Cinnoline Derivatives with Biological Activity - Wiley Online Library

Arch. Pharm. Chem. Life Sci. 2007, 340, 65 – 80

W. Lewgowd and A. Stanczak

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Review Article Cinnoline Derivatives with Biological Activity Wieslawa Lewgowd, Andrzej Stanczak Department of Hospital Pharmacy, Medical University of Lodz, Lodz, Poland

Although cinnoline belongs to a family of fairly well known heterocycles, the interest in the study of its derivatives continues. Cinnoline compounds demonstrate interesting bioactivity and many research papers have discussed the biological property, structure-activity relationship, and applications in medicinal science. Attention has been paid to the synthesis of heterocyclic compounds bearing a cinnoline moiety, mainly because of the interest in their broad spectrum of pharmacological activities. This chronological work summarizes almost all synthetic papers and patents concerning the biological properties of 107 cinnoline derivatives published over the last 50 years with 117 references. Keywords: Benzo[c]-1,2-diazine / Biological activity / Cinnoline / 1,2-Diazanaphtalene / Received: February 28, 2005; accepted: November 24, 2006 DOI 10.1002/ardp.200500194

Introduction Cinnoline 1, 1,2-diazanaphtalene or benzo[c]-1,2-diazine (Hantsch-Widmann system), C8H6N2 is a nitrogenous organic base, obtained from certain complex diazo compounds (Fig. 1). Their system is an isosteric relative to either quinoline or isoquinoline. Therefore, in many cases the synthesized compounds were designed as analogs of the previously obtained quinoline or isoquinoline derivatives. Cinnoline itself is toxic and shows antibacterial activity against Escherichia coli [1]. None of its derivatives have been found in nature. The synthesis of its nucleus was first carried out by V. Richter in 1883, after whom this heterocyclic system is named [2]. Although its derivatives have been reviewed in many books and journals, only some of them reported biological properties [3 – 6]. This review includes papers and patents after 1945 because earlier data are scarce. In 1957, Jacobs in his review on cinnoline and related compounds pointed out that this ring system was the least known of the condensed, bicyclic aromatic heterocycles containing two nitrogen atoms. Since then a significant interest in the synthesis of com-

Correspondence: Andrzej Stanczak, Department of Hospital Pharmacy, Medical University of Lodz, Muszynskiego str. 1, 90-151 Lodz, Poland E-mail: [email protected] Fax: + 48 42 677-9252

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2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Figure 1. Structure of Cinnoline 1.

pounds possessing the cinnoline ring system has developed. Some cinnolines have been screened and have received approval as bioactive drugs or are still under clinical trials. Of all substituted cinnolines, which have been prepared, mainly aminocinnolines are known to have biological activity. With the view of discovering a new antimalarial drugs such as chloroquine analogs, the derivatives of 4-aminocinnolines 2 (Fig. 2) were synthesized by Keneford et al. Biological tests demonstrated that some of them showed significant activity [7]. A year later in 1948, Kornfeld synthesized a series of 1,2-dihydrocinnolines to investigate compounds with possible estrogen-like activity, but the compound 3 (Fig. 2) exhibited only a weak estrogen activity [8]. A new group of 3,4-substituted cinnolines 4 (Fig. 2) structurally related to early obtained quinoline derivatives were synthesized as antimicrobial agents. Some of the tested compounds exerted bacteriostatic activity

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Figure 2. Chemical structures of 4-aminocinnolines 2, 1,2-dihydrocinnolines 3, 3,4-substituted cinnolines 4, and ethylenediamine derivatives with cinnoline moiety 5. Figure 4. Chemical structures of 3-phenylcinnoline derivatives 10, 11, 12.

Figure 3. Pyrazolo[1,2-a]cinnolines with anti-inflammatory property 6, 7, 8, 9.

against Gram-positive bacteria. Moreover, they exhibited one-fifth of the spasmolytic action of atropine [9]. Further information about cinnoline derivatives with biological activity appeared ten years later. Series of ethylenediamine derivatives with cinnoline moiety 5 (Fig. 2) showed moderate antihistaminic activity [10]. The French invention of patent No. 1393596 provided various pyrazolo[1,2-a]cinnolines 6 (Fig. 3) as analogs of pyrazoline-3,5-dione (butapyrazole), known as antiinflammatory drugs. One of the synthesized compounds was applied as a drug (cinnopentazon) [11]. As a continuation of the citation patent, Schatz et al. synthesized series of new cinnopentazone analogs described as structures 7 [12] (Fig. 3). The best anti-inflammatory properties were exerted by a compound named Scha 764 8 (Fig. 3). Inde-

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pendently, a drug with the trade name cinnofuradion 9 (Fig. 3) was introduced in medical practice [13, 14]. The 3-phenylcinnoline-4-carboxylic acid derivatives 10 (Fig. 4) were the subject of the comprehensive works of Lowrie, who disclosed the methods of preparation and pharmacological data of synthesized derivatives. It should be noted that the tested compounds exhibited diverse activity, depending on the structure. The amides, aminoalkyl amides and hydrazides showed anti-inflammatory properties, while another aminoalkyl amide showed hypotensive action. Moreover, piperazine amides exerted antiulcer activity, at 10 mg/kg [15]. The 4-amino3-phenylcinnolines 11 (Fig. 4) exerted antihypertensive, antibacterial, and fungicidal activity [16]. However, the closely related 3-aryl-4-dialkyloaminoaminoalkylocinnolines were claimed to show antibiotic action against bacteria (Diplococcus pneumoniae), protozoa (Tetrahymena geleii), fungi (Candida abicans), and algae (Chlorella vulgaris). These compounds also inhibited the germination of Trifolium seeds. In addition, the cinnoline derivatives, described as structures 12 (Fig. 4), exerted antihypertensive and antibacterial activity [17, 18]. If the substituent appointed as symbol X, was chlorine or NHR (where R = HOCH2CH2OCH2CH2), these cinnoline derivatives showed antiulcer and antialgal activity and inhibited secretion of pepsin [19]. The most active compounds (X = NHC6H4CO2CH3-o) inhibited ulceration in the rat at 10 mg/kg [20]. Antibacterial activity demonstrated the 3-phenyl-4-piperazinyl cinnolines 13 (Fig. 5) as well. Additionally, these compounds showed diuretic activity [21]. Gilman’s patent provided various 4-hydroxycinnoline3-carboxylic acids and related esters 14 (Fig. 5) as potenwww.archpharm.com


Cinnoline Derivatives with Biological Activity

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Figure 6. 4-Aziridinocinnolines 17 and 4a-(3-substituted phenyl)-1,2-disubstituted decahydrocinnolines 18.

Figure 5. Structures of 3-phenyl-4-piperazinylcinnolines 13, 4-hydroxycinnoline-3-carboxylic acids 14, 4-aminocinnoline 15, and 1-alkyl-4-oxo-1,4-dihydrocinnolin-3-propanoic acid derivatives 16.

tially antiallergic drugs. Some of the synthesized compounds were useful for alleviation of symptoms of asthma [22]. Cooper et al. continued the study and established the mechanism of the antiallergic action of the synthesized compounds as an inhibition of the antigen – antibody interaction [23, 24]. In 1973, Allais and Rousseau synthesized a series of 4-aminocinnoline derivatives 15 (Fig. 5) in order to investigate possible analogs of anthranilic acid with anti-inflammatory properties. Some of the tested compounds also exerted analgetic and antiphlogistic activity [25]. The 1,4-dihydrocinnolin-3-propanoic acid derivatives (16) (Fig. 5) synthesized by Holland and Jones as new analogs of cromolyn sodium, showed high activity in antiallergic bioassays. Some of them had activity comparable with those of known, clinically effective antiasthmatic agents such as cromolyn sodium (Intal) [26]. In the search for new agents as potent antitumor drugs, Yamazaki, Draper, and Castle synthesized the 4-aziridinocinnolines 17 (Fig. 6), variously substituted at the positions 5, 6, 7, 8. The most active compound within this series was 4-aziridino-6-nitrocinnoline [27]. Other Japanese researchers, looking into the cinnoline core, synthesized compounds with narcotic and analgesic action. Some of them e.g. 18 (Fig. 6) exerted a 27-times stronger action than morphine, used as a reference drug [28 – 30]. The 4-methoxystyryl compounds, including cinnoline core, were prepared and evaluated in vitro for antitumor activity with a panel of leukemia-, lymphoma-, carcinoma-, and neuroblastoma-derived cell lines. Out of 56 described compounds, only 4-(methoxystyryl)cinnoline

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Figure 7. Chemical structures of 4-(methoxystyryl)cinnoline 19, 7-piperazine-substituted 6-fluorocinnoline-3-carboxylic acids 20, 1-alkyl-1,4-dihydro-4-oxo[1,3]dioxolo[g]cinnoline-3-carboxylic acid 21, cinoxacin 22, and 4-oxo-1,4-dihydrocinnoline-3-carboxylic acid derivatives 23.

19 (Fig. 7) exerted antitumor activity [31]. In 1983, Japanese researchers synthesized the group of 7-piperazinesubstituted 6-fluorocinnoline-3-carboxylic acids as antimicrobial agents. The widest spectrum of antibacterial activity showed the compound with the structure presented by molecule 20 (Fig. 7) [32]. As a continuation of previous research, a series of 1-alkyl-1,4-dihydro-4oxo[1,3]dioxolo[g]cinnoline-3-carboxylic acid 21 (Fig. 7) have been synthesized by Conrad et al. and tested for their antibacterial profile against Gram-negative bacteria [33]. Some of them, e.g. the 1-ethyl-1,4-dihydro-4-oxo[1,3]dioxolo[g]cinnoline-3-carboxylic acid (22) – cinoxacin (cinobac, noxigram) as anawww.archpharm.com

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Figure 8. Pyrazolo[4,3c]cinnolines 24, 25, 26 and 3-aminotetrahydrocinnoline derivatives 27.

Figure 9. Derivatives of 4-oxocinnoline-3-carboxylic acid 28, 4-(hydroxyiminomethyl)cinnoline oxide 29, N-oxides of cinnoline-4-carboxylic acid derivatives 30, and 2-methyl-4-phosphonocinnolinium hydroxide 31.

log of oxolinic acid is used in urinary tract infections [13] (Fig. 7). Cinoxacin is active against Mycoplasma gallisepticum, Escherichia coli, Salmonella dublin, Vibrio coli, and Xanthomonas phaseali. Miyamoto et al. studied the chemical modification of cinoxacin in order to improve its spectrum of antibacterial activity. A series of 4-oxo-1,4dihydrocinnoline-3-carboxylic acid derivatives (23) was synthesized and their in vitro antibacterial activity evaluated (Fig. 7). 7-Pyrrolidine derivative (MIC 0.2 l/mL) showed the best antibacterial property against Staphylococcus aureus [34]. The French patent No. 2549833 from Astra Pharmaceuticals Ltd. disclosed a series of new condensed cinnoline derivatives. Among the pyrazolo[4,3c]cinnolines 24 (Fig. 8), some displayed anxiolytic activity [35]. The new group cinnoline condensed system, structurally related to earlier patented compounds, was also described by Takada et al. The synthesized pyrazolo[4,3-c]cinnolin-3one analogs 25 (Fig. 8) inhibited binding of 3H-diazepam to the benzodiazepine receptor in rat cortex [36]. The same activity was also reported in the Japanese patent No 61161285 [37]. One of the synthesized compounds 26 (Fig. 8) showed that the condensed pyrazolocinnoline systems are useful as psychotropic agents. In 1985, scientists from Sandoz patented the 3-aminotetrahydrocinnoline derivatives 27 (Fig. 8) with hypotensive properties [38]. However, in the same year Labowitz et al., while studying biological actions of 4-oxocinnoline3-carboxylic acids, discovered pollen suppressant activity of these compounds 28 (Fig. 9) [39, 40]. For controlling

the growth of unwanted plants, the 4-(hydroxyiminomethyl)cinnoline oxide 29 (Fig. 9) and their derivatives may also be used [41]. Many of the compounds listed in the patent from Shell disclosed biological activity. For example, the presented Noxides of cinnoline-4-carboxylates 30 (Fig. 9) were patented as herbicides [42]. In the same year, esters of 2-methyl-4-phosphonocinnolinium hydroxide inner salts 31 (Fig. 9) were covered by patent as herbicides [43]. With the view of searching for new analogs of sulfonamides 4-aminocinnoline 32 (Fig. 10) was synthesized by Boyle et al. These compounds also exerted hypotensive properties [44]. Finding new agents with action on the CNS system was the subject of yet other investigations. The substituted cinnoline-3-carboxamides 33 (Fig. 10), synthesized as sedatives, were patented as potential drugs with anxiolytic activity [45]. The series of new 3,4-substituted cinnoline derivatives 34 (Fig. 10) as tranquilizers were obtained by Resh. Some of them were also covered by patent [46]. The invention provided potent pharmaceutical compounds, acting as the benzodiazepine receptor agonists. The presented 4-amino-8-phenylcinnoline-3-carboxylic acid propylamide 35 (Fig. 10) antagonized the effects of diazepam, chlordiazepoxide, etc. [47]. The series of 4-oxocinnoline derivatives 36 (Fig. 11), structurally related to early analogs of naproxen, were synthesized by Dorn. The new class of compounds showed anti-inflammatory and analgesic properties. Moreover, some of them lowered high cholesterol levels

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Figure 10. Analogs of sulfonamides the 4-aminocinnoline 32, cinnoline-3-carboxamides 33, 4,5,6,7,8-substituted cinnoline-3carboxylic acid derivatives 34, and 4-amino-8-phenylcinnoline-3carboxylic acid propylamide 35.

Figure 11. 4-Oxocinnolines 36, 4a-(3-substituted phenyl)-1,2disubstituted decahydrocinnolines 37, and phenoxy-substituted nitrogen heterocycles 38.

[48]. Japanese scientists, however, looking for new analogs of benzomorphane drugs, synthesized derivatives of decahydrocinnolines 37 (Fig. 11) with strong analgesic action [49]. The phenoxy substituted nitrogen heterocycles, prepared by Munro, acted as herbicides 38 (Fig. 11). Several of them, including cinnoline derivatives, gave complete control of barnyard grass at 5 kg/ha [50]. In 1988, the 4-hydroxycinnoline-3-carboxylic acid derivatives 39 (Fig. 12) became the subject of EP patent No 277,791. The disclosed compounds were evaluated in vitro for antitumor activity, against a panel of leukemia-, lymphoma-, carcinoma-, and neuroblastoma-derived cell

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Figure 12. Chemical structures of 4-hydroxo-(39) and 4-oxo-N1substituted cinnoline-3-carboxylic acid derivatives 40, 41, and some 4,5,6,7,8-substituted cinnolines 42.

lines. Some of the tested compounds showed good antitumor activity [51]. Aiming at improving the antibacterial activity of cinnoxacin, Miyamoto and Matsumoto studied its chemical modification. Therefore, a new series of 4-oxo-1,4-dihydrocinnoline-3-carboxylic acid derivatives 40 (Fig. 12) were synthesized and their in vitro antibacterial activity was evaluated. Most of the compounds listed in the paper exert higher antibacterial activity compared to cinoxacin [52]. The chemical properties of 4-oxocinnoline derivatives and the possibilities of their use for the preparation of biologically active compounds have been studied extensively. In 1989, Japanese researchers synthesized and patented some of the 1,4-dihydro-4-oxo-1-phenylcinnoline-3-carboxylic acid derivatives 41 (Fig. 12) as a new group of herbicides [53, 54]. Other cinnoline compounds 42 (Fig. 12) were prepared as agrochemical fungicides as well [55]. Some of them exerted this property at 100 ppm, giving 90-100% control of Erysiphe graminis tritici. A similar chemical group, the derivatives of 1,4-dihydro-1-phenylcinnoline-3-carboxylic acid 43 (Fig. 13), was the subject of investigation of Radl et al. All the prepared compounds were tested for their antibacterial activity. However, the obtained results (MIC) did not have significant values [56]. The series of 4-aminocinnoline-3-carboxamides, structurally related to the characterized compounds [46, 47], were synthesized by Patel et al. as potent selective benzodiazepine receptor agonists. One of them, compound 44 www.archpharm.com

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Figure 14. Derivatives of 2-(4-chloro-2-fluoro-5-substituted)hexahydro-3(2H)cinnoline 47 and condensed pyrrolocinnoline 48.

Figure 13. Chemical structures of 4-oxo-1,4-dihydrocinnoline-3carboxylic acid 43, 45, 4-amino-, and 4-hydroxycinnoline-3-carboxamides 44, 46.

(Fig. 13), has the best properties and exerted minimal sedative liability, lower ethanol interaction, and possibly lower dependence liability than bezodiazepines (e.g. diazepam) [57]. Earlier studies on 4-oxocinnoline-3-carboxylic acid derivatives, were continued by Miyamoto et al.; he synthesized a new series of 5-substituted cinnolines 45 (Fig. 13), their esters and salts as bactericides [58]. The most active compounds showed in vitro a MIC of 0.78 lg/ mL against Staphylococcus aureus 209 JC-1. The derivatives of glycine amides of 4-hydroxycinnoline-3-carboxylic acid 46 (Fig. 13) with potent antifibrotic activity were prepared by Franklin et al. and evaluated in vitro and in vivo for the formation or maturation of connective tissue fibers. Although several cinnoline derivatives inhibited the enzyme in vitro, they were ineffective in vivo [59]. In 1990 Japanese researchers prepared a new group of 2-(4-chloro-2-fluoro-5-substituted)hexahydro-3(2H)cinnolines 47 (Fig. 14) as herbicides. These compounds showed a broad spectrum of activity at a low dose and high selectivity [60]. In the same year, Brown et al. prepared condensed pyrrolocinnolines 48 (Fig. 14), which were proven to show (H+/K+) ATP-ase inhibitory activity [61]. The antimicrobial and anti-inflammatory activities of some substituted 2-mercapto-3-arylpyrimido[5,4-c]cinnolin-4(3H)-ones 49 (Fig. 15) were reported by Narqud et al. Some of them showed potent antimicrobial and antifungal activities [62]. Continuing research on tricyclic cinnoline system, Menon et al. synthesized a series of 2-alkylthiopyrimido[5,4-c]cinnolines 51 (Fig. 15) and pyrimido[5,4-c]cinnolin-2,4(1,3H)-diones 52 (Fig. 15). A number of

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Figure 15. 2-Mercapto-3-arylpyrimido[5,4-c]cinnolin-4(3H)-ones 49, 3-hydrazino-5,6-dihydrobenzo[h]cinnoline 50, 2-alkylthiopyrimido[5,4-c]cinnolines 51, and pyrimido[5,4-c]cinnolin-2,4(1,3H)diones 52.

the obtained compounds showed promising antimicrobial activity as well [63, 64]. The 3-hydrazino-5,6-dihydrobenzo[h]cinnolines 50 derivatives (Fig. 15) were synthesized as the continuation of investigation on new structural analogs of hydralazine. The study reported preliminary results on the hypotensive and diuretic action. One of them presented below, reduced arterial pressure similarly to hydralazine and was used as the reference drug [65]. In 1994, Narqud et al. synthesized a series of tricyclic 4-aryloxypyrimido[5,4-c]cinnoline 53 (Fig. 16) derivatives with antibacterial activity [66]. Following studies on cinnoline-condensed systems, Narqud et al. prepared 7-substituted pyrimido[5,4-c]cinnoline 54 (Fig. 16) derivatives as anti-inflammatory agents [67, 68] or compounds with antibacterial properties 55 (Fig. 16) [69]. However, the 6-sulphonamide derivatives of 3-methyl-1H-pyrazolo[4,3-c]cinnoline 56 (Fig. 16), obtained by Abbady et al. also exerted antibacterial activity [70]. The 4-oxo-1,2,3,4-tetrahydro-2-cinnoline acetic acids 57 and 4-olate-2-cinnolinium acetic acids 58 (both Fig. 17), www.archpharm.com



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Figure 18. Chemical structures of 4-substituted cinnolines 61, 62.

Figure 16. Pyrimido[5,4-c]cinnolines 53, 54, 55 and 3-methyl1H-pyrazolo[4,3-c]cinnolines 56.

Figure 19. N1-substituted 4-oxocinnolines 63 and 4-aminocinnoline-3-carboxamides 64.

Figure 17. Derivatives of 4-oxo-1,2,3,4-tetrahydro-2-cinnoline acetic acid 57, 4-olate-2-cinnolinium acetic acid 58, 4-aminocinnoline-3-carboxylic acid (59) and N – alkyl-1,4-dihydrocinnoline3-carboxamide 60.

synthesized by Stanczak et al., were the continuation of their earlier investigations into the synthesis of new biologically active cinnoline derivatives. These compounds were evaluated in terms of their CNS activity in ten separate behavioral tests. Some of them showed sedative and neuroleptic activity [71]. As a continuation of previous studies on cinnoline systems as potent CNS drugs, the new 4-aminocinnoline-3-carboxylic acid derivatives 59 (Fig. 17) variously substituted at the positions 6, 7, 8 were synthesized. These compounds were also evaluated in nine separate behavioral tests and the obtained results demonstrated that unsubstituted 4-aminocinnoline-3carboxylic acids had no effect on the central nervous system. Only the derivatives with Cl, F, or CH3 as substitu-

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ents in the aromatic ring possessed weak neuroleptic and sedative activity [72]. A number of N-alkyl-1,4-dihydrocinnoline-3-carboxamides 60 (Fig. 17) were synthesized and patented by Maruyama et al. and most of the compounds listed in the patent were active as 5-HT3 receptor antagonists [73]. In 1995, Rewcastle et al. prepared 4,7-diaminocinnoline 61 (Fig. 18) derivatives to test them as human tyrosine kinase inhibitors [74]. In the same year, Japanese scientists looking for a new antagonist of the 5-HT3 receptors as antiemetic drugs applied after chemotherapy, synthesized a series of heterocyclic derivatives [75]. These compounds were evaluated for 5-HT3 receptor antagonism in vivo in rats by measuring their ability to inhibit the Bezold – Jarisch reflex induced by 2-methyl-5-HT. Most of the tested compounds bearing heteroaromatic rings such as pyrrole, thiophene, furan, pyridine, pyridazine, cinnoline 62 (Fig. 18), etc., demonstrated weak 5-HT3 receptor antagonistic activity. The new N1-substituted 4-oxocinnolines 63 (Fig. 19) were synthesized by Stanczak et al. The activity on the central nervous system was evaluated in behavioral tests, but no neuroleptic activity was found. All tested compounds exhibited in large doses analgesic activity in the writhing test in mice [76]. As an extension of the same study, the 4-aminocinnoline-3-carboxamides 64 (Fig. 19) were prepared and tested for their influence on the central nervous system in mice and rats using behavioral tests [77]. The pharmacological screening included the following tests: spontaneous- and amphetamine-induced locomotor activity in mice, apomorphine-induced stereowww.archpharm.com

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Figure 20. Hexahydro-2H-cinnolin-3-one 65 and tricyclic pyridazinones, including condensed cinnoline 66.

typy in rats, pentetrazole shock in mice, “four plate test in mice”, rectal body temperature in mice and rats, m-CPP induced hyperthermia in rats, behavioral despair test in mice, and writhing test in mice. Most of the synthesized amides showed sedative action, as well as anticonvulsive, analgesic, and antiserotoninergic activity. Thus, the obtained results suggest that the tested compounds may act as atypical neuroleptics. The patent No JP 0859627 of Japanese researchers disclosed a series of hydrogenated cinnoline derivatives 65 (Fig. 20), which exerted antiserotonic activity [78]. Constantino et al. sythesized three series of tricyclic pyridazinones, including condensed cinnoline derivatives (66) (Fig. 20) and tested them in vitro in order to assess their ability to inhibit aldose reductase enzyme (ALR2). The most effective compounds had an IC50 in the range of 6 to 13 lM [79]. Menon et al. continued their previous research [63, 64] by synthesizing the series of 2,4-dimercaptopyrimido[5,4-c]cinnolines 67, 2,4-bis(alkylthio)pyrimido[5,4-c]cinnolines 68, and 4-amino-2-methylthiopyrimido[5,4-c]cinnolines derivatives with weak antibacterial properties [80]. Next, in 1997 Menon et al. synthesized the 5-(4-hydroxycinnolin-3-yl)tetrazoles 69 and 2-metyl-5-(4-hydroxycinnolin-3-yl)-1,3,4-oxadiazoles 70 (all compounds Fig. 21). In a biological screening the compounds exhibited moderate antimicrobial activity [81]. Tricyclic cinnoline derivatives were the subject of the Pinna et al. study. Synthesized 4-amino- and 4-acetylaminodihydrobenzo[f]cinnolin-2(3H)ones 71 (Fig. 22) were tested for their hypotensive, antihypertensive, and antiaggregating properties. The activity of the compounds was also compared with 8-acetylamino-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one, reported as a potent antihypertensive agent. In vivo tests indicated that 71 displayed weaker hypotensive and antihypertensive properties than dihydralazine, the reference drug. Both compounds were also more potent in inhibiting collageninduced platelet aggregation than ASA [82]. As a continuation of previous research, a series of 4a-methyl-4,4a,5,6tetrahydrothieno[2,3h]cinnolin-3(2H)-one 72 were synthesized (Fig. 22) and their pharmacological profile tested.

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Figure 21. Thiopyrimido[5,4-c]cinnolines 67, 68, 5-(4-hydroxycinnolin-3-yl)tetrazoles 69, and 2-metyl-5-(4-hydroxycinnolin-3yl)-1,3,4-oxadiazoles 70.

Figure 22. Dihydrobenzo[f]cinnolin-2(3H)ones 71, tetrahydrothieno[2,3h]cinnolin-3(2H)-one 72, 2-aryl-2,5,6,7-tetrahydro-3Hthieno[29,39:6,7]cyclohepta[1,2-c]pyridazin-3-ones (TCP) 73, and 2-aryl-5,6-dihydrothieno[2,3-h]cinnolin-3(2H)-ones (TCN) 74, tetrahydrobenzo[h]cinnolin-3(2H)-ones 75.

The activity of the compounds tested was compared to that of 8-acetylamino-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)one, which was reported as potent antihypertensive agent. In vivo tests indicated that three of the investigated compounds had lower, if significant, levels of antihypertensive activity compared to the lead compound, www.archpharm.com



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Figure 23. 4-Phenylaminocinnolines 76.

while all new derivatives exhibited lower hypotensive activity. Tricyclic thienocinnolinones demonstrated fairly potent platelet antiaggregatory activity as well [83]. The scientists of Yoshitomi Pharmaceutical Industries Ltd. synthesized and evaluated the affinity of a series of 2-aryl derivatives to benzodiazepine receptors (BZRs) in the excised brain of rats and also the intrinsic efficacy in augmentation of the c-aminobutyric acid-induced chloride currents in the dissociated sensory neurons of frogs. These derivatives were identified as 2-aryl-2,5,6,7-tetrahydro-3H-thieno[29,39:6,7]cyclohepta[1,2-c]pyridazin-3-ones (TCP) 73 and 2-aryl-5,6-dihydrothieno[2,3-h]cinnolin-3(2H) ones (TCN) 74 (Fig. 22). All synthesized compounds showed a high affinity to BZRs and among the synthesized compounds, 8-(1-hydroxyethyl)-2-(4-methylphenyl)5,6-dihydrothieno[2,3-h]cinnolin-3(2H)-one, which can be classified as a BZR partial agonist, was found to exhibit anxioselective features [84]. As a continuation of previous studies [82, 83] on 7,8-disubstituted 4,4a5,6-tetrahydrobenzo[h]cinnolin-3(2H)ones, Pinna et al. synthesized a new series of derivatives 75 (Fig. 22) and tested them in comparison with previously reported compounds bearing potent antihypertensive and antithrombotic properties. Binding studies on phosphodiesterase (PDE) isoenzymes showed that the tested compounds exhibited a modest affinity towards PDE III [85]. The patent from Zeneca Ltd. WO 9734,876, disclosed a series of 4-phenylaminocinnolines 76 (Fig. 23). The title compounds were prepared as vascular endothelial growth factor antagonists [86]. In 1997, Stanczak et al. continuing the study on cinnoline-condensed systems as potent CNS drugs, synthesized a new series of 2-methylpyrimido[5,4-c]cinnolin-4(3H)ones 77 (Fig. 24), variously substituted at the positions 3, 7 – 9 [87]. The impact on the central nervous system was evaluated in mice and rats by behavioral tests and some of them exerted sedative effect in lower doses. However, the 2,4-dioxo-1,2,3,4-tetrahydropyrimido[5,4-c]cinnolines 78 (Fig. 24), variously substituted at the positions 3, 7 – 9, were synthesized and their influence on the central nervous system in mice and rats was evaluated. Some of them exerted high sedative activity at low doses [88].

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Figure 24. Pyrimido[5,4-c]cinnolines 77, 78, 79 and arylopyrazolo[4,3-c]cinnolines 80.

The same authors prepared also the substituted 3-aminopyrimido[5,4-c]cinnolines 79. The biological investigation showed activity in the CNS. The tested compounds significantly inhibited amphetamine-induced hypermotility and spontaneous locomotor activity in mice. Some of them showed anticolvulsive activity in the pentatetrazole test and prevented the m-chlorophenylopiperazineinduced hyperthermia in rats [89]. The cinnoline derivatives, synthesized by Ricci et al. were tested in order to trace a possible auxin- or antiauxin-like activity. The experimental tests were performed on pea seedlings, flax roots, and tomato regeneration. Although the compounds did not show an effect comparable to that of auxins, they inhibited auxin-induced rooting [90]. The arylopyrazolo[4,3-c]cinnolines 80 (Fig. 24) were synthesized by Bantic. Their pharmacological properties were determined using the chronic graft-vs. – host and the inhibition of eosinophilia tests [91]. The compounds (81) synthesized by Matsuna et al. inhibited the phosphorylation of PDGF acceptors and the abnormal proliferation or migration of cells. Thus, these compounds may be effective in preventing or treating cell proliferative diseases such as arterial sclerosis, vascular reocclusion diseases, cancer and glomerulosclerosis [92]. The patent from Astra Pharmaceuticals Ltd. WO 9745,428 prepared by Bantick, disclosed a series of new derivatives of condensed cinnolines 82 (Fig. 25), in particular pyrido[h]cinnoline, pyrido[h]cinnolinone, pyridocyclopenta[1,2-c]pyridazine, pyridocyclopenta[1,2-c]pyridazinone, pyridocyclohepta[1,2-c]pyridazine, and pyridocywww.archpharm.com

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Figure 25. The structure of 4,5,6,7,8-substituted cinnolines 81, pyrido[h]cinnolines, and pyrido[h]cinnolinone 82, 83.

clohepta[1,2-c]pyridazinone derivatives [93]. Some of them were found useful as antiallergic and anti-inflammatory agents. Compound 83 (Fig. 25) showed e. g. 45% inhibition of IgE production at 10 mg/kg and certain compounds 82 showed activities in the chronic graft-vs. – host test and the inhibition of eosinophilia test with ED50 values of 0.1 – 10 mg/kg. In further studies, Bantick synthesized a series of fused pyridazines 84 (Fig. 26) as allergy inhibitors and antiinflammatory agents [94]. One of them, 2-(4-chlorophenyl)-2,3,4,4a5,6-hexahydropyrido[2,3-h]cinnoline, at 10 mg/kg in mice inhibited IgE production by 58% in a screen for inhibition of graft-vs. – host disease. The indolo[3,2-c]cinnoline derivatives 85 (Fig. 26), prepared by Barraja et al., inhibited the proliferation of leukemia, lymphoma, and solid tumor-derived cell lines at micromolar concentrations. Some of them showed antibacterial activity, also against Gram-positive bacteria, being up to 200-times more potent than the reference drug streptomycin and were endowed with good antifungal activity, particularly against Cryptococcus neoformans [95]. Another group of antimicrobial agents of 4-[5-substituted-2-furanyl)amino]-7-substituted aryloxy-6-fluorocinnoline-3-carboxylic acids derivatives 86 (Fig. 26) were synthesized by Saravanan et al. Biological screening exhibited antimicrobial activity comparable with standard drugs at equivalent concentrations [96]. A new class of DNA intercalators of pyridazino[19,69:1,2]pyrido[4,3-b]indol-5-inium derivatives system

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Figure 26. Derivatives of 2-(4-chlorophenyl)-2,3,4,4a5,6-hexahydropyrido[2,3-h]cinnoline 84, indolo[3,2-c]cinnoline 85, and 4-[5-substituted-2-furanyl)amino]-7-substituted aryloxy-6-fluorocinnoline-3-carboxylic acids 86.

Figure 27. Pyridazino[19,69:1,2]pyrido[4,3-b]indol-5-inium derivatives 87, substituted 4phenylaminocinnolines 88, thieno[3,2-h]cinnolinone analogs 89, and benzo[h]cinnolinone carboxylic acids 90.

87 (Fig. 27) were prepared by Molina et al. Biological screening was performed using UV-vis spectroscopy, viscometric detections, and unwinding angle detections. It was found that only some of the derivatives acted as good DNA intercalators [97]. www.archpharm.com


Figure 28. The structure of 4-oxo-1,4-dihydrocinnoline-3-carboxamides 91.

The substituted 4-phenylaminocinnolines 88 (Fig. 27) and their related compounds were synthesized by Hennequin et al. as potential inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt and KDR) tyrosine kinase activity. Enzyme screening indicated that a narrow structure-activity relationship (SAR) existed for the bicyclic ring system, with quinazolines, quinolines, and cinnolines having activity and with quinazolines and quinolines generally being preferred. Replacement of the quinazoline nucleus by cinnolone was tolerated but led to the reduction in potency (about 160-fold) [98]. Another series of condensed cinnoline systems, the thieno[3,2-h]cinnolinone analogs 89 (Fig. 27), which is structurally related to the early obtained 2,3,4,4a,5,6-hexahydrothieno[3,2-h]cinnolin-3-one, was synthesized as a weak inhibitor of the matrix metalloproteinase MMP-8 (human neutrophil collagenase). Preliminary SAR studies have shown that the unsubstituted compound inhibitor does not seem to be able to coordinate the catalyticallyactive zinc ion but preferably interacts with the peptidebinding region of the active site [99]. As a continuation of previous studies on pyridazinone carboxylic acids as potent and selective aldose reductase (ALR2) inhibitors [79], a new series of benzo[h]cinnolinone carboxylic acids 90 (Fig. 27), variously substituted at the positions 4, 7 – 10 and differently modified both at the central ring and at the acidic side chain, were synthesized and tested by Costantino. Comparison with previously synthesized compounds allowed a more precise evaluation of structure-activity relationships for this class of compounds [100]. The patent from Pharmacia & Upjohn Company, disclosed a series of new derivatives of 4-oxo-1,4-dihydrocinnoline-3-carboxamides 91 (Fig. 28). The new compounds were prepared as antiviral agents. They are particularly effective against Varicella zoster virus (VZV), the EpsteinBarr virus, the Herpes simplex virus (HSV), the Human herpes virus type 8 (HHV-8), and Cytomegalovirus (CMV). These

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Figure 29. Dibenzo[c,h]cinnolines 92.

Figure 30. Derivatives of benzo[f]cinnoline N-oxide 93, (6-chlorocinnolinyl)thiazole 94, 4hydroxycinnoline-3-carboxamide 95.

compounds inhibited human CMV, HSV, and VZV polymerases with IC50 values of 2.7 mM, 1.7 mM, and 1.1 mM, respectively [101]. The patent of Lavoie et al. provided various dibenzo[c,h]cinnolines 92 (Fig. 29) and their pharmaceutically acceptable salts. These tested compounds were inhibitors of topoisomerases I and II and were effective as cytotoxic agents against cancer cells, including drug-resistant cancer cells. As topoisomerase potential inhibitors, the compounds may also possess antibacterial, antifungal, antiprotozoal, antihelmintic, and/or antiviral activity [102]. A number of 9H-indeno[2,1-c]pyridazine N-oxides and benzo[f]cinnoline N-oxides 93 (Fig. 30) synthesized by Gavini et al. were tested for antimicrobial activity. All new products were inactive against Gram-negative bacteria and fungi. Some of them showed a moderate activity against Gram-positive Staphylococcus aureus and Staphylococcus epidermidis. In the series, 9-nitrobenzo[f]cinnoline N-oxide possessed the highest activity especially against Trichomonas vaginalis (MIC = 3.9 mg/mL). It is www.archpharm.com

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Figure 31. (4-Aminocinnolin-3-yl)arylmethanones 96 and 1,2-dihydro-4-aryl-2-oxopyrido[3,2-c]cinnoline derivatives 97, and 2,7,8,9-tetrahydro-6-methoxy-3H-benzo[de]cinnolin-3-one 98.

worth mentioning that the structure of benzo[f]cinnoline N-oxide bearing a C-6 nitro group, is important for its antitrichomonas activity and the best of the tested compounds being about six times more active than metronidazole used as a reference drug [103]. However, a new (6-chlorocinnolinyl)thiazoles 94 (Fig. 30), synthesized by Vingkar et al. possessed antibacterial, antitubercular, and antifungal activities [104 – 106]. The 4-hydroxycinnoline-3-carboxamides were a subject of a patent of Pharmacia +Upjohn Company. The compounds presented (cf. 95; Fig. 30) may be used for the treatment or prevention of herpes viruses. Some of them showed a 51% inhibition of the HCMV polymerase at a concentration of 20 mM [107]. The disubstituted (4-aminocinnolin-3-yl)arylmethanones 96 and 1,2-dihydro-4-aryl-2-oxopyrido[3,2-c]cinnoline derivatives 97 (Fig. 31), described by Amer, were effective against sixty cancer types. Some compounds were also tested for antimicrobial activity against Gram-positive and Gram-negative bacteria [108]. The compounds of 2,7,8,9-tetrahydro-6-methoxy-3H-benzo[de]cinnolin-3-one 98 (Fig. 31) or their pharmaceutically acceptable salts, may be useful for the treatment of acute phase apoplexy, inflammation and Alzheimer's, Parkinson's, Huntington's disease [109]. The anthrapyridazones constitute a novel group of antitumor compounds that can overcome multidrug resistance. Synthesis and biological evaluation of some 2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-dione derivatives 99, 100 (Fig. 32) were described by Stefanska et al. All analogues showed in vitro cytotoxic activity against murine leukemia (L1210) and human leukemia (K562) cell lines. The compounds were also active against human leukemia multidrug resistant (K562/DX) cell line with a

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Figure 32. Chemical structures of tetracyclic cinnoline compounds 99, 100 and cinnoline derivatives described by Hennequin 101.

resistance index (RI) in a 1 to 3 range depending on the compound's structure. Two of the most active in vitro compounds were also tested in vivo against murine P388 leukemia and displayed antileukemic activity comparable with that of Mitoxantrone [110]. These findings relate to the compounds of the formula of 101 (Fig. 32) described by Hennequin. The patents disclosed preparation of compounds and their pharmaceutically acceptable salts as active ingredients. New agents inhibited the effects of vascular endothelial growth factor (VEGF), and this properties may be useful for the treatment of diseases such as cancer and rheumatoid arthritis [111, 112]. The chemical modification of cinnoxacin was studied with the aim of improving its antibacterial activity. A series of 4-imino-1,4-dihydrocinnoline-3-carboxylic acid derivatives 102, 103 (Fig. 33) was synthesized and their in vitro antibacterial activity was evaluated. These derivatives were designed as isosteric analogs of fluoroquinolones and characterized by the presence of an imine www.archpharm.com



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Figure 34. Derivatives of 11H-isoquino[4,3-c]cinnolin-12-one 106 and tetrahydrothieno[2,3-h]cinnolinone 107.

Figure 33. 4-Imino-1,4-dihydrocinnoline-3-carboxylic acid derivatives 102, 103, dibenzo[c,h]cinnolines 104, and pyrazolo[4,3-c]cinnolines 105.

group instead of an oxo group at the 4-position and nitrogen atom in position 2. The in vitro antibacterial activity of these compounds against Gram-positive and Gramnegative bacteria was examined. The MIC of the most active compounds lies in the range of the first generation of quinolones such as nalidixic acid. The compounds with dichlorobenzyl substituent showed enhanced activity against Gram-positive bacteria (MIC = 25 lg/mL) [113]. Several substituted dibenzo[c,h]cinnolines 104 (Fig. 33) were synthesized and their potential for targeting topoisomerase I and their relative cytotoxic activity were evaluated. Selected benzo[i]phenathridines are capable of stabilizing the cleavable complex formed with topoisomerase I and DNA. This study was initiated to examine if dibenzo[c,h]cinnolines, which are in essence aza analogues of benzo[i]phenanthridines and possess similar pharmacological properties. Compared to similarly substituted benzo[i]phenanthridines, the dibenzo[c,h]cinnoline analogues exhibit more potent topoisomerase I – targeting activity and cytotoxicity. These compounds with significant topoisomerase I-targeting activity did exhibit cross-resistance in camptothecin-resistant cell lines. The cytotoxicity of these dibenzo[c,h]cinnolines was not diminished in cells overexpressing the efflux transporter, MDR1. These data indicate that substituted dibenzo[c,h]cinnolines can exhibit potent topoisomerase Iactivity and are capable of overcoming the multi-drug resistance associated with this efflux transporter [114]. The pyrazolo[4,3-c]cinnolines 105 (Fig. 33) were prepared by Dahmen et al. as inhibitors of Itk kinase activity (Inter-

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leukin-2 inducible T-cell kinase). The new synthesized compounds may be useful for treating asthma and allergic rhinitis. One of them, 6-bromo-1H-pyrazolo[4,3-c]cinnolin-3-ol with phenylboronic acid, afforded IC50 of 0.53 lM against Itk kinase [115]. Novel anticancer agents with potent topoisomerase Itargeting activity and cytotoxicity are 11H-isoquino[4,3c]cinnolin-12-one derivatives 106 (Fig. 34). The presented compound and its 11-butyl- analog were evaluated for antitumor activity in the human tumor xenograft model using athymic nude mice. The non-estrogen responsive breast tumor cell line MDA-MB-435 was used in these assays, at dose levels which approached the maximum tolerated dose. Tested compounds proved to be effective in inhibiting tumor growth in vivo when administered orally or by i.p. injections [116]. A series of tetrahydrothieno[2,3-h]cinnolinone derivatives 107 (Fig. 34) were synthesized by Pau et al. and evaluated in vitro for their ability to inhibit pig lens aldose reductase (ALR2), an enzyme involved in the appearance of diabetic complications. Enzyme inhibition data were tested by spectrophotometric assay, following the consumption of NADPH. As reference compounds Sorbinil and Tolrestat were used. From the results obtained it seems that the tetrahydrothienocinnolinone core could act as a bioisoster for the tetrahydrobenzocinnolinone nucleus [117].

Conclusions In this paper, we have presented a general review of cinnoline derivatives. Cinnoline certainly seems to be an interesting heterocyclic system, and its derivatives exerted multidirectional biological activity. However, except for cinnoxacin and cinnofuradion, the remaining derivatives of cinnoline, despite profitable biological property are not fully established as potential drugs. On the other hand, the growing number of publications in the last decade allows scientists to speculate on the use of the new cinnoline derivatives as drugs. www.archpharm.com

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The condensed systems of cinnoline showing anticancer activity due to their topoisomerase inhibitory properties and the compounds showing anti-angiogenic, antibacterial, and antifungal properties seems to be particularly interesting. For that reason, cinnolines are subjects to rational and intensive biological investigations in trials to find new antimicrobial and other activities. These findings will be the driving forces in designing new cinnoline derivatives used as potential drugs or compounds with other biological activities.

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