively). with a significant In In addition, addition, decrease the the in decrease in potency against the promastigote form [12]. potencycinnolinecinnoline against derivative derivative thepromastigote exhi exhibitedbited increased increased form [12 potency potency]. againstagainst amastigotes (0.24 (0.24 μ μM)M) but but with with a significanta significant decreasedecrease in inpotency potency against against the the promastigote promastigote formform [12].

O NH

F OO NHNH FF Cl N Cl N Cl N N N N

20 20 20 O O S N O S O N N NHS O N N NH O N NH

Figure 12. N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl) FigureFigure 12. 12.N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl) N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl) phenyl)cinnolin-4-amine (NEU-1017). phenyl)cinnolin-4-amineFigurephenyl)cinnolin-4-amine 12. N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7 (NEU-1017). (NEU-1017). -(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl) phenyl)cinnolin-4-amine (NEU-1017). SomeSomeSome cinnolinecinnoline cinnoline derivativesderivatives derivatives 2121 21 (Figure(Figure (Figure 13 13)13)) werewerewere patentedpatented as asas compounds compoundscompounds active activeactive against againstagainst resistance resistanceresistance developingdevelopingdevelopingSome cinnoline bacteria.bacteria. bacteria. derivatives Glinka Glinka and and 21 co-workers co-workers (Figure 13) describeddescribed were patented the invention invention as compounds related related to toactive efflux eeffluxfflux against pump pumppump inhibitor resistance inhibitorinhibitor (EPI)developing(EPI)(EPI) compoundscompounds compounds bacteria. havinghaving having Glinka polybasicpolybasic polybasic and co-workers functionalities.functionalities. functionalities. described TheThe the compoundscompounds invention inhibited inhibitedinhibitedrelated tobacterial bacterialbacterial efflux pumpefflux eeffluxfflux pumpsinhibitor pumpspumps and(EPI)andand couldcould compounds could be be usedbe used used inhaving in combinationin combination combination polybasic with with withfunctionalities. an an an antibacterial antibacterantibacter Theial agent compoundsagentagent to treattoto treat treat or inhibited preventor or prevent prevent bacterial bacterial bacterial bacterial infections. efflux infections. infections. pumps [30 ]. and[30].[30]. could be used in combination with an antibacterial agent to treat or prevent bacterial infections. [30]. FF HH2N2N FFFFF H N 2 O NHNH22 FFO NN NH2 O N OO OO NH O O NH NH NH NH2 O N NH2 NH O N N N NH 21 O N 2 21 N FigureFigure 13. 13.Example Example of a a cinnoline cinnoline derivative derivative with with21 polybasic polybasic functionalities functionalities patented patented as an efflux as an pump efflux Figure 13. Example of a cinnoline derivative with polybasic functionalities patented as an efflux pump pumpinhibitor. inhibitor. inhibitor. Figure 13. Example of a cinnoline derivative with polybasic functionalities patented as an efflux pump inhibitor.

Molecules 2019, 24, 2271 7 of 25

MoleculesMolecules 2019 2019, 24, ,24 x , x 7 of7 of25 25 2.2. Analgesic and Antiinflamatory Activities 2.2.2.2. Analgesic Analgesic and and Antiinflamatory Antiinflamatory Activities Activities In an effort to find dual acting compounds, Chaudhary et al. designed a series of cinnoline derivativesInIn an an effortwith effort pyrazolineto to find find dual dual23 actingor acting without compounds, compounds, a pyrazoline Chaudhary Chaudhary nucleus et 22 etal. (Figureal. designed designed 14) asa aseries anti-inflammatory series of of cinnoline cinnoline derivativesandderivatives antibacterial with with pyrazoline agents. pyrazoline It has 23 23 beenor or without without shown a that pyrazolinea pyrazoline cinnolines nucleus nucleus bearing 22 22pyrazoline (Figure (Figure 14) 14) ring as as anti-inflammatory23 anti-inflammatory(Figure 14) and andhavingand antibacterial antibacterial electron donating agents. agents. It functional Ithas has been been groups shown shown atthat thethat cinnolines phenyl cinnolines moiety bearing bearing (methoxyl pyrazoline pyrazoline and hydroxyl)ring ring 23 23 (Figure (Figure exhibited 14) 14) and the and havinghighesthaving electron anti-inflammatory electron donating donating functional activity. functional In groups case groups of at antibacterial atthe the phenyl phenyl activity, moie moietyty an(methoxyl (methoxyl electron and withdrawing and hydroxyl) hydroxyl) substituent exhibited exhibited theatthe the highest phenylhighest anti-inflammatory groupanti-inflammatory of cinnoline derivativesactivity. activity. In In withoutcase case of of pyrazolineantibacterial antibacterial ring activity, 22activity,(Figure an an 14electron ),electron as well withdrawing aswithdrawing hydroxyl substituentsubstitutionsubstituent at of atthe the the phenyl phenyl ringgroup group of of cinnoline of cinno cinnoline derivativesline derivatives derivatives with without awithout pyrazoline pyrazoline pyrazoline moiety, ring werering 22 22 associated(Figure (Figure 14), 14), with as as wellincreasedwell as as hydroxyl hydroxyl activity substitution against substitution G+ ( S.of of aureusthe the phenyl ,phenylB. subtilis ring ring )of and of cinnoline cinnoline G bacteria derivatives derivatives (E. coli )[with 31with]. a pyrazolinea pyrazoline moiety, moiety, werewere associated associated with with increased increased activity activity against against G+ G+ (S. ( S.aureus aureus− , B., B.subtilis subtilis) and) and G −G bacteria− bacteria (E. (E. coli coli) [31].) [31].

R = 4-OCH ; 4-Cl; 2-OH; 4-OH; 4-NO ; H R = 4-OCH3 3; 4-Cl; 2-OH; 4-OH; 4-NO2 2; H

O O O O N O O N N N F F F F R R R R N N Cl Cl N N N N Cl Cl N N 22 2323 22 Figure 14. Cinnoline derivatives with dual anti-inflammatory and antibacterial activity. FigureFigure 14. 14. Cinnoline Cinnoline derivatives derivatives with with dual dual anti-inflammatory anti-inflammatory an and antibacteriald antibacterial activity. activity. A series of dual acting pyrazolo[4,3-c]cinnoline derivatives were also obtained by Tonk and A series of dual acting pyrazolo[4,3-c]cinnoline derivatives were also obtained by Tonk and co- co-workers.A series It wasof dual elucidated acting pyrazolo[4,3- that compoundsc]cinnoline with an derivatives electron donating were also group obtained in the by benzoyl Tonk and ring co- workers. It was elucidated that compounds with an electron donating group in the benzoyl ring exhibitedworkers. higher It was anti-inflammatoryelucidated that compounds activity than with compounds an electron with donating a benzoyl group ring in the substituted benzoyl byring exhibited higher anti-inflammatory activity than compounds with a benzoyl ring substituted by electronexhibited withdrawing higher anti-inflammatory groups. Moreover, activity a methylene than compounds spacer between with a benzoyl the phenyl ring group substituted and the by electronelectron withdrawing withdrawing groups. groups. Moreover, Moreover, a amethylene methylene spacer spacer between between the the phenyl phenyl group group and and the the carbonyl carbon increased anti-inflammatory activity, whereas the O-CH2 group caused a considerable carbonyl carbon increased anti-inflammatory activity, whereas the O-CH2 group caused a decreasecarbonyl in activity.carbon Compoundsincreased anti-inflammatory that exhibited excellent activity, protection whereas against the inflammationO-CH2 group24 causedand 25, a considerable decrease in activity. Compounds that exhibited excellent protection against depictedconsiderable in Figure decrease 15, also in showed activity. a strong Compounds cyclooxygenase-2 that exhibited (COX-2) excellent binding profile.protection They against were inflammation 24 and 25, depicted in Figure 15, also showed a strong cyclooxygenase-2 (COX-2) consideredinflammation safer 24 in and terms 25, of depicted gastric ulcerogenicity in Figure 15, and also lipid showed peroxidation a strongactivity cyclooxygenase-2 than the standard (COX-2) binding profile. They were considered safer in terms of gastric ulcerogenicity and lipid peroxidation drugbinding naproxen. profile. In They case were of antibacterial considered activity,safer in term compoundss of gastric with ulcerogenicity a 4-nitro- (26 and) or 2,4-dichlorolipid peroxidation (27) activity than the standard drug naproxen. In case of antibacterial activity, compounds with a 4-nitro- substituentactivity than at thethe benzoylstandard group drug naproxen. exhibited significantIn case of antibacterial activity against activity, G (compoundsE. coli and P. with aeruginosa a 4-nitro-) (26) or 2,4-dichloro (27) substituent at the benzoyl group exhibited significant− activity against G− (E. and(26 G) or+ (2,4-dichloroS. aureus) bacterial (27) substituent strains. However,at the benzoyl compounds group exhi withbited an unsubstitutedsignificant activity phenyl against ring G and− (E. coli and P. aeruginosa) and G+ (S. aureus) bacterial strains. However, compounds with an methylenecoli and spacerP. aeruginosa28 (Figure) and 15) wereG+ (S. found aureus to be) bacterial the best dualstrains. anti-inflammatory However, compounds and antibacterial with an unsubstituted phenyl ring and methylene spacer 28 (Figure 15) were found to be the best dual anti- agentunsubstituted (with significant phenyl activity ring and against methylene all three spacer strains) 28 (Figure [32]. 15) were found to be the best dual anti- inflammatoryinflammatory and and antibacterial antibacterial agent agent (with (with significant significant activity activity against against all all three three strains) strains) [32]. [32]. R X X R

O O 2424 R =R 4-methylphenyl;= 4-methylphenyl; X =X -= - N N N N 2525 R =R 4-methoxyphenyl;= 4-methoxyphenyl; X =X -= - 2626 R =R 4-nitrophenyl;= 4-nitrophenyl; X =X -= - F CH F CH3 3 2727 R =R 2,4-dichlorophenyl;= 2,4-dichlorophenyl; X =X -= - 28 R = phenyl; X = CH 28 R = phenyl; X = CH2 2 N N Cl Cl N N

FigureFigure 15. 15. SelectedSelected Selected pyrazolo[4,3- pyrazolo[4,3-c]-cinnoline]-cinnolinec]-cinnoline derivatives. derivatives.

CinnolineCinnoline derivatives derivatives have have have been been been also also also reported reported as as as phosphodiesterase phosphodiesterase 4 4 (PDE4)4 (PDE4) (PDE4) inhibitors inhibitors inhibitors [33]. [ 33[33].]. PDE4PDE4 isis theisthe the predominant predominant predominant isoenzyme isoenzyme isoenzyme in almostin in almost almost all immune all all immune immune and inflammatory and and inflammatory inflammatory cells and cells iscells an and important and is isan an importantregulatorimportant of regulator cyclicregulator adenosine of of cyclic cyclic monophosphateadenosine adenosine monophos monophos (cAMP)phatephate content (cAMP) (cAMP) in airway content content smooth in in airway airway muscle. smooth smooth Inhibition muscle. muscle. of InhibitionPDE4Inhibition leads of toof PDE4 bronchodilation PDE4 leads leads to to bronchodilation andbronchodilation the reduction and and in the the the reduction production reduction in ofin the inflammatorythe production production mediatorsof of inflammatory inflammatory such as α mediatorstumormediators necrosis such such factor as as tumor tumor (TNF- necrosis necrosis) by cAMP factor factor down (TNF- (TNF- regulation.α)α by) by cAMP cAMP A PDE4down down inhibitorregulation. regulation. could A APDE4 be PDE4 used inhibitor inhibitor as a potential could could beanti-inflammatorybe used used as as a potentiala potential agent anti-inflammatory anti-inflammatory in chronic obstructive agent agent in pulmonary in chronic chronic obstructive obstructive disease (COPD), pulmonary pulmonary asthma, disease disease rhinitis (COPD), (COPD), and asthma,asthma, rhinitis rhinitis and and rheumatoid rheumatoid arthritis arthritis [34]. [34]. Structurally Structurally related related to to quinoline quinoline PDE4 PDE4 inhibitors, inhibitors, 3- 3- amido-4-anilinocinnolineamido-4-anilinocinnoline 29 29 has has been been designed designed by by Lunniss Lunniss et etal. al. in in order order to to overcome overcome the the poor poor

Molecules 2019, 24, 2271 8 of 25 rheumatoid arthritis [34]. Structurally related to quinoline PDE4 inhibitors, 3-amido-4-anilinocinnoline 29Moleculeshas been 2019, 24 designed, x by Lunniss et al. in order to overcome the poor pharmacokinetic profile8 of in25 the cynomolgus monkey [33]. Compound 29 (Figure 16) retained excellent in vitro potency and pharmacokinetic profile in the cynomolgus monkey [33]. Compound 29 (Figure 16) retained excellent >pharmacokinetic100-fold selectivity profile versus in the other cynomolgus PDE isoenzymes monkey with [33]. improved Compound pharmacokinetics 29 (Figure 16) retained in the monkey excellent in in vitro potency and >100-fold selectivity versus other PDE isoenzymes with improved comparisonin vitro potency to the quinolineand >100-fold analog [33selectivity]. versus other PDE isoenzymes with improved pharmacokinetics in the monkey in comparison to the quinoline analog [33].

O HCNN

S CONH 2 O N N

29 Figure 16. The most promising phosphodiesterase 4 (PDE4) inhibitor with a cinnoline nucleus. Figure 16. The most promising phosphodiesterase 4 (PDE4) inhibitor with a cinnoline nucleus. Vanilloid receptor subtype VR1 (TRPV1) present in various brain regions, the spinal cord, peripheralVanilloid sensory receptor neurons subtype and VR1 non-neuronal (TRPV1) present tissues in is various considered brain as regions, a new the target spinal for cord, pain managementperipheral sensory but all naturalneurons vanilloid and non-neuronal receptor agonists tissu suches is as considered capsaicin cause as a an new initial target burning for epainffect. TRPV1management competitive but all antagonists, natural vanilloid which lackreceptor excitatory agonists effects, such were as capsaicin designed cause and evaluated an initialin burning vivo in animaleffect. TRPV1 pain models. competitive Urea antagonists, derivative bearing which cinnolinelack excitatory group effects,30 (Figure were 17 designed) was synthesized and evaluated among in othervivo in compounds animal pain with models. various Urea bicyclic derivative heteroaromatic bearing cinnoline pharmacophores group 30 as(Figure novel 17) potential was synthesized analgesics actingamong through other compounds the TRPV1 with receptor various antagonism bicyclic ([hete35]roaromatic and references pharmacophores therein). as novel potential analgesics acting through the TRPV1 receptor antagonism ([35] and references therein). O Cl HN NH

Cl N N

30 Figure 17. Urea derivative bearing a cinnoline nucleus evaluated as Vanilloid receptor subtype VR1 Figure 17. Urea derivative bearing a cinnoline nucleus evaluated as Vanilloid receptor subtype VR1 (TRPV1) receptor antagonist. (TRPV1) receptor antagonist. Since Bruton’s tyrosine kinase (BTK) is a kinase implicated in autoimmune disorders, BTK inhibitionSince isBruton’s considered tyrosine as an kinase attractive (BTK) approach is a kina forse the implicated treatment ofin autoimmuneautoimmune diseasesdisorders, such BTK as rheumatoidinhibition is arthritisconsidered [36 as]. Inan 2013,attractive scientists approach from for Takeda the treatment Pharmaceutical of autoimmune Company diseases Ltd. patented such as cinnolinerheumatoid derivatives arthritis [36]. of general In 2013, formula scientists31 depicted from Takeda in Figure Pharmaceutical 18 as BTK inhibitors Company [37 Ltd.]. In addition,patented cinnoline derivatives of general formula 31 depicted in Figure 18 as BTK inhibitors [37]. In addition, thecinnoline discovery derivatives of a series of general of 4-aminocinnoline-3-carboxamides formula 31 depicted in Figure 18 that as BTK exhibited inhibitors BTK [37]. inhibition In addition, were the discovery of a series of 4-aminocinnoline-3-carboxamides that exhibited BTK inhibition were reportedthe discovery by Smith of a et series al. A fragment-basedof 4-aminocinnoline-3-carboxamides screening approach incorporating that exhibited X-ray BTK co-crystallography inhibition were reported by Smith et al. A fragment-based screening approach incorporating X-ray co- wasreported used toby identify Smith aet cinnoline al. A fragmentfragment-based and characterize screening its approach binding mode.incorporating Optimization X-ray of theco- crystallography was used to identify a cinnoline fragment and characterize its binding mode. fragmentcrystallography hit resulted was inused the identificationto identify a of cinnoline compound fragment32 (Figure and 18), characterize an orally absorbed, its binding noncovalent mode. Optimization of the fragment hit resulted in the identification of compound 32 (Figure 18), an orally BTKOptimization inhibitor of reducing the fragment paw swelling hit resulted in a in dose- the identification and exposure-dependent of compound fashion 32 (Figure in a 18), rat modelan orally of absorbed, noncovalent BTK inhibitor reducing paw swelling in a dose- and exposure-dependent collagen-inducedabsorbed, noncovalent arthritis BTK [38 ].inhibitor reducing paw swelling in a dose- and exposure-dependent fashion in a rat model of collagen-induced arthritis [38].

Molecules 2019, 24, 2271 9 of 25 Molecules 2019, 24, x 9 of 25

MoleculesMolecules 2019 2019, ,24 24, ,x x NH2 O 99 of of 25 25

NH O NH NH22 O 2 1 2 R N R HON N NHNH22 3 1 R R 1 N 22 R N RR HOHONN NH2 NN 33 RR4 N R N NHNH22 NH 5 R 4 NN N R 4 N R N NHNH 3155 32 RR NN FigureFigure 18. Structure18. Structure of 4-aminocinnoline-3-carboxamideof 4-aminocinnoline-3-carboxamide derivati derivativesves that that exhibit exhibit Bruton’s Bruton’s tyrosine tyrosine 3131 3232 kinasekinase (BTK) (BTK) inhibition inhibition activity. activity. FigureFigure 18.18. StructureStructure ofof 4-aminocinnoline-3-carboxamide4-aminocinnoline-3-carboxamide derivatiderivativesves thatthat exhibitexhibit Bruton’sBruton’s tyrosinetyrosine CinnolinekinaseCinnolinekinase (BTK)(BTK) derivatives derivatives inhibitioninhibition wereactivity.activity. were also also evaluatedevaluated as human human neutrophil neutrophil elastase elastase (HNE) (HNE) inhibitors. inhibitors. ExcessiveExcessive HNE HNE activity activity is is connected connected with many many inflammatory inflammatory disorders disorders and compounds and compounds which are which are ableable toCinnolineCinnolineto inhibitinhibit derivatives thederivativesthe proteolyticproteolytic werewere activity activityalsoalso evaluatedevaluated of of HN HNEE asasrepresent representhumanhuman neutrophilpromisingneutrophil promising therapeuticelastaseelastase therapeutic (HNE)(HNE) agents inhibitors. agentsinhibitors. for the for the treatmentExcessivetreatmentExcessive of diseases HNEHNEof diseases activityactivity involving involving isis connectedconnected its its excessive excessivewithwith manymany activity.activity. inflammatoryinflammatory Potential Potential disordersdisorders HNE HNE inhibitors andand inhibitors compoundscompounds bearing bearing which whichcinnoline cinnoline areare able to inhibit the proteolytic activity of HNE represent promising therapeutic agents for the scaffoldsscaffoldsable wereto inhibit were designed designedthe byproteolytic transformation by transformation activity ofof indazole HNof Eindazole represent into theinto promising cinnolinethe cinnoline bytherapeutic enlargement by enlargement agents of thefor of pyrazolethe treatmentpyrazoletreatment ringofof diseasesdiseases of the Ninvolvinginvolving-benzoylindazoles itsits excessiveexcessive reported activity.activity. earlier PotentialPotential [39,40]. HNEHNE Studies inhibitorsinhibitors revealed bearingbearing that cinnolinecinnolinealthough ring of the N-benzoylindazoles reported earlier [39,40]. Studies revealed that although cinnoline scaffoldscinnolinescaffolds werewerederivatives designeddesigned (33 by byand transformationtransformation 34 were the ofmostof indazoleindazole potent) intointo (Figure thethe cinnoline cinnoline19) were bybyreversible enlargementenlargement competitive ofof thethe derivatives (33 and 34 were the most potent) (Figure 19) were reversible competitive inhibitors of pyrazoleinhibitorspyrazole ring ringof HNE ofof thethe with NN-benzoylindazoles-benzoylindazoles increased stability reportedreported in aqueous earlierearlier solution, [39,[39,40].40]. they StudiesStudies exhibited revealedrevealed lower thatthat potency althoughalthough in HNEcinnolinecomparisoncinnoline with increased derivativesderivatives to N-benzoylindazoles stability ((3333 andand in 34 aqueous34 werewere ([41] theandthe solution, most mostreferences potent)potent) they therein). exhibited(Figure(Figure 19)19) lower werewere potencyreversiblereversible in competitivecompetitive comparison to N-benzoylindazolesinhibitorsinhibitors ofof HNEHNE ([ 41withwith] and increasedincreased references stabilityOstability therein). inin aqueousaqueous solution,solution, theytheyO exhibitedexhibited lowerlower potencypotency inin comparisoncomparison toto NN-benzoylindazoles-benzoylindazoles ([41]([41] andand referencesreferences therein).therein). OO OO N N N N

NN CH3 NN O NN O NN

CHCH33 OO OO 33 34

Figure 19. The most potent cinnoline3333 human neutrophil elastase3434 (HNE) reversible competitive inhibitors. FigureFigureFigure 19. The 19.19. mostTheThe most potentmost potentpotent cinnoline cinnolinecinnoline human humanhuman neutrophil neutrophilneutrophil elastase elastaseelastase (HNE) (HNE)(HNE) reversible reversiblereversible competitive competitivecompetitive inhibitors. inhibitors.Ainhibitors. cinnoline fused Mannich base with a large hydrophobic diphenyl substituent at amino group A35 cinnoline(Figure 20) fused exhibited Mannich higher base analgesic with aactivity large hydrophobicwhen compared diphenyl to diclofenac substituent at 120 min at amino and 180 group 35 (Figuremin.A A 20In cinnolinecinnoline )addition, exhibited fusedfused its higher MannichMannichdose analgesiclevel basebase (50 withwith activitymg/kg) aa largelarge whenresu hydrophobichydrophobiclted compared in similar diphdiph toenylenyl diclofenacanti-inflammatory substituentsubstituent at 120 atat amino minamino activity and groupgroup 180in min. In addition,35comparison35 (Figure(Figure its 20)20) doseto exhibited exhibitedcelecoxib level (50higher(20higher mg/kg). mg analgesic/analgesickg) What resulted activityactivity is more, in when similarwhen compound comparedcompared anti-inflammatory 35 as toto well diclofenacdiclofenac as 36 (with activityatat 120120 a dicyclohexane minmin in andand comparison 180180 to celecoxibmin.moiety)min. InIn (20addition,(Figureaddition, mg /kg).20) itsits also Whatdosedose exhibited levellevel is more, (50(50 antibacterial mg/kg) compoundmg/kg) resuresu aclted35ltedtivityas inin wellwith similarsimilar asa larger 36 anti-inflammatoryanti-inflammatory(with zone a dicyclohexaneof inhibition activityactivity when moiety)inin (Figurecomparisoncomparedcomparison 20) also to toto exhibitedstreptomycin celecoxibcelecoxib antibacterial(20(20 in mg/kg).mg/kg). S. aureus WhatWhat activityand isis E. more,more, coli with, respectively compoundcompound a larger 3535[42]. zone asas wellwell of inhibitionasas 3636 (with(with a whena dicyclohexanedicyclohexane compared to moiety) (Figure 20) also exhibited antibacterial activity with a larger zone of inhibition when streptomycinmoiety) (Figure in S. aureus 20) alsoand exhibitedE. coli, respectively antibacterial [ 42ac].tivity with a larger zone of inhibition when comparedcompared toto streptomycinstreptomycin inin S.S. aureusaureus andand E.E. colicoli,, respectivelyrespectively [42].[42].

O N R OO N N R = N N RR N R = NN R = NN NN 35, 36

35, 36 35, 36

Figure 20. Cinnoline fused Mannich base derivatives. Molecules 2019, 24, x 10 of 25 Molecules 2019,, 24,, 2271x 10 of 25

FigureFigure 20.20. CinnolineCinnoline fusedfused MannichMannich basebase derivatives.derivatives. 2.3. Potential for Neurological Disorders 2.3.2.3. PotentialPotential forfor NeurologicalNeurological DisordersDisorders Compounds bearing a cinnoline nucleus fused with various heterocyclic scaffolds were also designedCompoundsCompounds as potential bearingbearing therapeutic aa cinnolinecinnoline agents nucleusnucleus aiming atfusedfused treating withwith many variousvarious neurological heterocyclicheterocyclic and psychiatricscaffoldsscaffolds werewere disorders alsoalso designede.g.,designed Huntington’s asas potentialpotential [43] ortherapeutictherapeutic Alzheimer’s agentsagents disease aimingaiming [44]. atat treatingtreating manymany neurolneurologicalogical andand psychiatricpsychiatric disordersdisordersAmer e.g.,e.g., et al. Huntington’sHuntington’s synthesized [43][43] dibenzopyrazolocinnolines oror Alzheimer’sAlzheimer’s diseasedisease [44].and[44]. evaluated their antiparkinsonian activity. TheAmer pharmacologicalAmer etet al.al. synthesizedsynthesized screening dibenzopyrazolocinnolinesdibenzopyrazolocinnolines revealed that the most active andand compounds evaluatedevaluated their37theirand antiparkinsonianantiparkinsonian38, depicted in activity.Figureactivity. 21 TheThe, exhibited pharmacologicalpharmacological antiparkinsonian screeningscreening activity rerevealedvealed comparable thatthat thethe mostmost to benzatropine activeactive compoundscompounds [45]. 3737 andand 38,38, depicteddepicted inin FigureFigure 21,21, exhibitedexhibited antiparkinsonianantiparkinsonian activityactivity comparablecomparable toto benzatropinebenzatropine [45].[45].

OO NN NN NHNH

OO NN NN N N N N N N NHNH NN N NN N 22

37 3838 37 Figure 21. Dibenzopyrazolocinnolines with antiparkinsonian activity. FigureFigure 21.21. DibenzopyrazolocinnolinesDibenzopyrazolocinnolines withwith antiparkinsonianantiparkinsonian activity.activity. Mutations in the leucine-rich repeat kinase 2 (LRRK2) protein have been associated with Mutations in the leucine-rich repeat kinase 2 (LRRK2) protein have been associated with Parkinson’sMutations disease. in the Inhibition leucine-rich of LRRK2repeat kinase activity2 (LRRK2) by aprotein selective have small-molecule been associated inhibitor with Parkinson’s disease. Inhibition of LRRK2 kinase activity by a selective small-molecule inhibitor has hasParkinson’s been proposed disease. as Inhibition a potential of treatment LRRK2 kinase for this ac diseasetivity by [46 a]. selective Scientists small-molecule from Elan Pharmaceuticals inhibitor has been proposed as a potential treatment for this disease [46]. Scientists from Elan Pharmaceuticals workedbeen proposed on a series as a ofpotential cinnoline treatment LRRK2 small-moleculefor this disease inhibitors[46]. Scientists identified from fromElan aPharmaceuticals kinase-focused worked on a series of cinnoline LRRK2 small-molecule inhibitors identified from a kinase-focused highworked throughput on a series screening of cinnoline (HTS) LRRK2 of an in-housesmall-mole librarycule inhibitors [47]. In addition, identified Garofalo from a kinase-focused et al. reported high throughput screening (HTS) of an in-house library [47]. In addition, Garofalo et al. reported 4- 4-aminocinnoline-3-carboxamidehigh throughput screening (HTS) of derivatives an in-house39, libr40 ary(Figure [47]. 22In) addition, potent against Garofalo both et wild-typeal. reported and 4- aminocinnoline-3-carboxamide derivatives 39, 40 (Figure 22) potent against both wild-type and mutantaminocinnoline-3-carboxamide LRRK2 kinase activity inderivatives biochemical 39, and40 (Figure cellular 22) assays. potent In against addition, both these wild-type compounds and mutant LRRK2 kinase activity in biochemical and cellular assays. In addition, these compounds exhibitedmutant LRRK2 excellent kinase central activity nervous in biochemical system penetration. and cellular Unfortunately, assays. In dueaddition, to disappointing these compounds kinase exhibited excellent central nervous system penetration. Unfortunately, due to disappointing kinase specificity,exhibited excellent they were central no longer nervous studied system [48]. penetration. Unfortunately, due to disappointing kinase specificity,specificity, theythey werewere nono longerlonger studiedstudied [48].[48]. RR NHNH OO RR NHNH OO NH NH22 NH NN NH22 N N N O N O NN SS NN OO 40 39 40 39 Figure 22. General structures of cinnoline leucine-rich repeat kinase 2 (LRRK2) inhibitors. FigureFigure 22.22. GeneralGeneral structuresstructures ofof cinnolicinnolinene leucine-richleucine-rich repeatrepeat kikinasenase 22 (LRRK2)(LRRK2) inhibitors.inhibitors. The phosphodiesterase 10A (PDE10A) enzyme is involved in cellular signaling pathways in schizophrenia.TheThe phosphodiesterasephosphodiesterase As a consequence, 10A10A inhibitors(PDE10A)(PDE10A) of enzymeenzyme PDE10A isis o involvedffinvolveder a promising inin cellularcellular therapeutic signalingsignaling approach pathwayspathways for the inin schizophrenia.treatmentschizophrenia. or prevention AsAs aa consequence,consequence, of psychiatric inhibitorsinhibitors disorders, ofof PDE10APDE10A especially offeroffer schizophrenia aa promisingpromising and therapeutictherapeutic related diseases approachapproach [49 forfor]. thethe treatmenttreatmentHu et al. or describedor preventionprevention 6,7-dimethoxy-4-(pyridine-3-yl)cinnolines ofof psychiatricpsychiatric disorderdisorders,s, especiallyespecially schizophreniaschizophrenia as novel phosphodiesterase andand relatedrelated diseasesdiseases 10A [49].inhibitors.[49]. The mode of binding in the enzyme’s catalytic domain was also elucidated. Selective inhibitor of PDE10AHuHu etet al.al.41 describeddescribed(Figure 23 6,7-dimethoxy-4-(pyridine-3-yl)cinnolines6,7-dimethoxy-4-(pyridine-3-yl)cinnolines) was selected. It demonstrated efficacy as inas novel anovel rodent phosphodiesterasephosphodiesterase behavioral model 10A10A of inhibitors.schizophreniainhibitors. TheThe andmodemode good ofof bindinginbinding vivo metabolic inin thethe enzyme’senzyme’s stability catalyticcatalytic in rats [ 50domaindomain]. Yang waswas et al.alsoalso described elucidated.elucidated. high SelectiveSelectivein vitro inhibitorpotencyinhibitorof ofof compounds PDE10APDE10A 414141 (Figure(Figureand 42 (Figure 23)23) waswas 23 selected.)selected. for PDE10A ItIt demonstrateddemonstrated with the half maximal efficacyefficacy inhibitoryinin aa rodentrodent concentration behavioralbehavioral modelmodel ofof schizophreniaschizophrenia andand goodgood inin vivovivo metabolicmetabolic stabilitystability inin ratsrats [50].[50]. YangYang etet al.al. describeddescribed highhigh inin (IC50) values of 1.52 0.18 nM and 2.86 0.10 nM, respectively and 1000-fold selectivity over vitrovitro potencypotency ofof compoundscompounds± 4141 andand 4242 (Figure(Figure± 23)23) forfor PDE10APDE10A withwith thethe halfhalf maximalmaximal inhibitoryinhibitory concentrationconcentration (IC(IC5050)) valuesvalues ofof 1.521.52 ±± 0.180.18 nMnM andand 2.862.86 ±± 0.100.10 nM,nM, respectivelyrespectively andand 1000-fold1000-fold selectivityselectivity

Molecules 2019, 24, 2271 11 of 25 Molecules 2019, 24, x 11 of 25 Molecules 2019, 24, x 11 of 25

PDE3Aover PDE3A/B/B and PDE4A and PDE4A/B./B. These These compounds compounds were alsowere suitable also suitable for positron for positron emission emission tomography tomography (PET) over PDE3A/B and PDE4A/B. These compounds were also suitable for positron emission tomography radionuclide(PET) radionuclide labelling labelling [51]. [51]. (PET) radionuclide labelling [51].

F F HNO HNO HNO HNO

N N N N

N N N N

O O O O

N N N O N N O N O N O N

42 41 42 41 FigureFigure 23.23. Structure of 6,7-dimethoxy-4-(pyridine-3-yl)cinnolines6,7-dimethoxy-4-(pyridine-3-yl)cinnolines withwith potentpotent phosphodiesterasephosphodiesterase 10A10A Figure 23. Structure of 6,7-dimethoxy-4-(pyridine-3-yl)cinnolines with potent phosphodiesterase 10A (PDE10A)(PDE10A) inhibitoryinhibitory activity.activity. (PDE10A) inhibitory activity.

SinceSince some 6,7-dimethoxy-4-(pyridine-3-yl)cinnolines 6,7-dimethoxy-4-(pyridine-3-yl)cinnolines also also exhibited exhibited PDE3 PDE3 activity activity (a risk (a risk of off- of Since some 6,7-dimethoxy-4-(pyridine-3-yl)cinnolines also exhibited PDE3 activity (a risk of off- otargetff-target effects), effects), optimization optimization of structure of structure 43 43(Figure(Figure 24) 24 led) led to the to the discovery discovery of ofcompounds compounds 44 44andand 45 target effects), optimization of structure 43 (Figure 24) led to the discovery of compounds 44 and 45 45(Figure(Figure 24) 24 with) with significantly significantly improved improved selectiv selectivityity against against PDE3 PDE3 but but maintaining their PDE10APDE10A (Figure 24) with significantly improved selectivity against PDE3 but maintaining their PDE10A inhibitoryinhibitory activityactivity andand inin vivovivo metabolicmetabolic stabilitystability comparablecomparable toto43 43(Figure (Figure 24 24))[ [52].52]. inhibitory activity and in vivo metabolic stability comparable to 43 (Figure 24) [52].

OH OH OH OH OH OH

N N N N N N CHF 2 N N N CHF 2 N N N

O O O O O O

N N N N N O N O N O N N O N O N O N

43 44 45 43 44 45 FigureFigure 24.24. PDE10A inhibitors with improved selectivity.selectivity. Figure 24. PDE10A inhibitors with improved selectivity. Recently, Geneste et al. described the optimization of HTS hit structure 46 (Figure 25) supported Recently, Geneste et al. described the optimization of HTS hit structure 46 (Figure 25) supported by X-rayRecently, crystal Geneste structure et al. analysis described and th moleculare optimization modeling of HTS which hit gavestructure 3H-pyrazolo[3,4- 46 (Figure 25)c]cinnolines supported by X-ray crystal structure analysis and molecular modeling which gave 3H-pyrazolo[3,4-c]cinnolines 47by andX-ray48 crystal(Figure structure 25), which analysis are potent, and molecular selective modeling and brain-penetrant which gave 3 PDE10AH-pyrazolo[3,4- inhibitorsc]cinnolines with an 47 and 48 (Figure 25), which are potent, selective and brain-penetrant PDE10A inhibitors with an improved47 and 48 pharmacokinetic(Figure 25), which profile are potent, in rats [53selective]. Preparation and brain-penetrant of 3H-pyrazolo[3,4- PDE10Ac]cinnoline inhibitors derivatives with an improved pharmacokinetic profile in rats [53]. Preparation of 3H-pyrazolo[3,4-c]cinnoline derivatives asimproved PDE10A pharmacokinetic inhibitors was also profile the subjectin rats [53]. of patent Preparation WO2014 of/ 0270783H-pyrazolo[3,4- [54]. c]cinnoline derivatives as PDE10A inhibitors was also the subject of patent WO2014/027078 [54]. as PDE10A inhibitors was also the subject of patent WO2014/027078 [54].

Molecules 2019, 24, 2271 12 of 25 Molecules 2019, 24, x 12 of 25

N N N N N N N NH O NH N F N O N N N N N N N O O O O

48 46 47 48 46 Figure 25. Selected 3H-pyrazolo[3,4-c]cinnolines that act as potent, selective and brain-penetrant Figure 25. Selected 3H-pyrazolo[3,4-c]cinnolines that act as potent, selective and brain-penetrant PDE10A inhibitors. PDE10A inhibitors. The cinnoline scaffold turned out to be a useful building block in designing compounds targeting The cinnoline scaffold turned out to be a useful building block in designing compounds histamine receptor H3. Involvement of the H3 receptor subtype in the presynaptic regulation targeting histamine receptor H3. Involvement of the H3 receptor subtype in the presynaptic regulation oftargeting the release histamine of various receptor neurotransmitters H3. Involvement inof the the H central3 receptor nervous subtype system in the makespresynaptic it an regulation attractive of the release of various neurotransmitters in the central nervous system makes it an attractive target targetof the release for treating of various diseases neurotransmitters such as attention-deficit in the central hyperactivity nervous system disorder, makes Alzheimer’sit an attractive disease, target for treating diseases such as attention-deficit hyperactivity disorder, Alzheimer’s disease, mild mildfor treating cognitive diseases impairment such as and attention-deficit schizophrenia. hyperactivity Josef and co-workers disorder, obtainedAlzheimer’s compounds disease, withmild cognitive impairment and schizophrenia. Josef and co-workers obtained compounds with the thecognitive tricyclic impairment benzocinnolinone and schizophrenia. pyridazinone Josef core and as co-workers analogues ofobtained irdabisant. compounds The compounds with the tricyclic benzocinnolinone pyridazinone core as analogues of irdabisant. The compounds 2H- 2H-benzo[h]cinnolin-3-ones and 3H-benzo[f ]cinnolin-2-ones exhibited high H3 receptor binding benzo[h]cinnolin-3-ones and 3H-benzo[f]cinnolin-2-ones exhibited high H3 receptor binding affinity affinity with excellent selectivity against the H1R, H2R and H4R subtypes of histamine receptor. with excellent selectivity against the H1R, H2R and H4R subtypes of histamine receptor. Modification Modificationwith excellent toselectivity the linker against/amine the region H1R, H of2R the and pharmacophore H4R subtypes of resultedhistamine in receptor.49 as aModification mixture of to the linker/amine region of the pharmacophore resulted in ±49 as a mixture± of diastereoisomers diastereoisomersto the linker/amine (Figure region 26 of), whichthe pharmacophore showed improved resulted metabolic in ±49 stability as a mixture and rat of pharmacokinetics diastereoisomers (Figure 26), which showed improved metabolic stability and rat pharmacokinetics following oral following(Figure 26), oral which administration showed improved ([55] and metabolic references stability therein). and rat pharmacokinetics following oral administration ([55] and references therein). H N N OO

N +/- 49

Figure 26. Potent benzocinnolinone analogue of irdabisant with high histamine receptor H3 H3R Figure 26. Potent benzocinnolinone analogue of irdabisant with high histamine receptor H3 H3R binding affinity. binding affinity. Cinnoline derivatives are also enumerated among non-benzodiazepine modulators of Cinnoline derivatives are also enumerated among non-benzodiazepine modulators of γ- γ-aminobutyric acid receptor A (GABA A) [56]. Astra Zeneca works on an orally bioavailable aminobutyric acid receptor A (GABA A) [56]. Astra Zeneca works on an orally bioavailable positive positive modulator of the GABA A α2 and α3 subunits and developed novel compound 50 depicted modulator of the GABA A α2 and α3 subunits and developed novel compound 50 depicted in Figure in Figure 27 as a possible treatment or prophylaxis of anxiety disorders, cognitive disorders, and/or 27 as a possible treatment or prophylaxis of anxiety disorders, cognitive disorders, and/or mood mood disorders [57]. AZD7325 (51) and AZD6280 (52) depicted in Figure 27 were identified as disorders [57]. AZD7325 (51) and AZD6280 (52) depicted in Figure 27 were identified as positive positive modulators at α2/α3 and negative modulators at α5 GABA A receptors and exhibited a modulators at α2/α3 and negative modulators at α5 GABA A receptors and exhibited a potent potent anxiolytic-like effect without sedation or cognitive impairment [13,58]. These compounds anxiolytic-like effect without sedation or cognitive impairment [13,58]. These compounds have have undergone clinical trial phase I [59,60]. Moreover, AZD7325 was studied in two phase II undergone clinical trial phase I [59,60]. Moreover, AZD7325 was studied in two phase II proof-of- proof-of-concept trials in patients with general anxiety disorders (NCT 00807937 and NCT00808249) as concept trials in patients with general anxiety disorders (NCT 00807937 and NCT00808249) as well well as in a phase II proof-of-mechanism in patients with autism spectrum disorders (NCT01966679). as in a phase II proof-of-mechanism in patients with autism spectrum disorders (NCT01966679). In In addition, the diverse metabolite profile of AZD7325 was investigated [61]. In vivo studies in rat addition, the diverse metabolite profile of AZD7325 was investigated [61]. In vivo studies in rat and and in vitro studies in human, rat, mouse, rabbit and dog liver microsomes were performed with in vitro studies in human, rat, mouse, rabbit and dog liver microsomes were performed with radiolabeled AZD7325, revealing approximately 40 metabolites [61,62]. radiolabeled AZD7325, revealing approximately 40 metabolites [61,62].

Molecules 2019, 24, x 13 of 25 Molecules 2019, 24, 2271 13 of 25 Molecules 2019, 24, x 13 of 25 NH2 O 2 NH2 O 3 R NH2 O R HN 2 O NH2 O NH R 4 3 1 NH R R HN O R N NH 4 NH 1 N NH N R R N N NH N 5 N OFN R N O N N 5 6 OF R R N O 6 R O O 50 51 (AZD6280) 52 (AZD7325) 50 51 (AZD6280) 52 (AZD7325) Figure 27. Cinnoline non-benzodiazepine modulators of γ-aminobutyric acid receptor A (GABA A). Figure 27. Cinnoline non-benzodiazepine modulators of γ-aminobutyric acid receptor A (GABA A). Figure 27. Cinnoline non-benzodiazepine modulators of γ-aminobutyric acid receptor A (GABA A). Cinnolinones (53, 54) (Figure 28) as diaza analogues of known aminobutyrophenones were Cinnolinones (53, 54) (Figure 28) as diaza analogues of known aminobutyrophenones were designed as potential atypical psychotics. Determination of the binding affinities towards the designedCinnolinones as potential (53 atypical, 54) (Figure psychotics. 28) as Determination diaza analogues of the of binding known a ffiaminobutyrophenonesnities towards the serotonin were designedserotonin asreceptors potential 5-HT atypical2A and psychotics. 5-HT2C, and Determination the dopamine of theD2 bindingreceptors affinities revealed towards that these the receptors 5-HT2A and 5-HT2C, and the dopamine D2 receptors revealed that these compounds lacked serotonincompounds receptors lacked appreciable 5-HT2A and affinity 5-HT 2Cfor, andthe dopaminethe dopamine D2 receptors, D2 receptors and as revealeda consequence, that these they appreciable affinity for the dopamine D2 receptors, and as a consequence, they were not suited as compoundswere not suited lacked as potentialappreciable psychotics. affinity forHowever, the dopamine they displayed D2 receptors, the highest and as affinity a consequence, for the 5-HT they2C potential psychotics. However, they displayed the highest affinity for the 5-HT2C receptor [63]. werereceptor not [63].suited as potential psychotics. However, they displayed the highest affinity for the 5-HT2C receptor [63]. O O O O

N N N N N N N N N N N N

N O ON O F O F F 53F 54 53 54 Figure 28. Cinnolinone-diaza analogs of known aminobutyrophenones. Figure 28. Cinnolinone-diaza analogs of known aminobutyrophenones. 2.4. Anticancer PropertiesFigure 28. Cinnolinone-diaza analogs of known aminobutyrophenones. 2.4. Anticancer Properties Cinnoline derivatives were also designed as potential anticancer drugs. Extensive studies have 2.4. Anticancer Properties beenCinnoline performed derivatives to assess thewere topoisomerase also designed 1-targeting as potential (TOP1-targeting) anticancer drugs. activity Extensive and studies cytotoxicity have ofbeen substitutedCinnoline performed dibenzo[derivatives to assessc,h the]cinnolines were topoisomerase also designed55, 56 (Figure 1-target as pote 29ingntial) as(TOP1-targeting) non-CPT anticancer (camptothecin) drugs. activity Extensive and TOP1 cytotoxicity studies inhibitors. have of Structure-activitybeensubstituted performed dibenzo[ to relationship assessc,h]cinnolines the topoisomerase (SAR) 55 studies, 56 (Figure 1-target of dibenzo[ 29)ing as (TOP1-targeting) c,hnon-CPT]cinnolines (cam revealedptothecin) activity that and TOP1 removalcytotoxicity inhibitors. of the of methylenedioxysubstitutedStructure-activity dibenzo[ group relationshc,h on]cinnolines theip D (SAR) ring 55 or ,studies its56 replacement(Figure of dibenzo[ 29) byas c,h othernon-CPT]cinnolines substituents (cam revealedptothecin) (methoxy-, that TOP1 removal benzyloxy- inhibitors. of the or hydroxy-Structure-activitymethylenedioxy groups) group resultedrelationsh on in the aip substantial D(SAR) ring orstudies its loss replacemof of TOP1-targeting dibenzo[ent byc,h other]cinnolines activity. substituents Therevealed presence (methoxy-, that of removal 2,3-dimethoxy benzyloxy- of the substituentsmethylenedioxyor hydroxy- ingroups) ring group A wasresulted on also the determined Din ring a substantial or its as replacem a crucial loss ofent structural TOP1-targeting by other element substituents foractivity. retaining (methoxy-, The TOP1 presence activitybenzyloxy- of and2,3- cytotoxicity.ordimethoxy hydroxy- substituents Althoughgroups) resulted the in substitutedring in A a wassubstantial dibenzo[ also determin c,hloss]cinnolines ofed TOP1-targeting as a withcrucial significant structural activity. TOP1-targeting elementThe presence for retaining activityof 2,3- exhibiteddimethoxyTOP1 activity cross-resistance substituents and cytotoxicity. in in ring camptothecin-resistant A Although was also determinthe substituted celled lines, as a dibenzo[ theircrucial cytotoxicity structuralc,h]cinnolines waselement not with diminished for significant retaining in cellsTOP1TOP1-targeting overexpressing activity and activity cytotoxicity. multidrug exhibited resistance Although cross-resistan protein the substituted 1 MDR1ce in [camptothecin-resistant64 dibenzo[]. c,h]cinnolines cellwith lines, significant their TOP1-targetingcytotoxicity was notactivity diminished exhibited in cells cross-resistan overexpressingce in multidrug camptothecin-resistant resistance protein cell 1 MDR1lines, [64].their cytotoxicity was not diminished in cells overexpressing multidrug resistance protein 1 MDR1 [64].

Molecules 2019, 24, x 14 of 25

Molecules 2019, 24, 2271x 14 of 25 Molecules 2019, 24, x 1 14 of 25 OCH 3 R

B A 11 1 OCH 3 R R OCH 3 O R2 OCH R B A 3 1 D C B A R21 N O N 2 RR OCH OO R 2 N OCH33 N R DD CC 2 N N R 2 N O N R NN O NN 55 R1 = H, OCH3; R2 = H, OCH3, OBn, OH; 56 R1 = H, OCH3; R2 = H, OCH3 OBn, OH, CH2OH;

57 R1, R2 = OCH3 55 R1 = H, OCH3; R2 = H, OCH3, OBn, OH; 56 R1 = H, OCH3; R2 = H, OCH3 OBn, OH, CH2OH; 55 R1 = H, OCH3; R2 = H, OCH3, OBn, OH; 56 R1 = H, OCH3; R2 = H, OCH3 OBn, OH, CH2OH; 5757 R R1, ,R R2 = = OCH OCH3 Figure 29. Dibenzo[c,h]cinnoline topoisomerase1 2 1 (TOP1)3 inhibitors. Figure 29. Dibenzo[c,h]cinnoline topoisomerase 1 (TOP1) inhibitors. As a continuationFigureFigure of studies29. 29. Dibenzo[ Dibenzo[ on thec,hc,h ]cinnolinemost]cinnoline potent topoisomerase topoisomerase derivative 1 571 (TOP1) (TOP1), 5,6,11-triazachrysen-12-ones inhibitors. inhibitors. with variousAs asubstituents continuation at of 11-positio studies onn the were most synthesized potent derivative [65]. Compound57, 5,6,11-triazachrysen-12-ones 58 (ARC-31, Figure with 30) As a continuation of studies on the most potent derivative 57, 5,6,11-triazachrysen-12-ones with variousexhibitedAs substituents a ancontinuation enhanced at 11-position ofability studies to wereoninduce the synthesized most DNA potent clea [65vage derivative]. Compound in the 57presence, 5,6,11-triazachrysen-12-ones58 (ARC-31, of TOP1 Figure and 30 exceptional) exhibited with various substituents at 11-position were synthesized [65]. Compound 58 (ARC-31, Figure 30) ancytotoxicvarious enhanced substituentsactivity ability with to induceat IC11-positio50 DNAvalues cleavagen belowwere insynthesized2 thenM presence against [65]. of the TOP1 Compound human and exceptional lymphoblastoma 58 (ARC-31, cytotoxic Figure cell activity line 30) exhibitedexhibited anan enhancedenhanced abilityability toto induceinduce DNADNA cleacleavagevage inin thethe presencepresence ofof TOP1TOP1 andand exceptionalexceptional with(RPMI8402) IC50 values but dose below limiting 2 nM toxicity against limited the human in vivo lymphoblastoma efficacy in the huma celln line tumor (RPMI8402) xenograft but athymic dose cytotoxic activity with IC50 values below 2 nM against the human lymphoblastoma cell line limitingnudecytotoxic mouse toxicity activity model limited (MDA-MB-435with inIC vivo50 valueseffi breastcacy below in tumor the 2 human cellnM line)against tumor [66]. xenografttheIn an human effort athymic tolymphoblastoma obtain nude a less mouse toxic cell analog model line (RPMI8402) but dose limiting toxicity limited in vivo efficacy in the human tumor xenograft athymic (MDA-MB-435with(RPMI8402) improved but breastefficacy, dose limiting tumor a numb cell toxicityer line) of compounds [limited66]. In in an vivo erelatedffort efficacy to to obtain 58 in (Figure the a less huma toxic30)n weretumor analog synthesized xenograft with improved athymic where nude mouse model (MDA-MB-435 breast tumor cell line) [66]. In an effort to obtain a less toxic analog ethenudefficacy, 11-ethyl mouse a number group model ofwas (MDA-MB-435 compounds substituted related atbreast its 2-position to tumor58 (Figure cell with line) 30 )vari were[66].ous In synthesized polar an effort moieties to where obtain (N-methylamino-, the a less 11-ethyl toxic groupanalog N- with improved efficacy, a number of compounds related to 58 (Figure 30) were synthesized where wasisopropylamino-,with substituted improved atefficacy, hydroxy- its 2-position a numb and witherhydroxylamino- of variouscompounds polar groups).related moieties to These (58N-methylamino-, (Figure analogs 30) wereN synthesized-isopropylamino-,prepared via where the the 11-ethyl group was substituted at its 2-position with various polar moieties (N-methylamino-, N- hydroxy-trimethylammoniumthe 11-ethyl and group hydroxylamino- was derivatives substituted groups). of at ARC-31 its These2-position according analogs withwere tovari methodsous prepared polar described moieties via the trimethylammonium (inN -methylamino-,[67]. All analogs N- isopropylamino-, hydroxy- and hydroxylamino- groups). These analogs were prepared via the derivativesexhibitedisopropylamino-, high of ARC-31 cytotoxic hydroxy- according activiand toty.hydroxylamino- methods Although, described derivatives groups). in [67 These]. Allwith analogs analogsN-methylamine exhibited were prepared high 59 cytotoxicand via Nthe- trimethylammonium derivatives of ARC-31 according to methods described in [67]. All analogs activity.isopropylaminetrimethylammonium Although, 60 derivatives(Figure derivatives 31) withexhibited ofN -methylamineARC-31 greater according cytotoxic59 and toactivityN -isopropylaminemethods in vitro described in comparison60 (Figure in [67]. 31 Allto) exhibited ARC-31, analogs exhibited high cytotoxic activity. Although, derivatives with N-methylamine 59 and N- greaterevaluationexhibited cytotoxic inhigh vivo activitycytotoxic in athymicin vitroactivi nudety.in mice comparisonAlthough, showed tominimalderivatives ARC-31, differences evaluationwith N in-methylamine efficacyin vivo inin athymiccomparison 59 and nude toN- isopropylamine 60 (Figure 31) exhibited greater cytotoxic activity in vitro in comparison to ARC-31, miceARC-31isopropylamine showed without minimal therapeutic60 (Figure differences 31) index exhibited improvement in effi cacygreater in comparisoncytotoxic[11]. activity to ARC-31 in vitro without in comparison therapeutic to ARC-31, index evaluationevaluation in in vivo vivo in in athymic athymic nude nude mice mice showed showed minimal minimal differences differences in in efficacy efficacy in in comparison comparison to to improvement [11]. O ARC-31ARC-31 without without therapeutic therapeutic index index improvement improvement [11]. [11]. N OCH 3 N OO

NN OCHOCH3 O N 3 N OCH 3 O N OO OCH N OCH33 N O 58 N O NN 5858 Figure 30. The structure of compound ARC-31. Figure 30. The structure of compound ARC-31. FigureFigure 30. 30. The The structure structure of of compound compound ARC-31. ARC-31. O

X OCH 3 N OO

XX OCHOCH3 O N 3 N OCH 3 O N OO OCH N OCH33 N O 59 X = NHCHN 3 O NN 60 X = NHCH(CH3)2 59 X = NHCH3 59 X = NHCH3 Figure 31. TOP1-acting6060 X X = = NHCH(CH NHCH(CH agents related3)2) to ARC-31. Figure 31. TOP1-acting agents related3 2 to ARC-31. Zoidis and co-workers obtained tetra- and pentacyclic cinnoline based compounds Figure 31. TOP1-acting agents related to ARC-31. indeno[1,2-Zoidis cand]cinnoline co-workers and benzo[obtainedFigure h31.]indeno[1,2- tetra-TOP1-acting and cpe]cinnoline, agentsntacyclic related cinnoline respectively, to ARC-31. based bearing compounds protonable indeno[1,2- amino groups.c]cinnoline All and tested benzo[ compoundsh]indeno[1,2- inhibitedc]cinnoline, proliferation respectively, of human bearin cervicalg protonable carcinoma (HeLa)amino groups. and human All Zoidis and co-workers obtained tetra- and pentacyclic cinnoline based compounds indeno[1,2- breasttestedZoidis adenocarcinomacompounds and co-workers inhibited (MCF-7) obtainedproliferation cell lines tetra- asof and wellhuma pe asntacyclicn displayedcervical cinnoline carcinoma intercalating based (HeLa) compounds properties and human on indeno[1,2- di ffbreasterent c]cinnoline and benzo[h]indeno[1,2-c]cinnoline, respectively, bearing protonable amino groups. All nucleicadenocarcinomac]cinnoline acid strands,and benzo[(MCF-7) withh]indeno[1,2- preference cell lines as forc ]cinnoline,well G-quadruplex as displayed respectively, sequences. intercalating bearin Theg aminobutylamideproperties protonable on amino different derivative groups. nucleic All61 tested compounds inhibited proliferation of human cervical carcinoma (HeLa) and human breast tested compounds inhibited proliferation of human cervical carcinoma (HeLa) and human breast adenocarcinomaadenocarcinoma (MCF-7) (MCF-7) cell cell lines lines as as well well as as displayed displayed intercalating intercalating properties properties on on different different nucleic nucleic

Molecules 2019, 24, 2271 15 of 25 Molecules 2019, 24, x 15 of 25 acid(Figure strands, 32) exhibited with preference the highest for antiproliferative G-quadruplex sequences. activity with The IC 50aminobutylamidevalues of 45 nM andderivative 85 nM 61 on (FigureHeLa and 32) MCF-7,exhibited respectively, the highest whereas antiproliferative the pentacyclic activity derivative with IC50 with values the of same 45 nM protonable and 85 nM moiety on HeLa(N,N-dimethylamine) and MCF-7, respectively,62 (Figure whereas 32) caused the pentacyclic the highest derivative thermal stabilization with the same in melting protonable studies moiety and (exertedN,N-dimethylamine) acceptable inhibitory 62 (Figure activity 32) caused on human the highest topoisomerase thermal IIstabilizationα [68]. in melting studies and exerted acceptable inhibitory activity on human topoisomerase IIα [68]. O N N

NH N N N O N

O O

61 62 Figure 32. Selected indeno[1,2-c]cinnoline) and benzo[h]indeno[1,2-c]cinnoline derivatives. Figure 32. Selected indeno[1,2-c]cinnoline) and benzo[h]indeno[1,2-c]cinnoline derivatives. Borowski and co-workers obtained a series of anthrapyridazone derivatives 63 (Figure 33) bearing Borowski and co-workers obtained a series of anthrapyridazone derivatives 63 (Figure 33) one or two basic side chains at various positions of the tetracyclic core [69,70]. The compounds bearing one or two basic side chains at various positions of the tetracyclic core [69,70]. The 2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-diones 64 and 65 (Figure 33) exhibited in vitro cytotoxic compounds 2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-diones 64 and 65 (Figure 33) exhibited in vitro activity against murine (L1210) and human (K562) leukemia cell lines. In addition, they were active cytotoxic activity against murine (L1210) and human (K562) leukemia cell lines. In addition, they against human leukemia multi-drug-resistant (K562/DX) cell lines. The most active compounds 64 and were active against human leukemia multi-drug-resistant (K562/DX) cell lines. The most active 65 (Figure 33) were also tested in vivo against murine P388 leukemia and showed activity comparable compounds 64 and 65 (Figure 33) were also tested in vivo against murine P388 leukemia and showed to mitoxantrone [71]. activity comparable to mitoxantrone [71].

Molecules 2019, 24, x 16 of 25

MoleculesMolecules2019 2019, 24, ,24 2271, x 16 of16 25 of 25 N 1 NN N O R 10 R 11 R N O N 1 NNABN O RN 10 R 11 when X = O, R1-R3 = H, R1 = (CH ) OH orR (CH ) NR4R5; q = 2-3; R4,R5 = alkyl; or N O AB2 q 2 q N NR4R5 = 6-membered cyclic ring optionally containing additional N or O atoms; R2 = 1 3 61 4 5 4 57 6 when2 NH(CHX = O,2 )RmY-Rn(CH = 2H,)pR R; m= (CH= 0-3;2)qOH n = or 0-1; (CH p2 )=qNR 0-2;R Y; q= =C(O) 2-3; orR NR,R ;= Ralkyl; = H, or OH or Ph; R4 5 7 3 8 9 8 9 2 NR RR = =6-membered H or alkyl; cyclicR = Hring or optionally NH(CH2) rcontainingNR R ; r =additional 1-3; R ,R N or= OH, atoms; alkyl, PhR =substituted 2 6 7 6 X R 2 NH(CHwith2)m Yalkyl;n(CH2)pR ; m = 0-3; n = 0-1; p = 0-2; Y = C(O) or NR ; R = H, OH or Ph; R 7 when X = N,3 R3 = H; R2 is attached8 9 to N atom and8 9 together form the group presented R = H or alkyl; R = H or NH(CH2)rNR R ; r = 1-3; R ,R = H, alkyl, Ph substituted 632 1 , 10 1 11 X R with alkyl;by A or B; R , R =(CH2)2NMe2, R ,R = (CH2)2NEt2; when X = N, R3 = H; R2 is attached to N atom and together form the group presented 63 1 , 10 1 11 by A or B; R , R =(CH1 2)2NMe2, R ,R = (CH2)2NEt2; 1 R R

1 N O 1 N O X R N R N N O N O X N N

O X 3 N 2 2 NH O R R R O X 3 N 2 2 NH O 1 R R R R = H, alkylaminoalkyl; R1 = H, alkylaminoalkyl 2 1 R = H, CH 2 R = H, alkylaminoalkyl;3 R1 = H, Ralkylaminoalkyl = H, alkylaminoalkyl 2 3 R = H, alkylaminoalkyl; 2 R = H, CH3 R = H, alkylaminoalkyl R3 = H,X =alkylaminoalkyl; H, OH; X = H, OH; 64 65 64 65 FigureFigure 33. General 33. General structure structure of 2,7-dihydro-3 of 2,7-dihydro-3H-dibenzo[H-dibenzo[de,h]cinnoline-3,7-diones.de,h]cinnoline-3,7-diones. Figure 33. General structure of 2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-diones. ParrinoParrino et al. et described al. described 11H-pyrido[3 11H-pyrido[30,20:4,5]pyrrolo[3,2-′,2′:4,5]pyrrolo[3,2-c]cinnolinec]cinnoline derivative derivative66 (Figure 66 (Figure 34) 34) whichwhich exhibitedParrino exhibited et highal. described high cytotoxic cytotoxic 11 activityH-pyrido[3 activity against′ ,2against′:4,5]pyrrolo[3,2- a panel a panel of 60ofc ]cinnoline human60 human tumor derivative tumor cell cell lines 66 lines (Figure screened screened 34) by by the thewhich NationalNational exhibited Cancer Cancer high Institute cytotoxicInstitute (Bethesda, activity(Bethe sda,against MD, MD, USA).a pa USA).nel Particularof 60Particular human effi tumor cacyefficacy ofcell tested linesof tested screened compounds compounds by the was was National Cancer Institute (Bethesda, MD, USA). Particular efficacy of tested compounds was observedobserved against against the leukemia the leukemia subpanel. subpanel. In addition, In addition they, they were were also foundalso found to be to active be active in cells in cells observed against the leukemia subpanel. In addition, they were also found to be active in cells overexpressingoverexpressing MDR1. MDR1. The compounds The compounds caused caused apoptosis, apopto mitochondrialsis, mitochondrial depolarization, depolarization, generation generation of overexpressing MDR1. The compounds caused apoptosis, mitochondrial depolarization, generation reactiveof reactive oxygen species,oxygen andspecies, the activation and the activation of caspase-3, of caspase-3, caspase-8, caspase-8, and caspase-9. and caspase-9. Moreover, theyMoreover, acted they of reactive oxygen species, and the activation of caspase-3, caspase-8, and caspase-9. Moreover, they as topoisomeraseacted as topoisomerase I inhibitors I [ 72inhibitors]. [72]. acted as topoisomerase I inhibitors [72].

N N R R N R = H; Cl; CH3; OCH3; N R = H; Cl; CH3; OCH3; 1 1 R = H; Cl; OCH3; R = H; Cl; OCH3; 1 1 R R NH NH N N 66 66 Figure 34. General structure of 11H-pyrido[3 ,2 :4,5]pyrrolo[3,2-c]cinnolines. FigureFigure 34. General 34. General structure structure of 11H of-pyrido[3 11H-pyrido[3′0,2′:4,5]pyrrolo[3,20 ′,2′:4,5]pyrrolo[3,2-c]cinnolines.-c]cinnolines. Barlaam and co-workers, while working on the optimization of selective quinoline based inhibitors BarlaamBarlaam and and co-workers, co-workers, while while working working on the on optimization the optimization of selective of selective quinoline quinoline based based of ataxia teleangiectasia mutated (ATM) kinase involved in the repair of DNA double strand breaks, inhibitorsinhibitors of ataxiaof ataxia teleangiectasia teleangiectasia mutated mutated (ATM) (ATM) kinase kinase involved involved in the inrepair the ofrepair DNA of double DNA double synthesized a series of cinnoline-3-carboxamides as suitable replacements of quinoline carboxamides. strandstrand breaks, breaks, synthesized synthesized a series a series of cinnoline-3-carboxamides of cinnoline-3-carboxamides as suitable as suitable replacements replacements of quinoline of quinoline Compound 67 (Figure 35) was identified as a potent ATM inhibitor with excellent kinase selectivity carboxamides.carboxamides. Compound Compound 67 (Figure 67 (Figure 35) was 35) identifiedwas identified as a potent as a potent ATM inhibitorATM inhibitor with excellent with excellent and good physicochemical and pharmacokinetic properties. Monotherapy with ATM inhibitor 67 did kinasekinase selectivity selectivity and andgood good physicochemical physicochemical and pharmacokineticand pharmacokinetic properties. properties. Monotherapy Monotherapy with with notATM cause inhibitor tumor 67 regression did not cause in the tumor SW620 regression colorectal in tumorthe SW620 xenograft colorectal model, tumor whereas xenograft combination model, ATM inhibitor 67 did not cause tumor regression in the SW620 colorectal tumor xenograft model, withwhereas irinotecan combination resulted with in significantly irinotecan resulted greater tumorin significantly growth inhibition greater tumor in comparison growth inhibition to irinotecan in whereas combination with irinotecan resulted in significantly greater tumor growth inhibition in alone [14,73]. The 1,3-dihydroimidazo[4,5-c]cinnoline-2-one derivatives of general formula 68 (Figure 35)

Molecules 2019, 24, x 17 of 25

Molecules 2019, 24, 2271 17 of 25 comparisonMolecules to2019 irinotecan, 24, x alone [14,73]. The 1,3-dihydroimidazo[4,5-c]cinnoline-2-one derivatives17 of 25 of general formula 68 (Figure 35) were patented as ATM modulators used to treat or prevent ATM mediatedcomparison diseases, to irinotecanincluding alone cancer [14,73]. [74]. The 1,3-dihydroimidazo[4,5-c]cinnoline-2-one derivatives of weregeneral patented formula as ATM 68 (Figure modulators 35) were used patented to treat as ATM or prevent modulators ATM used mediated to treat diseases,or prevent includingATM cancermediated [74]. diseases, including cancer [74]. 1 R O N O X A 1 R N O N O X A 2 N N R 4 N 2 R R O 4 3 N NH O R R N O 13 N NH O R = cycloalkyl,N C1-6 alkyl, heterocycloalkyl; N 12 R == cycloalkyl,H, CH ; C1-6 alkyl, heterocycloalkyl; N NH 3 23 R = H, CH3; NH R = C1-6 alkyl, halogen; N 3 R4 = C1-6 alkyl, halogen; 4 N N R = C1-6 alkyl, halogen; A = N, CR ; R4 = C alkyl, halogen; A = N, CR4; N X = -O-(CH1-6 ) - NR8 R9 or NR6 R7, n = 2,3,4; X = -O-(CH )2 -n NR8 R9 or NR6 R7, n = 2,3,4; R8,R9 = H,2 (Cn )alkyl; R8,R9 together with the nitrogen 67 68 R8,R9 = H, (C 1-3)alkyl; R8,R9 together with the nitrogen 67 68 1-3 atom formform a a 4, 4, 5 5or or 6-membered 6-membered non-aromatic non-aromatic monocyclic ring ring comprising comprising carbon carbon which which can becan be optionally substituted substituted with with halogen; halogen; 6 7 R6,R,R7 togethertogether with with the the nitrogen nitrogen atom atom form form a 4, 5a or4, 5 or 6-membered non-aromatic non-aromatic monocyclic monocyclic ring ring 10 comprising carbon carbon which which is substitutedis substituted with withNR NR= H,10 = H, 1111 (C1-3)alkyl,)alkyl, R R = =(C (C1-3)alkyl;)alkyl; 1-3 1-3 FigureFigure 35. Cinnoline35. Cinnoline based based ataxia ataxia teleangiectasia teleangiectasia mutated mutated (ATM) (ATM) inhibitors. inhibitors. Figure 35. Cinnoline based ataxia teleangiectasia mutated (ATM) inhibitors. Colony-stimulatingColony-stimulating factor-1 factor-1 (CSF-1) (CSF-1) throughthrough bindingbinding to to its its receptor receptor (CSF-1R (CSF-1R) )regulates regulates the the migration,Colony-stimulatingmigration, proliferation, proliferation, function,factor-1 function, (CSF-1) and and survival survival through of of macrophages macrophagesbinding to [75].its [75 ].receptor Since Since CSF-1R CSF-1R (CSF-1R is overexpressed is overexpressed)regulates the inmigration, manyin many tumors proliferation, tumors and and at sites atfunction, sites of inflammation,of inflammation, and survival CSF-1R CSF-1R of macrophages inhibitorsinhibitors seem seem[75]. to Since to be be an CSF-1R an attractive attractive is therapeuticoverexpressed therapeutic strategyin manystrategy fortumors cancer for and ascancer wellat sites asasautoimmune ofwell inflammation, as autoimmune and inflammatory CSF-1R and inhibitors inflammatory diseases. seem The todiseases. 3-amido-4-anilinocinnolinesbe an attractive The 3-amido-4- therapeutic ofstrategy generalanilinocinnolines for formula cancer69 of(Figureas general well 36 formula )as were autoimmune 69 reported (Figure as36) potent, andwere reportedinflammatory highly as selective potent, diseases. highly CSF-1R selective inhibitorsThe CSF-1R3-amido-4- [76 ,77]. Theyanilinocinnolinesinhibitors were designed [76,77]. of general They in order were formula designed to overcome 69 (Figurein order the 36)to overcomecardiovascular were reported the cardiovascular as liability potent, of liabilityhighly potent selectiveof potent and selective andCSF-1R selective 3-amido-4-anilinoquinoline CSF-1R inhibitor (AZ683), which was able to reduce the level of 3-amido-4-anilinoquinolineinhibitors [76,77]. They were designed CSF-1R inhibitor in order to (AZ683), overcome which the cardiovascular was able to liability reduce of the potent level and of selectivetumor-associated 3-amido-4-anilinoquinoline macrophages in aCSF-1R breast cancer inhibitor xenograft (AZ683), model. which The was 3-amido-4-anilinocinnoline able to reduce the level of tumor-associatedcompound with macrophages 1-hydroxyethylpi in a breastperazine cancer substituent xenograft at model.7 position The of 3-amido-4-anilinocinnoline cinnoline scaffold 70 tumor-associated macrophages in a breast cancer xenograft model. The 3-amido-4-anilinocinnoline compound(AZD7507, with 1-hydroxyethylpiperazineFigure 36) was a potent CSF-1R substituent inhibitor at 7demonstrating position of cinnoline good oral sca pharmacokineticffold 70 (AZD7507, compound with 1-hydroxyethylpiperazine substituent at 7 position of cinnoline scaffold 70 Figureprofile 36) was as well a potent as reduced CSF-1R risk inhibitor of cardiotoxicity demonstrating in comparison good to oral AZ683 pharmacokinetic [78]. profile as well as reduced(AZD7507, risk Figure of cardiotoxicity 36) was a inpotent comparison CSF-1R to inhi AZ683bitor [78 demonstrating]. good oral pharmacokinetic profile as well as reduced risk4 of cardiotoxicity in comparison to AZ683 [78]. R F n 4 R HO 3 m N NHF O R n HN O 2 N R HO m NH2 3 NH2 N NH O R HN O N N 2 1 O N R R N N NH2 NH2 N 1 69N 70 R N O N Figure 36. Structure of 3-amido-4-anilinocinnoline derivatives exhibiting colony-stimulating factor-1 receptor (CSF-1R) inhibition. 69 70 Figure 36. Structure of 3-amido-4-anilinocinnoline derivatives exhibiting colony-stimulating factor-1 Figurec-Met 36. Structure receptor oftyrosine 3-amido-4-anilinocinnoline kinase is another cellul derivativesar target exhibitingfor compounds colony-stimulating designed as potential factor-1 receptor (CSF-1R) inhibition. receptoranticancer (CSF-1R) agents inhibition.because it has been found to be overexpressed or mutated in various human cancer cells [79]. Some 4-(2-fluorophenoxy)quinoline derivatives bearing a 4-oxo-1,4-dihydrocinnoline-3- c-Metcarboxamide receptor moiety tyrosine 71 (Figure kinase 37) were is designed another as cellular c-Met inhibitors target forand evaluated compounds against designed five c- as c-Met receptor tyrosine kinase is another cellular target for compounds designed as potential potential anticancer agents because it has been found to be overexpressed or mutated in anticancer agents because it has been found to be overexpressed or mutated in various human cancer various human cancer cells [79]. Some 4-(2-fluorophenoxy)quinoline derivatives bearing a cells [79]. Some 4-(2-fluorophenoxy)quinoline derivatives bearing a 4-oxo-1,4-dihydrocinnoline-3- 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety 71 (Figure 37) were designed as c-Met inhibitors and carboxamide moiety 71 (Figure 37) were designed as c-Met inhibitors and evaluated against five c-

Molecules 2019, 24, 2271 18 of 25 MoleculesMolecules 20192019,, 2424,, xx 1818 ofof 2525

Met-dependentevaluatedMet-dependent against cancercancer five c-Met-dependent cellcell lineslines andand oneone cancer c-Met-inc-Met-in cell linesdependentdependent and one cancercancer c-Met-independent cellcell [80,81].[80,81]. MostMost cancer compoundscompounds cell [80,81]. wereMostwere activeactive compounds againstagainst were c-Metc-Met active andand againstthethe testedtested c-Met cellcell and lineslines the [82].[82]. tested cell lines [82].

11 RR OO NN

HHOO FF OO

1 RR1 == piperidinyl;piperidinyl; 4-methylpiperidinyl;4-methylpiperidinyl; NH O pyrrolidinyl;pyrrolidinyl; morpholinyl;morpholinyl; NH O 2 RR2 == H,H, F;F; 3 3 O R = H, F, Cl, Br, CF3, OCF3, CH3 O R = H, F, Cl, Br, CF3, OCF3, CH3 N N 22 NN RR 7171

33 RR FigureFigure 37.37. c-Metc-Metc-Met inhibitorinhibitor inhibitor withwith with 4-oxo-1,4-dihy4-oxo-1,4-dihy 4-oxo-1,4-dihydrocinnoline-3-carboxamidedrocinnoline-3-carboxamidedrocinnoline-3-carboxamide moiety.moiety.

NewNew dihydrobenzo[ dihydrobenzo[hh]cinnoline-5,6-dione]cinnoline-5,6-dione derivativesderivatives derivatives 727272 (Figure(Figure(Figure 38)38)38) werewere alsoalso prepared prepared and and evaluatedevaluated asasas potential potentialpotential antitumor antitumorantitumor agents. agents.agents. The TheThe majority majomajo ofrityrity tested ofof tested derivativestested derivativesderivatives exhibited exhibitedexhibited at least moderate atat leastleast moderatecytotoxicmoderate cytotoxicactivitycytotoxic against activityactivity a against epidermoidagainst aa epidermoidepidermoid carcinoma carcinomacarcinoma cell line (KB) cellcell lineline and (KB)(KB) a hepatoma andand aa hepatomahepatoma carcinoma carcinomacarcinoma cell line cell(Hep-G2).cell lineline (Hep-G2).(Hep-G2). Nine of Nine theNine new ofof thethe dihydrobenzo[ newnew dihydrobenzo[dihydrobenzo[h]cinnoline-5,6-dioneshh]cinnoline-5,6-d]cinnoline-5,6-d displayedionesiones displayeddisplayed a considerable aa considerableconsiderable activity µ activityprofileactivity with profileprofile IC50 withwithvalues ICIC5050 below valuesvalues 5 belowMbelow against 55μμMM both againstagainst cell lines. bothboth Acellcell compound lineslines.. AA compoundcompound with a 4-NO withwith2C6H aa4 4-NO4-NOsubstituent22CC66HH44 µ µ substituentwassubstituent identified waswas as identifiedidentified the most promisingasas thethe mostmost agent promisingpromising with IC agentagent50 values withwith of ICIC 0.565050 valuesvaluesM and ofof 0.77 0.560.56 μμMMM against andand 0.770.77 the μμ KBMM againstandagainst Hep-G2 thethe KBKB cell andand lines, Hep-G2Hep-G2 respectively cellcell lines,lines, [83 respectivelyrespectively]. [83].[83].

OO ArylAryl OO ArylAryl

NN NN

72 72 Figure 38. General structure of dihydrobenzo[h]cinnoline-5,6-diones. FigureFigure 38.38. GeneralGeneral structurestructure ofof dihydrobenzo[dihydrobenzo[hh]cinnoline-5,6-diones.]cinnoline-5,6-diones. Many cinnoline derivatives (Figure 39) such as 9-substituted-4,10-dimethylpyrano[2,3-f ] Many cinnoline derivatives (Figure 39) such as 9-substituted-4,10-dimethylpyrano[2,3- cinnolin-2-onesMany cinnoline with derivativesN-piperazinyl (Figure moieties 39) such at C-9as 9-substitu73 [84],ted-4,10-dimethylpyrano[2,3- 6-substituted-4-methyl-3-(4- f]cinnolin-2-ones with N-piperazinyl moieties at C-9 73 [84], 6-substituted-4-methyl-3-(4- farylpiperazin-1-yl)cinnolines]cinnolin-2-ones with N-piperazinyl74 [85], hexahydrocinnolinesmoieties at C-9 7375 [84],[86] and6-substituted-4-methyl-3-(4- pyrazolo[4,3-c]cinnoline arylpiperazin-1-yl)cinnolines 74 [85], hexahydrocinnolines 75 [86] and pyrazolo[4,3-c]cinnoline arylpiperazin-1-derivatives 76 [yl)cinnolines87] were synthesized 74 [85], andhexahydrocinnolines evaluated in vitro 75for [86] their and antitumor pyrazolo[4,3- activityc]cinnoline against derivatives 76 [87] were synthesized and evaluated in vitro for their antitumor activity against breast derivativesbreast cancer 76 cell[87] lines were MCF-7 synthesized and MDA-231 and evaluated for bicinnolines in vitro for77 their[88]. antitumor activity against breast cancercancer cellcell lineslines MCF-7MCF-7 anandd MDA-231MDA-231 forfor bicinnolinesbicinnolines 7777 [88].[88].

Molecules 2019, 24, x 19 of 25

Molecules 2019, 24, 2271 19 of 25 Molecules 2019, 24, x Aryl 19 of 25 N NH2 O(NH) X N Aryl NC N NH O(NH)N O ON 2 N X N N NC CN N N N O ON X = O, S, CH , N-R, N-Ar Ar = Ph; CH Ph; C H F(p) 2 2 N6 4 CN N N N X = H; F; Cl; NBr 74 75 X = O, S, CH73, N-R, N-Ar 2 Ar = Ph; CH2Ph; C6H4F(p) N X = H; F; Cl; Br 1 X 74 75 N 73 R X N N N 1 X N R N X N N N N N N X R R = Cl; H; COOH; NO ; F N N 2 N 1 77 N R = C H N X R R = Cl;6 H;5 COOH; NO ; F N 2 N 77 76 N R1 = C H 6 5 76 Figure 39. Compounds bearing cinnoline moieties evaluated against breast cancer cell lines. Figure 39. Compounds bearing cinnoline moieties evaluated against breast cancer cell lines. Figure 39. Compounds bearing cinnoline moieties evaluated against breast cancer cell lines. 2.5. Miscellaneous Miscellaneous 2.5.A Miscellaneous compound with cinnoline moiety 78 (Figure 40) is patented by Stein and co-authors for very A compound with cinnoline moiety 78 (Figure 40) is patented by Stein and co-authors for very interestingA compound uses. Among with othercinnoline hydrazone moiety 78derivatives, (Figure 40) it iswas patented tested byas inhibitorStein and ofco-authors a transient for receptor very interesting uses. Among other hydrazone derivatives, it was tested as inhibitor of a transient receptor potentialinteresting cation uses. channel, Among othersubfamily hydrazone M, member derivatives, 5 (TRPM5) it was tested protein as inhibitor which ofhas a transient been shown receptor to be potential cation channel, subfamily M, member 5 (TRPM5) protein which has been shown to be essentialpotential for cation taste transduction.channel, subfamily Such compoundsM, member coul5 (TRPM5)d be used protein as taste which inhibitors has been when shown administered to be essential for taste transduction. Such compounds could be used as taste inhibitors when administered as essentiala component for taste of transduction.pharmaceutical Such or compounds food produc coults dto be improve used as tasteacceptance. inhibitors Moreover, when administered these agents as a component of pharmaceutical or food products to improve acceptance. Moreover, these agents are areas intended a component for useof pharmaceutical in treating diabetes or food mellitus products, obesity,to improve insulin acceptance. resistance Moreover, syndrome these and agents many intended for use in treating diabetes mellitus, obesity, insulin resistance syndrome and many more [89]. moreare [89].intended for use in treating diabetes mellitus, obesity, insulin resistance syndrome and many more [89]. N O N N O N N N NHN N NH

78 78

Figure 40. Cinnoline transient receptor potential cation channel, subfamily M, member 5 Figure 40. Cinnoline transient receptor potential cation channel, subfamily M, member 5 (TRPM5) (TRPM5)Figure 40. inhibitor. Cinnoline transient receptor potential cation channel, subfamily M, member 5 (TRPM5) inhibitor.inhibitor. Cinnoline derivatives were also patented as thyroid hormone receptor agonists [90], orexin Cinnoline derivatives were also patented as thyroid hormone receptor agonists [90], orexin receptorCinnoline antagonists derivatives [91–95], were histone also deacetylase patented as (HDAC) thyroid inhibitors hormone [receptor96], liver agonists X receptors [90],β orexinselective receptor antagonists [91–95], histone deacetylase (HDAC) inhibitors [96], liver X receptors β selective modulatorsreceptor antagonists for the treatment [91–95], histone of atherosclerosis deacetylase (HDAC) [97], somatostatin inhibitors [96], regulators liver X receptors [98] or cannabinoid-1 β selective modulatorsmodulators for for the the treatment treatment ofof atherosclerosisatherosclerosis [97][97],, somatostatinsomatostatin regulators regulators [98] [98] or or cannabinoid-1 cannabinoid-1 receptor inverse agonists [99] and many more. receptorreceptor inverse inverse agonists agonists [99] [99] and and manymany more. 3. Conclusions 3. 3.Conclusions Conclusions In this paper, we have presented a review of studies focused on the biological activity of cinnoline In this paper, we have presented a review of studies focused on the biological activity of derivativesIn this conductedpaper, we byhave many presented research a groupsreview worldwide of studies betweenfocused 2005on the and biological 2019. The activity provided of cinnoline derivatives conducted by many research groups worldwide between 2005 and 2019. The cinnolineinformation derivatives clearly indicates conducted the by enormous many research significance groups of worldwide the cinnoline between framework 2005 and as a2019. building The provided information clearly indicates the enormous significance of the cinnoline framework as a providedblock of many information valuable clearly compounds. indicates Compounds the enormous bearing significance the cinnoline of the sca cinnolineffold are framework able to interact as a buildingbuilding block block of of many many valuable valuable compounds.compounds. Compoundsnds bearing bearing the the cinnoline cinnoline scaffold scaffold are are able able to to with a variety of molecular targets including receptors such as GABA A, CSF-1R, H3R and enzymes interact with a variety of molecular targets including receptors such as GABA A, CSF-1R, H3R and interactsuch as cyclooxygenase-2,with a variety of molecular topoisomerases, targets phosphodiesterase,including receptors humansuch as neutrophil GABA A, elastase,CSF-1R, H Bruton’s3R and enzymesenzymes such such as as cyclooxygenase-2, cyclooxygenase-2, topoisomerasestopoisomerases,, phosphodiesterase,phosphodiesterase, human human neutrophil neutrophil elastase, elastase, tyrosineBruton’s kinase tyrosine involved kinase in involved pathogenesis in pathogenesis of many diseases. of many As diseases. a consequence, As a consequence, they are intended they are to be Bruton’s tyrosine kinase involved in pathogenesis of many diseases. As a consequence, they are usedintended as antibacterial, to be used as antifungal, antibacterial, antimalarial, antifungal, anti-inflammatory, antimalarial, anti-inflammatory, analgesic, anxiolytic analgesic, and anxiolytic antitumor intended to be used as antibacterial, antifungal, antimalarial, anti-inflammatory, analgesic, anxiolytic agents.and antitumor Some cinnoline agents. Some derivatives cinnoline are derivatives under evaluation are under inevaluation clinical trials.in clinical There trials. is noThere doubt is no that and antitumor agents. Some cinnoline derivatives are under evaluation in clinical trials. There is no developmentdoubt that development of cinnoline basedof cinnoline molecules based constitutes molecule as significantconstitutes contributiona significant tocontribution the identification to the of doubtlead compounds that development with optimized of cinnoline pharmacodynamic based molecule ands constitutes pharmacokinetic a significant properties. contribution to the

Molecules 2019, 24, 2271 20 of 25

Author Contributions: Conceptualization, M.S. Writing—Original Draft Preparation, M.S.; Writing—Review and Editing, M.S. and A.S.; Visualization, M.S.; All authors read and approved the final manuscript. Funding: This review was funded by the Medical University of Lodz, Poland, Research Programme No. 503-03/3-011-03/503-31-001 and 503/3-011-03/503-36-001. Conflicts of Interest: The authors declare no conflict of interest.

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