Journal of Chemistry

Volume 2014 (2014), Article ID 563406, 21 pages

http://dx.doi.org/10.1155/2014/563406

Review Article

Pharmacological Profile of Quinoxalinone

Youssef Ramli,¹ Ahmed Moussaif,² Khalid Karrouchi,³ and El Mokhtar Essassi⁴

¹Laboratoire National de Contrôle des Médicaments, D M P, Ministère de la Santé, Madinat Al Irnane, BP 6206, Rabat, Morocco

²Unité de la Radioimmunoanalyse, Centre National d’Etudes Scientifiques et Techniques d’Energie Nucléaire, BP 1382, Rabat, Morocco

³Laboratoire de Chimie Thérapeutique, Faculté de Médecine et de Pharmacie de Rabat-Souissi, Université Mohamed V, BP 6203, Rabat, Morocco

⁴Laboratoire de Chimie Organique Hétérocyclique, RAC 21, Université Mohammed V-Agdal, Rabat, Morocco

Received 19 May 2013; Accepted 22 October 2013; Published 9 February 2014

Academic Editor: Marc Visseaux

Copyright © 2014 Youssef Ramli et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Quinoxalinone and its derivatives are used in organic synthesis for building natural and designed synthetic compounds and they have been frequently utilized as suitable skeletons for the design of biologically active compound. This review covers updated information on the most active quinoxalinone derivatives that have been reported to show considerable pharmacological actions such as antimicrobial, anti-inflammatory, antidiabetic, antiviral, antitumor, and antitubercular activity. It can act as an important tool for chemists to develop newer quinoxalinone derivatives that may prove to be better agents in terms of efficacy and safety.

1. Introduction

The quinoxalinones are a class of heterocyclic compounds with different applications in various fields; these have been studied intensively as important heterocyclic system for the synthesis of biologically active compounds ranging from herbicides and fungicides to therapeutically usable drugs. A literature survey identified several quinoxalinones derivatives in the development phase as potential new drugs. The versatility of the quinoxalinones skeleton, in addition to its relative chemical simplicity and accessibility, makes these chemicals amongst the most promising sources of bioactive compounds. This has led to the discovery of a wide variety of compounds that are of high interest from the point of view of antimicrobial, antifungal, antiviral, anti-inflammatory, and antitumor effects among others.

2. Antimicrobial Activity

Antimicrobial agents are essential for the treatment of a number of diseases of bacterial or fungal origin, and many such agents are used clinically and industrially. Recently, however, bacteria have acquired drug resistance and so the development of new antimicrobial agents is required [1–3]. A number of compounds based on nitrogen-containing heterocycles show antimicrobial activity and have been developed for clinical use [4]. Among the various classes of heterocyclic units, the quinoxaline ring has frequently been used as a component of various antibiotic molecules, such as hinomycin, levomycin, and actindeutin, which inhibit the growth of Gram-positive bacteria and are active against various transplantable tumors [5–7].

Another notable activity of quinoxalinones is the antimicrobial one. In fact, Kotharkar and Shinde [8] have shown that 9,10-dimethyl-2-methoxy-6-oxo-7,12-dihydro-chromo-[3,4-b]quinoxaline 1 has both antibacterial and antifungal activities. In another study [9], it has been shown that quinoxalinones 2, 3, 4, and 5 (Figure 1) possess the same activities.

Figure 1: Chemical structures of compounds tested.

In the search for new antimicrobial agents, 2(1H)-quinoxalinones and their hexahydro derivatives were prepared [10]. Thiosemicarbazide 6 (Figure 2) derived from hexahydro-2(1H)-quinoxalinone showed a high in vitro antibacterial activity.

Figure 2: Chemical structure of compound 6.

A series of 3-(3-oxo-3,4-dihydroquinoxalin-2-yl) propionic acid derivatives was synthesized and then treated with hydrazine hydrate to yield its hydrazones 7 (Figure 3). This was further reacted with substituted aromatic aldehydes to produce final compounds 7a–r (Table 1). All the synthesized compounds were evaluated for their antimicrobial and anti-inflammatory activity [11].

Table 1: List of compounds prepared 7a–r.

Compounds
R
R₁
Compounds
R
R₁

7a
H
4-F-C₆H₄
7j
H
4-NO₂-C₆H₄

7b
H
2-Cl-C₆H₄
7k
CH₃
4-F-C₆H₄

7c
H
3-Cl-C₆H₄
7l
CH₃
2-Cl-C₆H₄

7d
H
4-Cl-C₆H₄
7m
CH₃
3-Cl-C₆H₄

7e
H
4-OH-C₆H₄
7n
CH₃
4-Cl-C₆H₄

7f
H
4-OCH₃-C₆H₄
7o
CH₃
4-OH-C₆H₄

7g
H
3,4-OCH₃-C₆H₃
7p
CH₃
4-OCH₃-C₆H₄

7h
H
3,4,5-OCH₃-C₆H₂
7q
CH₃
2-NO₂-C₆H₄

7i
H
2-NO₂-C₆H₄
7r
CH₃
4-NO₂-C₆H₄

Figure 3: Chemical structures of compounds tested.

Ishikawa et al. [12] synthesized some derivatives of 2,3-bis(bromomethyl)quinoxaline with substituents at the 6- and/or 7-positions and evaluated their activities against bacteria and fungi. Of the 12 compounds (Table 2), nine 9a–h, 9j, 9k showed antibacterial activity. The derivative 9g, which bears a trifluoromethyl group at the 6-position, showed the highest activity against Gram-positive bacteria, while 16c, which has a fluoro-group at the 6-position, showed the widest antifungal activity spectrum. However, only the derivative with an ethyl ester substitution 9k showed activity against Gram-negative bacteria (Figure 4 and Table 3).

Table 2: List of compounds tested.

Compounds
R₁
R₂
Compounds
R₁
R₂

9a
CH₃
CH₃
9g
CF₃
H

9b
CN
H
9h
NO₂
H

9c
F
H
9i
CO₂
H

9d
Cl
H
9j
CO₂CH₃
H

9e
Br
H
9k
CO₂CH₂CH₃
H

9f
OCH₃
H
9l
OH
H

Table 3: Antifungal activities of compounds 9a–l.

MIC (g/mL)

R₁
R₂
Mold
Yeast

A. n.a
P. c.b
C. c.c
A. p.d
A. s.e
M. s.f
G. v.g
R. r.h
S. c.i

9a
CH₃
CH₃
>100
>100
>100
>100
>100
>100
>100
>100
>100

9b
CN
H
50
25
25
50
25
25
>100
100
50

9c
F
H
50
50
50
100
50
25
100
100
50

9d
Cl
H
50
100
25
>100
>100
50
>100
>100
>100

9e
Br
H
100
100
50
>100
>100
50
>100
>100
>100

9f
OCH₃
H
50
>100
50
100
100
50
>100
>100
100

9g
CF₃
H
50
50
100
50
100
25
>100
100
50

9h
NO₂
H
100
100
50
100
25
50
100
>100
50

9i
COOH
H
>100
>100
>100
>100
>100
>100
>100
>100
>100

9j
CO₂CH₃
H
50
100
100
50
100
25
>100
>100
50

9k
CO₂CH₂CH₃
H
>100
>100
>100
100
>100
100
>100
100
100

9l
OH
H
>100
>100
>100
>100
>100
>100
>100
>100
>100

Aspergillus niger, bPenicillium citrinum, cCladosporium cladosporioides, dAureobasidium pullulans, eAlternaria sp., fMucor spinescens, gGliocladium virens, hRhodotorula rubra, iSaccharomyces cerevisiae.

Figure 4: Chemical strucure of compound 9a–l.

Seven derivatives of thiadiazolo[20,30:2,3]imidazo quinoxalines 10a–g were synthesized [13] for potential antimicrobial agents. The antimicrobial evaluation of the newly synthesized products against a broad spectrum of bacteria was performed using the disc diffusion technique and the agar streak dilution method. It was found that, among the synthesized compounds, only the unsubstituted and electron donating group containing molecules has shown better antimicrobial activity when compared to electron withdrawing compound on the phenyl group. Of all the synthesized compounds 10a, 10b, and 10d had shown good antibacterial and antifungal activity (Scheme 1).

Scheme 1: Synthesis of compounds 10a–g.

The compound 2,6-dimethyl-3-f-quinoxaline 1,4-dioxide 11f was found to inhibit 50% of Leishmania growth at 8.9 lM, with no impact against proliferative kidney cells and with low toxicity against THP-1 cells and murine macrophages. The compounds belonging to the propenone quinoxaline series were moderately active against T. cruzi. Among these compounds (Figure 5), two were particularly interesting, (2E)-1-(7-fluoro-3-methyl-4 quinoxalin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propenone and 12b (2E)-3-(3,4,5-trimethoxy-phenyl)-1-(3,6,7-trimethyl-quinoxalin-2-yl)-propenone 12f. The former possessed selective activity against proliferative cells (cancer and parasites) and was inactive against murine peritoneal macrophages; the latter was active against Leishmania and inactive against the other tested cells [14].

Figure 5: Chemical structures of compounds tested.

Novel 8-chloro-1,4-substituted-triazoloquinoxaline derivatives 13a–j have been synthesized by Suresh et al. [15] (Figure 6 and Table 4). All the above compounds were screened for antimicrobial activity and antioxidant activity and their bioassay showed them to possess significant antimicrobial activity and anti-oxidant activity.

Table 4: List of compounds prepared.

Compound
R
R₁

13a

13b

13c

13d

13e

13f

13g

13h

13i

13j

Figure 6: Chemical structures of compounds 13a–j.

In an effort to develop potent antimicrobial agents, Ghadage and Shirote [16] have synthesized some substituted quinoxalin-2(1H)-one derivatives. Final derivatives 14a–e (Figure 7) were screened for their in vitro antibacterial activity against range of Gram positive and Gram-negative; also for their anti-fungal activity against a strain of Candida albicans species. It was found that all the selected compounds exhibit wide antimicrobial activity. Amongst these compounds, compound 14b was highly active against E. coli. The compounds 14d and compound 14c were highly active against P. aeruginosa and S. aureus. The compounds 14c and 14d were highly active against C. albicans.

Figure 7: Chemical structures of compounds tested.

A series of quinoxalines 15a–g (Figure 8 and Table 5) screened for antibacterial activity among them compound 15a was displayed activity against E. coli, compounds 15d and 15f against P. mirabilis, compound 15c against B. subtilis, and compound 15e against S. aureus shows maximum activity at 200 μg/disc [17].

Table 5: List of compounds prepared.

a
b
c
d
e
F
g

R₁
CH₃
2-Furyl
CH₃
2-Furyl
CH₃
H
CH₃

R₂
Ph
2-Furyl
Ph
2-Furyl
Ph
Ph
Ph

R₃
H
CH₃
H
PhCO
PhCO
H
MeOPhCO

R₄
H
CH₃
Cl
H
H
CH₃
H

X
N
C
C
C
C
C
C

Figure 8: Chemical structures of compounds 15a–g.

A series of ethyl 2-[(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetyl]-3-oxo-2,3-dihydro-1Hpyrazole-4-carboxylate derivatives 16a–i (Figure 9 and Table 6) was prepared and evaluated for their antitubercular activities [18]. All compounds were screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv (MTB). Minimum inhibitory concentrations were determined and interpreted for Mycobacterium tuberculosis H37Rv according to the procedure of the approved macrodilution reference method of antimicrobial susceptibility testing. Among all the compounds synthesized 16b, 16c, and 16f were found to be the most active compounds against MTB with MIC (25 μg/mL) [18].

Table 6: List of compounds tested.

Compound
R

16a

16b

16c

16d

16e

16f

16g

16h

16i

Figure 9: Chemical structures of compounds tested 16a–i.

A series of 2-quinoxalinone-3-hydrazone derivatives (Figure 10) synthesized was evaluated for their antimicrobial activities [19]. The results showed that this skeletal framework exhibited marked potency as antimicrobial agents. The most active antibacterial agent was 3-{2-[1-(6-chloro-2-oxo-2H-chromen-3 yl) ethylidene]hydrazinyl}quinoxalin-2(1H)-one 23, while 3-[2-(propan-2 ylidene)hydrazinyl]quinoxalin-2(1H)-one 18, appeared to be the most active antifungal agent.

Figure 10: Chemical structures of compounds 17–33.

The compound 1-methyl-7-nitro-4-(5-(piperidin-1-yl) pentyl)-3,4-dihydroquinoxalin-2(1H)-one 34 (Figure 11) was evaluated [20] against a blood-induced infection with chloroquine-sensitive Plasmodium yoelii yoelii lethal strain in CD1 mice in a 4-day test scheme. The results obtained in this study showed that the infection outcome of P. yoelii yoelii-infected mice is affected by compound 34 by slowing down the parasite replication, retarding the patency time, and increasing their survival time. Although compound 34 was active at higher doses than chloroquine, these results leave a door open to the study of its structure in order to improve its antimalarial activity.

Figure 11: Chemical structures of compound 34.

Some novel pyrido[2,3-g]quinoxalinones 35–46 (Figure 12), variously substituted at the C-3 position, were synthesized [21], structurally determined, and submitted to a preliminary in vitro evaluation for antibacterial, anti-Candida activities (1). Results of the antimicrobial screening showed that all compounds, with the exception of 38, 43, and 44, exhibited interesting activity against all strains tested.

Figure 12: Chemical structures of compounds tested.

3. Anti-Inflammatory Activity

In the search for new anti-inflammatory agents, 2(1H)-quinoxalinones and their hexahydro derivatives were prepared [10]. The 2(1H)-quinoxalinone derivative bearing 4-chlorophenyl-2,3-dihydrothiazole moiety 45 (Figure 13) exhibited the highest anti-inflammatory activity without causing any ulcer side effects like the selective COX-2 inhibitor celecoxib.

Figure 13: Chemical structures of compound 45.

Burguete et al. [22] studied the anti-inflammatory and antioxidant activity of several quinoxalines. Compound 46 (Figure 14) presented the most interesting activity.

Figure 14: Chemical structures of compounds 46 and 47.

Similarly, in the study of the same anti-inflammatory activity, Li et al. [23] have evaluated the activity of the quinoxaline 47 by varying R and R′ substituents. Compounds B1 and B2 (Figures 14 and 15) were found to be nonpeptide antagonists of the interleukin-8 molecule receptor, which is involved in several inflammatory diseases and cancer [23].

Figure 15: Chemical structures of compounds tested.

4. Antiviral Activity

Since 2005, the World Health Organization (WHO) estimated that worldwide more than 40 million people were infected with the human immunodeficiency virus (HIV). In particular, South America is facing a rapidly growing number of HIV infections which require an effective antiviral therapy. Ideally, anti-HIV drugs should be highly selective and have good oral availability and favorable pharmacokinetics. Moreover, large-scale production, at low costs to make them accessible for patients in developing countries, would constitute a crucial advantageous feature. Several derivatives of quinoxaline display interesting activity against HIV as nonnucleosidic inhibitors of the reverse transcriptase (RT) [24, 25]. Some of quinoxalinone derivatives synthetized by Gris et al. [26] exhibited good inhibitor activity against some human tumoral cells and the lymphoma related to HIV-1. The studies against HIV were developed for compound 48e and the methyl ester of 49c, and no activity was observed, as compared to efavirenz, though it is worth mentioning that the assayed concentrations up to the order 10−6 M were not cytotoxic. On the other hand, potential antitumoral activity of compounds 49a and 49b has been investigated in the National Cancer Institute (USA). Compound 49a displayed in vitro activity against a nonsmall lung cell line (EKVX) and human kidney cells (CL A498), while 49b displayed in vitro activity against central nervous system (CNS) human cells. However, the cytotoxicity shown in both cases was higher than the minimal required to continue the screening. 4c was evaluated by the Biological Evaluation committee (BEC). Findings indicated a higher activity against AIDS-related lymphoma than the reference compound employed by the NCI. Nevertheless, it did not reach the lower toxicity level to perform in vivo studies (Figure 16).

Figure 16: Chemical structures of Compounds tested.

Great efforts have been dedicated to the design of compounds acting as selective inhibitors of the HIV-1, and in this case a series of novel N4-(hetero)arylsulfonylquinoxalinonederivatives 50 (Figure 17) way prepared by Xu et al. in a straight and efficient way [27]. Of all the synthesized compounds, five compounds exhibited potent anti-HIV-1 replication activities with IC₅₀ value at the level of 10−7 mol/L. Preliminary structure-activity relationships were studied in detail and that will shed light on the discovery of more potent nonnucleoside reverse-transcriptase inhibitors [27] (Table 7).

Table 7: Antiviral activity of compounds 50a–h.

Compound
R₃
ArSO2
(M)

50a
H
Quinoline-8-sulfonyl
0.98

50b
H
3-Cyanobenzene-1-sulfonyl
>100

50c
H
2-Methyloxycarbonylthiophene-3-sulfonyl
2.02

50d
CH₃
Quinoline-8-sulfonyl
7.0

50e
CH₃
4-Nitrobenzene-1-sulfonyl
>100

50f
CH₃
3-Cyanobenzene-1-sulfonyl
55

50g
CH₃
2-Methyloxycarbonylthiophene-3-sulfonyl
0.2

50h
CH₃
2,5-Dichlorothiophene-3-sulfonyl
>100

Figure 17: Chemical strucure of compound 50a–h.

Similarly, other quinoxalinone derivatives have antiviral properties [28, 29]. Many studies have shown the activity of a few quinoxaline compounds towards the human immunodeficiency virus (HIV-1), including the 6,7-dimethyl-2-(pent-4-enyloxy)quinoxaline 52, [30] and 53, which not only inhibited HIV-1 RT, but also prevented its replication at the cellular membrane [31] (Figures 18 and 19, Table 8).

Table 8: List of compounds tested.

Compound
R₃
(M)

51a
H
2.02

51b
CH₃
0.2

51c
C₂H₅
5.0

51d
CH₂CH₂SCH₃
>100

51e
CH₂COOCH₃
>100

Figure 18: Chemical structures of compounds 51a–h.

Figure 19: Chemical structures of compounds prepared.

5. Enzyme Inhibitory Activity

We will mention a few patents showing various activities of quinoxalinone, as an inhibitor of the kinase protein [32].

The compound 54 [33] is a new molecular macrocycle derived from the quinoxalin-2-one inhibitor of cyclin-dependent kinases CDK1, 2, 4, and 6, while the compound 55 [34] inhibiting glycogen phosphorylase is the enzyme responsible for the metabolism of glycogen to glucose since glucose is overproduced in patients suffering from diabetes (Figure 20).

Figure 20: Chemical structures of compounds 54 and 55.

Imidazo[1,5-a]quinoxalines were synthesized that function as irreversible Bruton’s tyrosine kinase (BTK) inhibitors. The syntheses and SAR of this series of compounds are presented as well as the X-ray crystal structure of the lead compound 56 in complex with a gate-keeper variant of ITK enzyme (Figures 21 and 22). The lead compound showed good in vivo efficacy in preclinical RA models [35].

Figure 21: Chemical structure of compound 56.

Figure 22: X-ray structure of 56 in complex with a gate-keeper variant of ITK enzyme in the ATP binding site.

6. Antitumor Activity

Multidrug resistance (MDR) is a critical issue in cancer chemotherapy. Overexpression of P-gp is the most frequent cause of MDR. P-gp, a transmembrane glycoprotein, functions as an ATP-dependent drug transporter which unilaterally transports intracellular drugs out of cells to acquire drug resistance. A range of agents that can reverse the MDR phenotype and restore drug sensitivity to cancer cells have been developed [36, 37]. However, most of these agents have proven to be intrinsic toxic and having undesired effects on the pharmacokinetics of accompanying anticancer drugs. For instance, initial attempts to develop MDR modulators focused on verapamil and cyclosporin A [38–40]; these compounds demonstrated excellent in vitro reversal of MDR but failed to achieve clinical success due to their toxicity and/or their alteration of the pharmacokinetics of the coadministered anticancer drugs [40, 41]. Screening 11,000 compounds from commercially available libraries, Lawrence et al. [42] identified several structural platforms with good potential as MDR antagonists. Among these, the 2 oxoquinoxaline or quinoxalinone scaffold showed promise as a versatile scaffold to study P-gp antagonist [42]. Sun et al. [43] have designed and synthesized a series of substituted 1,3-dimethyl-1H-quinoxalin-2-ones. They found that some of the compounds displayed potential inhibition effect on MDR of cancer.

The compounds 57 and 58 (Figure 23) are the novel substituted 1,3-dimethyl-1H-quinoxalin-2-ones with high reversal folds on multidrug resistance in K562/A02 cells. These compounds might be the candidate agents for reversing MDR of cancer.

Figure 23: Chemical structures of compounds 57 and 58.

Quinoxalinone derivatives continue to be a standing interest of lot of research groups. So far, a great deal of data concerning the anticancer activity of more than 300 compounds constitute a library for the antifolic analogs [44–57]. During their investigation, Piras et al. [58] have taken into account as antifolate models either the classical methotrexate or the nonclassical trimetrexate as well as the corresponding dideazafolic derivatives. In this context they have proved that bioisosteric replacement of pteridine ring with Trifluoro-6-methylquinoxaline and trifluoro-7-quinoxaline affords a good substrate for the biological activity in the series of the classical antifolate analogs, whereas this was so in a few cases of the series of nonclassical ones. Another aspect being considered was also the bioisosteric replacement of 2-NH group with an oxygen that in some cases was of relevance in the anticancer activity. However, for development of the knowledge about the pharmacophoric pattern, the authors [58] thought to replace the 2-NH bridge in the above-cited series with oxygen on the ground that very recently American authors have found that quinoxalines bearing a 2-(4-substituted phenoxy) substituent were endowed with potent antitumor activity [59]. Thus, the list of compounds 59a–v (Figure 24 and Table 9) was prepared and the results of their activity presented in Table 10.

Table 9: List of compounds prepared.

Compound
R
R₁
R₂

59a
H
6,7-F
OMe

59b
Ph
H
OMe

59c
2-Th
H
OMe

59d
COOEt
H
OMe

59e
COOEt
7-CF₃
OMe

59f
COOEt
6,7-F
OMe

59g
Ph
H
OH

59h
2-Th
H
OH

59i
COOH
H
OH

59j
COOH
7-CF₃
OH

59k
COOH
6,7-F
OH

59l
Ph
H
NHgluH

59m
2-Th
H
NHgluH

59n
CONHgluEt
H
NHgluH

59o
COOH
7-CF₃
NHgluH

59p
CONHgluEt
7-CF₃
NHgluH

59q
Ph
H
NHgluH

59r
2-Th
H
NHgluH

59s
CONHgluH
H
NHgluH

59t
COOH
7-CF₃
NHgluH

59v
CONHgluH
7-CF₃
NHgluH

Table 10: , , and mean graph midpoints (MG-MID)a of in vitro inhibitory activity against human tumor cell linesb.

Compounds
= M
= M
= M

59c
4.14 = 72.44
4.02 = 95.49
4.00 = 100

59f
4.10 = 79.43
4.01 = 97.72
4.00 = 100

59g
4.22 = 60.25
4.01 = 97.72
4.00 = 100

59h
4.26 = 54.95
4.01 = 97.72
4.00 = 100

59i
4.20 = 63.09
4.00 = 100
4.00 = 100

59m
4.13 = 74.13
4.00 = 100
4.00 = 100

59n
4.63 = 23.44
4.15 = 70.79
4.02 = 95.49

Figure 24: Chemical structure of compound 59a–v.

There are many quinoxaline derivatives which showed antitumor activity; Corona et al. [60] showed that 5,7-diamino-3-phenyl-2-[(3,5-dimethoxy)phenoxy]quinoxaline 60 has an antitumor activity in vitro, towards several types of tumors. Also the 3-(4-bromophenyl)-2-(ethylsulfonyl)-6 methylquinoxaline-1,4-dioxide 61 (Figure 25), has an activity against the tumor in the hypoxia stage, which is a phase where the tumor shows a resistance during chemotherapy and radiotherapy [61].

Figure 25: Chemical structures of compounds 60 and 61.

Other compounds, derivatives of quinoxalinone, were submitted to a primary screening for anticancer activity following the known in vitro disease-oriented antitumor screening program, against a panel of about 60 human tumor cell lines [21]. The activity of each compound tested was deduced from a dose-response curve according to the data provided by NCI while compound 62 (Figure 26) was found to have encouraging in vitro anticancer activity at a concentration of 10–4 M.

Figure 26: Chemical structure of compound 62.

Fourteen out of 21 quinoxaline derivatives described by Piras et al.’s [62] present paper were selected at NCI for evaluation of their in vitro anticancer activity. Preliminary screening showed that some derivatives exhibited a moderate to strong growth inhibition activity on various tumor panel cell lines between 10–5 and 10⁴ M concentrations. Interesting selectivities were also recorded between 10–8 and 10–6 M for the compounds 63 and 64 (Figure 27).

Figure 27: Chemical structures of compounds tested.

Based on screening hit 1, a series of tricyclic quinoxalinones 65–71 (Figure 28) has been designed and evaluated for inhibition of PARP-1 [63]. Substitutions at the 7- and 8-positions of the quinoxalinone ring led to a number of compounds with good enzymatic and cellular potency. The tricyclic quinoxalinone class is sensitive to modifications of both the amine substituent and the tricyclic core.

Figure 28: Chemical structures of compounds 65–71.

The antitumor activity of synthesized quinoxalines 72–77 (Figure 29) has been evaluated by studying their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Said compounds demonstrated strong inhibitory effects on the EBV-EA activation without showing any cytotoxicity and their effects being stronger than that of a representative control, oleanolic acid. Furthermore, compound 72 exhibited a remarkable inhibitory effect on skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter [64].

Figure 29: Chemical structure of compound 72–77.

A series of ruthenium(II) arene complexes with 3-(1H-benzimidazol-2-yl)-1H-quinoxalin-2-one 78 (Figure 30), bearing pharmacophoric groups of known protein kinase inhibitors, related benzoxazole and benzothiazole derevatives have been synthtised, therefore antiproliferative activity in three human cancer cell lines (A549, CH1, and SW480) was determined by MTT assays, yielding IC₅₀ values of 6–60 μM for three unsubstituted metal-free ligands, whereas values for the metal complexes vary in a broad range from 0.3 to 140 μM. Complexation with osmium of quinoxalinone derivatives results in a more consistent increase in cytotoxicity than complexation with ruthenium [65].

Figure 30: Chemical structure of compound 78.

Deregulation of cellcycle control is a hallmark of cancer. Thus, cyclin-dependent kinases (Cdks) are an attractive target for the development of anticancer drugs. Rübsamen-Waigmann et al. [28] report the biological characterization of a highly potent pan-Cdk inhibitor with a macrocycle-quinoxalinone structure. Compound 79 (Figure 31) inhibited Cdk1, 2, 4, 5, 6, and 9 with equal potency in the nM range and was selective against kinases other than Cdks. This compound inhibited multiple events in the cell cycle in vitro, including retinoblastoma protein (pRb) phosphorylation, E2F-dependent transcription, DNA replication (determined by bromodeoxyuridine incorporation), and mitosis completion (assayed by flow cytometry) in the 10 nM range (Table 11).

Table 11: Enzyme inhibition activity of compound 79 against the Cdk family and other kinases.

Kinases
IC₅₀ (nM)
Selectivity (fold)

Cdk4
4.1
1.0

Cdk6
12

Cdk2
3.4

Cdk1
1.0

Cdk5
4.5

Cdk7
660

PKA

>730

PKC

230

ERK1

>730

ERK2

>730

P38

>2400

KDR

250

Flt-1

330

Flt-4

71

FGFR1

2000

FGFR2

610

Src

260

Tle-2

>4900

PDGF

480

EGFR

>2400

Figure 31: Chemical structure of compound 79.

Moreover, this compound induced cell death, as determined by induction of the subG1 fraction, activated caspase-3, and an exin V. In vivo, compound 79 showed antitumor efficacy at a tolerated dose. In a nude rat xenograft tumor model, an 8 h constant infusion of compound 79 inhibited pRb phosphorylation and induced apoptosis in tumor cells at 30 nM, which led to the inhibition of tumor growth. Immunosuppression was the only liability observed at this dose, but immune function returned to normal after 10 days. Suppression of pRb phosphorylation in tumor cells was clearly correlated with tumor cell growth inhibition and cell death in vitro and in vivo. In vivo, compound M inhibited pRb phosphorylation in both tumor and gut crypt cells. Rb phosphorylation may be a suitable pharmacodynamic biomarker in both tumors and normal tissues for monitoring target engagement and predicting the efficacy of compound 79 [66].

The KRAS oncogene is found in up to 30% of all human tumors. In 2009, RNAi experiments revealed that lowering mRNA levels of a transcript encoding the serine/threonine kinase STK33 was selectively toxic to KRAS-dependent cancer cell lines, suggesting that small-molecule inhibitors of STK33 might selectively target KRAS-dependent cancers. To test this hypothesis [67], we initiated a high-throughput screen using compounds in the Molecular Libraries Small Molecule Repository (MLSMR). Several hits were identified, and one of these, a quinoxalinone derivative, was optimized. Extensive SAR studies were performed and led to the chemical probe 53 that showed low nanomolar inhibition of purified recombinant STK33 and a distinct selectivity profile as compared to other STK33 inhibitors that were reported in the course of these studies. Even at the highest concentration tested (10 μM), 80 (Figure 32) had no effect on the viability of KRAS-dependent cancer cells. These results are consistent with other recent reports using small-molecule STK33 inhibitors. Small molecules having different chemical structures and kinase-selectivity profiles are needed to fully understand the role of STK33 in KRAS-dependent cancers. In this regard, 80 is a valuable addition to small-molecule probes of STK33.

Figure 32: Chemical structure of compound 80.

P-glycoprotein-mediated drug efflux from cells is believed to be an important mechanism in multidrug resistance (MDR) in cancer chemotherapy. The identification and development of P-glycoprotein inhibitors with high potency and low cytotoxicity hold great promise for overcoming MDR. A series of quinoxalinone derivatives was synthesized and evaluated primarily for their antiproliferative effect and MDR reversal activity in in vitro assay systems [56]. Biological assays demonstrated that the compounds 81a–t (Figure 33 and Table 12) were, in general, endowed with good activity as P-glycoprotein inhibitors. Among them, compounds which showed the highest MDR reversal activity without significant cytotoxicity displayed potent P-glycoprotein inhibition activities and may be worthy of further research as potential adjunctive agents for tumor chemotherapy [68].

Table 12: List of compounds tested.

Compound
R₁
R₂
Compound
R₁
R₂

81a
H

81l
H

81b
H

81m
H

81c
H

81n
H

81d
H

81o
H

81e
H

81p
F

81f
H

81q
OCH₃

81j
F

81r
H

81k
OCH₃

81s
H

81t
H

Figure 33: Chemical structure of compounds 81a–t.

7. Receptor Antagonist Activity

A series of quinoxalinones was synthesized as antagonists of bradykinin, which is a peptide responsible for the dilatation of blood vessels, thus leading to the lowering of blood pressure [69].

Bayoumi et al. [70] showed that 1,2,4-triazolo(4,3-a)quinoxalin-4-5H-one derivatives 82 and 83 (Figure 34) act as AMPA receptor antagonists.

Figure 34: Chemical structures of compounds tested.

8. Antithrombotic Activity

Excessive uncontrolled activation of the hemostatic system results in thromboembolic diseases, a major cause of morbidity and mortality in our society. The central role of the serine proteases factor Xa and thrombin in hemostasis make them attractive targets for antithrombotic therapy. Factor Xa, factor Va, calciums and phospholipids form the prothrombinase complex, which converts prothrombin into thrombin. Thrombin very efficiently initiates fibrin formation, platelet aggregation, and activation of factors V and VIII. Selective inhibitors of thrombin and factor Xa are expected to be therapeutically useful in the treatment or prophylaxis of thromboembolic diseases [71–73].

In order to design and develop orally active coagulation inhibitors containing heterocyclic core structures, Ries et al. [74] identified some compounds as potent thrombin inhibitors 2 in vitro.

Based on this lead structure novel coagulation inhibitors having quinoxalinone 84 (Figure 35) as the central template have been designed. These compounds inhibited thrombin and factor Xa in the nanomolar range.

Figure 35: Chemical strucure of compound 84.

9. Antidiabetic Activity

Diabetes is a serious metabolic disorder with micro- and macrovascular complications which causes significant morbidity and mortality. In the developing world, the diabetes epidemic is accelerating with an increased proportion of affected people in the younger population.

Recently, some reports described that type 2 diabetes was being diagnosed even in children and adolescents [75]. The latest WHO Global Burden of Disease estimate the worldwide burden of diabetes in adults to be around 173 million in the year 2002 [76] and around two-thirds of these live in developing countries. So, nowadays, it has become a growing public health concern worldwide causing severe and costly complications including blindness cardiac and kidney diseases [77]. Current therapies do little in preventing complications although they provide good glycemic control.

Besides this, these drugs are also associated with side effects. Thus, it is necessary to continue research for new and, if possible, more efficacious drugs, particularly bioactive quinoxalinone-based compounds, which are effective in the treatment of diabetes and its complications. Through this procedure, a new class of quinoxalinone-based aldose reductase inhibitors were synthesized successfully 85. Most of the inhibitors, with an N1-acetic acid head group and a substituted C3-phenoxy side chain, proved to be potent and selective. Their IC₅₀ values ranged from 11.4 to 74.8 nM. Among them, 2-(3-(4-bromophenoxy)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid 57 and 2-(6-bromo-3-(4-bromophenoxy)-2-oxoquinoxalin-1(2H)-yl)acetic acid were the most active 86 [78] (Figure 36).

Figure 36: Chemical strucure of compounds tested.

To conclude this review of biological activity of the quinoxalinone derivatives, we will mention that the compounds 87–89 (Figure 37) are considered as a novel potential therapeutic avenue for autism [79]; it is pharmacophore models are a promising milestone to a class of SSRIs with dual action.

Figure 37: Chemical structures of compounds 87–89.

Finally, a series of new quinoxaline derivatives 90 (Figure 38), which could act as modulators of the AMPA receptor mediators of synaptic responses, has been synthetized [80].

Figure 38: Chemical structure of compound 90.

The circle containing nitrogen designates a heterocycle of 5 to 8 rings, and the group R′ may be a group 2- or 3-alkyl, cycloalkyl, hydroxy, alkoxy, alkoxy-alkyl, hydroxy-alkyl, or carbamoyl.

10. Conclusion

In recent years, the quinoxalinone made a tremendous achievement in the biological and pharmacological fields. Also, the modifications in the basic structure of the quinoxalin-2-one have enabled the emergence of new derivatives with a wide spectrum of biological activities.

In conclusion a wide variety of biological activities of quinoxalinone have been described. Quinoxaline moiety containing 1,4-di-N oxide shows broad spectrum of activity against wide number of bacterial species and also exhibited cytotoxic activity. Those drugs containing quinoxaline moiety are Carbadox and Brimonidine. Carbadox, a well-known synthetic antibacterial agent used for treatment of various bacterial diseases, and Brimonidines showed the importance of quinoxalines as a pharmaceutical agent as it palliates the symptoms of glaucoma through reducing intraocular pressure.

Studies of these derivatives have shown that structural modification can improve its pharmacological profile conferring antibacterial, anticancer, anti-HIV, antidiabetic, and anti-inflammatory properties.

Conflict of Interests

The authors certify that there is no actual or potential conflict of interests in relation to their paper titled “Pharmacological Profile of Quinoxalinone.” This manuscript updated information on the most active quinoxalinone derivatives that have been reported to show considerable pharmacological actions.

References

S. K. Fridkin, J. C. Hageman, M. Morrison et al., “Methicillin-resistant Staphylococcus aureus disease in three communities,” The New England Journal of Medicine, vol. 352, no. 14, pp. 1436–1505, 2005.

W. T. Siebert, N. Moreland, and T. W. Williams Jr., “Methicillin-resistant Staphylococcus epidermidis,” Southern Medical Journal, vol. 71, no. 11, pp. 1353–1355, 1978.

A. H. C. Uttley, N. Woodford, A. P. Johnson et al., “Vancomycin-resistant enterococci,” The Lancet, vol. 342, no. 8871, pp. 615–617, 1993.

J. Ohkanda and A. Katoh, “N-hydroxyamide-containing heterocycles: synthesis, reactivities, and iron(III)-chelating properties,” Reviews on Heteroatom Chemistry, vol. 18, pp. 87–118, 1998.

A. Dell, D. H. Williams, and H. R. Morris, “Structure revision of the antibiotic echinomycin,” Journal of the American Chemical Society, vol. 97, no. 9, pp. 2497–2502, 1975.

C. Bailly, S. Echepare, F. Gago, and M. J. Waring, “Recognition elements that determine affinity and sequence-specific binding to DNA of 2QN, a biosynthetic bis-quinoline analogue of echinomycin,” Anti-Cancer Drug Design, vol. 14, no. 3, pp. 291–303, 1999.

K. Sato, O. Shiratori, and K. Katagiri, “The mode of action of quinoxaline antibiotics. Interaction of quinomycin A with deoxyribonucleic acid,” Journal of Antibiotics, vol. 20, no. 5, pp. 270–276, 1967.

S. A. Kotharkar and D. B. Shinde, “Synthesis of antimicrobial 2,9,10-trisubstituted-6-oxo-7,12-dihydro-chromeno[3,4-b]quinoxalines,” Bioorganic and Medicinal Chemistry Letters, vol. 16, no. 24, pp. 6181–6184, 2006.

A. Carta, M. Loriga, S. Zanetti, and L. A. Sechi, “Quinoxalin-2-ones. Part 5: synthesis and antimicrobial evaluation of 3-alkyl-, 3-halomethyl- and 3-carboxyethylquinoxaline-2-ones variously substituted on the benzo-moiety,” Farmaco, vol. 58, no. 12, pp. 1251–1255, 2003.

O. I. El-Sabbagh, M. E. El-Sadek, S. M. Lashine, S. H. Yassin, and S. M. El-Nabtity, “Synthesis of new 2(1H)-quinoxalinone derivatives for antimicrobial and antiinflammatory evaluation,” Medicinal Chemistry Research, vol. 18, no. 9, pp. 782–797, 2009.

S. A. Khan, P. Mullick, S. Pandit, and D. Kaushik, “Synthesis of hydrazones derivatives of quinoxalinone- prospective antimicrobial and antiinflammatory agents,” Acta Poloniae Pharmaceutica, vol. 66, no. 2, pp. 169–172, 2009.

H. Ishikawa, T. Sugiyama, K. Kurita, and A. Yokoyama, “Synthesis and antimicrobial activity of 2,3-bis(bromomethyl)quinoxaline derivatives,” Bioorganic Chemistry, vol. 41-42, pp. 1–5, 2012.

Y. Estevez, M. Quiliano, A. Burguete et al., “Trypanocidal properties, structure-activity relationship and computational studies of quinoxaline 1,4-di-N-oxide derivatives,” Experimental Parasitology, vol. 127, pp. 745–751, 2011.

O. M. Ghoneim, D. A. Ibrahim, I. M. El-Deeb, S. H. Lee, and R. G. Booth, “A novel potential therapeutic avenue for autism: design, synthesis and pharmacophore generation of SSRIs with dual action,” Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 22, pp. 6714–6723, 2011.

M. Suresh, P. Lavanya, D. Sudhakar, K. Vasu, and C. Venkata Rao, “Synthesis and biological activity of 8-chloro-[1, 2, 4]triazolo[4, 3-a]quinoxalines,” Journal of Chemical and Pharmaceutical Research, vol. 2, no. 1, pp. 497–504, 2010.

R. V. Ghadage and P. J. Shirote, “Antimicrobial activities of some substituted quinoxalin-2(1H)-one derivatives,” Journal of Chemical and Pharmaceutical Research, vol. 3, no. 5, pp. 260–266, 2011.

K. Aravind, A. Ganesh, and D. Ashok, “Microwave assisted synthesis, characterization and antibacterial activity of quinoxaline derivatives,” Journal of Chemical and Pharmaceutical Research, vol. 5, no. 2, pp. 48–52, 2013.

G. K. Raoa, R. B. Kotnal, and P. N. Sanjay Paib, “In vitro screening of quinoxaline-2-one derivatives for antitubercular activity,” Journal of Chemical and Pharmaceutical Research, vol. 2, no. 3, pp. 368–373, 2010.

O. O. Ajani, C. A. Obafemi, O. C. Nwinyi, and D. A. Akinpelu, “Microwave assisted synthesis and antimicrobial activity of 2-quinoxalinone-3-hydrazone derivatives,” Bioorganic and Medicinal Chemistry, vol. 18, no. 1, pp. 214–221, 2010.

N. Rivera, Y. M. Ponce, V. J. Arán, C. Martínez, and F. Malagón, “Biological assay of a novel quinoxalinone with antimalarial efficacy on Plasmodium yoelii yoelii,” Parasitology Research, vol. 112, no. 4, pp. 1523–1527, 2013.

A. Carta, P. Sanna, L. Gherardini, D. Usai, and S. Zanetti, “Novel functionalized pyrido[2,3-g]quinoxalinones as antibacterial, antifungal and anticancer agents,” Farmaco, vol. 56, no. 12, pp. 933–938, 2001.

A. Burguete, E. Pontiki, D. Hadjipavlou-Litina et al., “Synthesis and anti-inflammatory/antioxidant activities of some new ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives and of their 4,5-dihydro-(1H)-pyrazole analogues,” Bioorganic and Medicinal Chemistry Letters, vol. 17, no. 23, pp. 6439–6443, 2007.

J. J. Li, K. G. Carson, B. K. Trivedi et al., “Synthesis and structure-activity relationship of 2-amino-3-heteroaryl-quinoxalines as non-peptide, small-molecule antagonists for interleukin-8 receptor,” Bioorganic and Medicinal Chemistry, vol. 11, no. 17, pp. 3777–3790, 2003.

J.-P. Kleim, R. Bender, R. Kirsch et al., “Preclinical evaluation of HBY 097, a new nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 replication,” Antimicrobial Agents and Chemotherapy, vol. 39, no. 10, pp. 2253–2257, 1995.

J. Balzarini, A. Karlsson, C. Meichsner et al., “Resistance pattern of human immunodeficiency virus type 1 reverse transcriptase to quinoxaline S-2720,” Virology, vol. 68, p. 1986, 1994.

J. Gris, R. Glisoni, L. Fabian, B. Fernández, and A. G. Moglioni, “Synthesis of potential chemotherapic quinoxalinone derivatives by biocatalysis or microwave-assisted Hinsberg reaction,” Tetrahedron Letters, vol. 49, no. 6, pp. 1053–1056, 2008.

B. Xu, Y. Sun, Y. Guo, Y. Cao, and T. Yu, “Synthesis and biological evaluation of N4-(hetero)arylsulfonylquinoxalinones as HIV-1 reverse transcriptase inhibitors,” Bioorganic and Medicinal Chemistry, vol. 17, no. 7, pp. 2767–2774, 2009.

H. Rübsamen-Waigmann, E. Huguenel, A. Shah et al., “Resistance mutations selected in vivo under therapy with anti-HIV drug HBY 097 differ from resistance pattern selected in vitro,” Antiviral Research, vol. 42, no. 1, pp. 15–24, 1999.

M. Patel, R. J. McHugh Jr., B. C. Cordova et al., “Synthesis and evaluation of quinoxalinones as HIV-1 reverse transcriptase inhibitors,” Bioorganic and Medicinal Chemistry Letters, vol. 10, no. 15, pp. 1729–1731, 2000.

I. A. I. Ali, I. A. Al-Masoudi, H. G. Hassan, and N. A. Al-Masoudi, “Synthesis and anti-HIV activity of new homo acyclic nucleosides, 1-(pent-4-enyl)quinoxalin-2-ones and 2-(pent-4-enyloxy)quinoxalines,” Chemistry of Heterocyclic Compounds, vol. 43, no. 8, pp. 1052–1059, 2007.

J.-P. Kleim, R. Bender, U.-M. Billhardt et al., “Activity of a novel quinoxaline derivative against human immunodeficiency virus type 1 reverse transcriptase and viral replication,” Antimicrobial Agents and Chemotherapy, vol. 37, no. 8, pp. 1659–1664, 1993.

G. W. Bemis and J. P. Duffy, “Quinoxalines useful as inhibitors of protein kinases,” WO 2005/056547 A2, 2005.

C. Kalinski, M. Umkehrer, G. Ross, J. Kolb, C. Burdack, and W. Hiller, “Highly substituted indol-2-ones, quinoxalin-2-ones and benzodiazepin-2,5-diones via a new Ugi(4CR)-Pd assisted N-aryl amidation strategy,” Tetrahedron Letters, vol. 47, no. 20, pp. 3423–3426, 2006.

J. Dudash Jr., Y. Zhang, J. B. Moore et al., “Synthesis and evaluation of 3-anilino-quinoxalinones as glycogen phosphorylase inhibitors,” Bioorganic and Medicinal Chemistry Letters, vol. 15, no. 21, pp. 4790–4793, 2005.

S. A. Galal, A. S. Abdelsamie, H. Tokuda et al., “Part I: synthesis, cancer chemopreventive activity and molecular docking study of novel quinoxaline derivatives,” European Journal of Medicinal Chemistry, vol. 46, no. 1, pp. 327–340, 2011.

C. Avendano and J. C. Menendez, “Inhibitors of Multidrug Resistance to Antitumor Agents (MDR),” Current Medicinal Chemistry, vol. 9, pp. 159–193, 2002.

J. Robert, “Approaches to multidrug resistance reversal,” Expert Opinion on Investigational Drugs, vol. 7, no. 6, pp. 929–939, 1998.

A. Aszalos, A. Ladányi, J. Bocsi, and B. Szende, “Induction of apoptosis in MDR1 expressing cells by daunorubicin with combinations of suboptimal concentrations of P-glycoprotein modulators,” Cancer Letters, vol. 167, no. 2, pp. 157–162, 2001.

E. C. Lopes, M. Garcia, F. Benavides, J. Shen, C. J. Conti, E. Alvarez, et al., “Multidrug resistance modulators PSC 833 and CsA show differential capacity to induce apoptosis in lymphoid leukemia cell lines independently of their MDR phenotype,” Leukemia Research, vol. 27, pp. 413–423, 2003.

F. Shen, S. Chu, A. K. Bence, B. Bailey, X. Xue, and P. A. Erickson, “Quantitation of doxorubicin uptake, efflux, and modulation of multidrug resistance (MDR) in MDR human cancer cells,” Journal of Pharmacology and Experimental Therapeutics, vol. 324, pp. 95–102, 2008.

P. Mistry, A. J. Stewart, W. Dangerfield et al., “In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576,” Cancer Research, vol. 61, no. 2, pp. 749–758, 2001.

D. S. Lawrence, J. E. Copper, and C. D. Smith, “Structure: activity studies of substituted quinoxalinones as multiple-drug-resistance antagonists,” Journal of Medicinal Chemistry, vol. 44, pp. 594–601, 2001.

L.-R. Sun, X. Li, Y.-N. Cheng et al., “Reversal effect of substituted 1,3-dimethyl-1H-quinoxalin-2-ones on multidrug resistance in adriamycin-resistant K562/A02 cells,” Biomedicine and Pharmacotherapy, vol. 63, no. 3, pp. 202–208, 2009.

M. Loriga, M. Fiore, P. Sanna, and G. Paglietti, “Quinoxaline chemistry. Part 4. 2-(R)-anilinoquinoxalines as nonclassical antifolate agents: synthesis, structure elucidation and evaluation of in vitro anticancer activity,” Farmaco, vol. 50, no. 5, pp. 289–301, 1995.

M. Loriga, M. Fiore, P. Sanna, and G. Paglietti, “Quinoxaline chemistry. Part 5. 2-(R)-benzylaminoquinoxalines as nonclassical antifolate agents: synthesis and evaluation of in vitro anticancer activity,” Farmaco, vol. 51, no. 8-9, pp. 559–568, 1996.

M. Loriga, S. Piras, P. Sanna, and G. Paglietti, “Quinoxaline chemistry. Part 7. 2-[aminobenzoates]- and 2-[aminobenzoylglutamate]-quinoxalines as classical antifolate agents. Synthesis and evaluation of in vitro anticancer, anti-HIV and antifungal activity,” Farmaco, vol. 52, no. 3, pp. 157–166, 1997.

M. Loriga, P. Moro, P. Sanna, G. Paglietti, and S. Zanetti, “Quinoxaline chemistry. Part 8. 2-[anilino]-3- [carboxy]-6(7)-substituted quinoxalines as non classical antifolate agents. Synthesis and evaluation of in vitro anticancer, anti-HIV and antifungal activity,” Farmaco, vol. 52, no. 8-9, pp. 531–537, 1997.

M. Loriga, G. Vitale, and G. Paglietti, “Quinoxaline chemistry. Part 9. Quinoxaline analogues of trimetrexate (TMQ) and 10-propargyl-5,8-dideazafolic acid (CB 3717) and its precursors. Synthesis and evaluation of in vitro anticancer activity,” Farmaco, vol. 53, no. 2, pp. 139–149, 1998.

G. Vitale, P. Corona, M. Loriga, and G. Paglietti, “Quinoxaline chemistry. part 10. Quinoxaline 10-oxa-analogues of trimetrexate (TMQ) and of 5,8-dideazafolic acid. Synthesis and evaluation of in vitro anticancer activity,” Farmaco, vol. 53, no. 2, pp. 150–159, 1998.

P. Corona, G. Vitale, M. Loriga, G. Paglietti, and M. P. Costi, “Quinoxaline chemistry. Part 11.3-Phenyl-2[phenoxy- and phenoxymethyl]- 6(7) or 6,8-substituted quinoxalines and n-[4-(6(7)-substituted or 6,8- disubstituted-3-phenylquinoxalin-2,yl) hydroxy or hydroxymethyl] benzoylglutamates. Synthesis and evaluation of in vitro anticancer activity and enzymatic inhibitory activity against dihydrofolate reductase and thymidylate synthase,” Farmaco, vol. 53, no. 7, pp. 480–493, 1998.

G. Vitale, P. Corona, M. Loriga, and G. Paglietti, “Quinoxaline chemistry. Part 12. 3-Carboxy-2[phenoxyl-6(7)substituted quinoxalines and N-[4-(6(7) substituted-3-carboxyquinoxalin- 2-yl)hydroxy]-benzoylglutamates. Synthesis and evaluation of in vitro anticancer activity,” Farmaco, vol. 53, no. 8-9, pp. 594–601, 1998.

P. Corona, G. Vitale, M. Loriga, and G. Paglietti, “Quinoxaline chemistry. Part 13: 3-carboxy-2-benzylamino-substituted quinoxalines and N-[4-[(3-carboxyquinoxalin-2-yl) aminomethyl]benzoyl]-L-glutamates: synthesis and evaluation of in vitro anticancer activity,” Farmaco, vol. 55, no. 2, pp. 77–86, 2000.

P. Corona, G. Vitale, M. Loriga, S. Alleca, and G. Paglietti, “Pirrolo[1, 2-, a]quinoxalines analogues of antifolic trimetrexate and methotrexate,” in Proceedings of the 16th International Symposium on Medicinal Chemistry, p. 526, Bologna, Italy, September 2000.

S. Piras, M. Loriga, and G. Paglietti, “Quinoxaline chemistry. Part 14. 4-(2-Quinoxalylamino)-phenylacetates and 4-(2-quinoxalylamino)-phenylacetyl-l-glutamates as analogues-homologues of classical antifolate agents: synthesis and evaluation of in vitro anticancer activity,” Farmaco, vol. 57, no. 1, pp. 1–8, 2002.

S. Piras, M. Loriga, and G. Paglietti, “Quinoxalines analogues-homologues of methotrexate,” in Proceedings of the Hungarian-German-Italian-Polish Joint Meeting on Medicinal Chemistry (HGIP JMMC), p. 141, Budapest, Hungary, September2001.

P. Corona, M. Loriga, G. Paglietti, P. la Colla, M. G. Setzu, and R. Loddo, “Imidazo[1, 2-, a]- and 1, 2, 4-triazolo[4, 3-, a]quinoxalines analogues of antifolic trimetrexate and methotrexate,” in Proceedings of the Hungarian-German-Italian-Polish Joint Meeting on Medicinal Chemistry (HGIPJMMC), p. 64, Budapest, Hungary, September2001.

G. Vitale, M. Loriga, G. Paglietti et al., “Quinoxalines analogues of thymitaq and 2-(arylthio)quinoxalines analogues of trimetrexate and methotrexate,” in Proceedings of the of Hungarian-German-Italian-Polish Joint Meeting on Medicinal Chemistry (HGIP JMMC), p. 184, Budapest, Hungary, September2001.

S. Piras, M. Loriga, and G. Paglietti, “Quinoxaline chemistry. Part XVII. Methyl [4-(substituted 2-quinoxalinyloxy) phenyl] acetates and ethyl N-{[4-(substituted 2-quinoxalinyloxy) phenyl] acetyl} glutamates analogs of methotrexate: synthesis and evaluation of in vitro anticancer activity,” Farmaco, vol. 59, no. 3, pp. 185–194, 2004.

S. T. Hazeldine, L. Polin, J. Kushner et al., “II. Synthesis and biological evaluation of some bioisosteres and congeners of the antitumor agent, 2-{4-[(7-chloro-2-quinoxalinyl)oxylphenoxy}propionic acid (XK469),” Journal of Medicinal Chemistry, vol. 45, no. 14, pp. 3130–3137, 2002.

P. Corona, A. Carta, M. Loriga, G. Vitale, and G. Paglietti, “Synthesis and in vitro antitumor activity of new quinoxaline derivatives,” European Journal of Medicinal Chemistry, vol. 44, no. 4, pp. 1579–1591, 2009.

Q. Weng, D. Wang, P. Guo et al., “Q39, a novel synthetic Quinoxaline 1,4-Di-N-oxide compound with anti-cancer activity in hypoxia,” European Journal of Pharmacology, vol. 581, no. 3, pp. 262–269, 2008.

S. Piras, M. Loriga, and G. Paglietti, “Quinoxaline chemistry. Part XVII. Methyl [4-(substituted 2-quinoxalinyloxy) phenyl] acetates and ethyl N-{[4-(substituted 2-quinoxalinyloxy) phenyl] acetyl} glutamates analogs of methotrexate: synthesis and evaluation of in vitro anticancer activity,” Farmaco, vol. 59, no. 3, pp. 185–194, 2004.

J. Miyashiro, K. W. Woods, C. H. Park et al., “Synthesis and SAR of novel tricyclic quinoxalinone inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1),” Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 15, pp. 4050–4054, 2009.

R. Teja, S. Kapu, S. Kadiyala, V. Dhanapal, and A. N. Raman, Journal of Saudi Chemical Society. In press

W. Ginzinger, G. Mühlgassner, V. B. Arion et al., “A SAR study of novel antiproliferative ruthenium and osmium complexes with quinoxalinone ligands in human cancer cell lines,” Journal of Medicinal Chemistry, vol. 55, no. 7, pp. 3398–3413, 2012.

H. Hirai, I. Takahashi-Suziki, T. Shimomura et al., “Potent anti-tumor activity of a macrocycle-quinoxalinone class pan-Cdk inhibitor in vitro and in vivo,” Investigational New Drugs, vol. 29, no. 4, pp. 534–543, 2011.

M. Weïwer, J. Spoonamore, J. Wei, et al., “A potent and selective quinoxalinone-based STK33 inhibitor does not Show Synthetic Lethality in KRAS-Dependent Cells,” ACS Medicinal Chemistry Letters, vol. 3, no. 12, pp. 1034–1038, 2012.

H. Yuan, X. Li, X. Qu, L. Sun, W. Xu, and W. Tang, “Synthesis and primary evaluation of quinoxalinone derivatives as potent modulators of multidrug resistance,” Medicinal Chemistry Research, vol. 18, no. 8, pp. 671–682, 2009.

F. Grant, S. Bartulis, L. Brogley et al., “Alpha-amino acid derivatives and use thereof as medicines,” ,WO 03/093245 A1, 2003.

A. Bayoumi, A. Ghiaty, A. El-Morsy, H. Abul-Khair, M. H. Hassan, and S. Elmeligie, “Synthesis and evaluation of some new 1, 2, 4-triazolo(4, 3-a)quinoxalin-4-5H-one derivatives as AMPA receptor antagonists,” Bulletin of Faculty of Pharmacy, Cairo University, vol. 50, pp. 141–146, 2012.

J. Hauptmann and J. Stürzebecher, “Synthetic inhibitors of thrombin and factor Xa: from Bench to bedside,” Thrombosis Research, vol. 93, no. 5, pp. 203–241, 1999.

A. E. P. Adang and J. B. M. Rewinkel, “A new generation of orally active antithrombotics: comparing strategies in the GPllb/Illa, thrombin and factor XA areas,” Drugs of the Future, vol. 25, no. 4, pp. 369–383, 2000.

J. M. Fevig and R. R. Wexler, in Annual Reports in Medicinal Chemistry, W. Greenlee, Ed., vol. 34, p. 81, Academic Press, New York, NY, USA, 1999.

U. J. Ries, H. W. M. Priepke, N. H. Hauel et al., “Heterocyclicthrombin inhibitors. Part 2: quinoxalinone derivatives as novel,potent antithrombotic agents,” Bioorganic and Medicinal Chemistry Letters, vol. 13, no. 14, pp. 2297–2302, 2003.

WHO, “Definition, diagnosis and classification of diabetes mellitus and its complications, 1999,” Report of a WHO Consultation, WHO, Geneva, Switzerland, 2003.

S. Wild, G. Roglic, R. Sicree, A. Green, and H. King, “Global burden of diabetes mellitus in the year 2000,” in Global Burden of Disease, 2000.

R. J. Marles and N. R. Farnsworth, “Antidiabetic plants and their active constituents,” Phytomedicine, vol. 2, no. 2, pp. 137–189, 1995.

Y. Yang, S. Zhang, B. Wu et al., “An efficient synthesis of quinoxalinone derivatives as potent inhibitors of aldose reductase,” ChemMedChem, vol. 7, no. 5, pp. 823–835, 2012.

K.-H. Kim, A. Maderna, M. E. Schnute et al., “Imidazo[1,5-a]quinoxalines as irreversible BTK inhibitors for the treatment of rheumatoid arthritis,” Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 21, pp. 6258–6263, 2011.

D. Peters, J. K. Christensen, K. Harpsoe, and T. Liljefors, “Novel quinoxaline derivatives and their medical use,” WO 2007/060144 A2, 2007.