1,2,3-Triazine Scaffold As a Potent Biologically Active Moiety: a Mini Review

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Send Orders for Reprints to [email protected] 72 Mini-Reviews in Medicinal Chemistry, 2014, 14, 72-83 1,2,3-Triazine Scaffold as a Potent Biologically Active Moiety: A Mini Review

Rajeev Kumar1*, Amar Deep Singh1, Jitendra Singh1, Hariram Singh1, R.K. Roy1 and Anurag Chaudhary2

1Dr. K.N. Modi Institute of Pharmaceutical Education and Research, Inside Cotton Mill Compound, Modinagar, Ghaziabad, Pin-201201, U.P., India; 2Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Baghpat Crossing, Meerut Bypass Road, Meerut-250005, India

Abstract: 1,2,3-Triazine is an interesting class of heterocyclic compounds. Various synthetic analogs of 1,2,3-triazine have been prepared and evaluated for many pharmacological activities in different models with desired findings. Some analogs have shown potent pharmacological activity and may be considered as lead molecule for the development of future drugs. This review is an attempt to organize the chemical and pharmacological aspects of 1,2,3-triazine analogs reported till date systematically since 1970. Keywords: Anticancer activity, antimicrobial activity, antiprotozoal, in vivo, 1,2,3-triazine.

INTRODUCTION which have significant pharmacological activities. Tubercidin inhibits the growth of several strains of bacteria. Tubercidin Triazines are six membered ring compounds containing and its 5-substituted derivatives inhibit both DNA and RNA three nitrogen atoms. Depending on the position of the viruses at the concentrations that inhibit DNA, RNA and nitrogen atom, three different triazine systems namely, 1,3,5- protein synthesis in mice and human cell lines. Toyocamycin triazine (s-triazine, 1), 1,2,4-triazine (2) and 1,2,3-triazine (3) is a known antineoplastic antibiotic with specific antitumor are possible. Among them 1,2,3-triazine is the novel class of activity. Sangivamycin is active against L1210 leukemia, heterocycles [1]. In addition to the name of 1,2,3-triazine, V- P338 leukemia and lewis lung carcinoma and under clinical triazine or beta triazine can also be found in older literature trials against colon cancer, gall bladder cancer and acute [2]. Out of the above three possible triazine nucleus, 1,2,3- myelogenous leukemia in humans. 2-Aza-adenosine (7) triazine is the least explored one, till date. But, clinically exhibits five times greater cytotoxicity than 8-azapurine, 1,2,3-triazine derivatives are more acceptable because of against human epidermoid carcinoma cells in vitro [4]. potent efficacy and minimal side effect. So by looking on its clinical output and safety margin, the 1,2,3-triazine NH nucleus is becoming the prime choice of the researchers 2 R NH2 N for further study. Currently 1,2,3-triazine represents a widely N N used lead structure with multitude of interesting applications N N in the numerous pharmacological fields, Thus various N N N N pharmacological activities have been reported and explored O O out till date [1, 3]. HO OH HO OH 1 1 1 HO HO N N 2 N 6 2 6 N 6 2 N 4 R=H, 5 R=CN, 6 R=CONH2, 7 NN 5 N 5 3 N 3 5 3 4 4 4 2-Aza-2-desamino-5,8-dideazafolic acid (8) is an inhibitor of recombinant mouse thymidylate synthase. 1 2 3 Inhibition by compound (8) is found to be competitive with 5,10-methylenetetrahydrofolate as variable substrate. It is Drugs containing 1,2,3-triazine ring have got its origin also a substrate for murine folylpolyglutamate synthetase from natural and synthetic sources as exemplified by with kinetic characteristics comparable to those of Tubercidin (4), Toyocamycin (5) and Sangivamycin (6), aminopterin. It is also found to inhibit the growth of L1210 cells (IC50 = 0.52 M) [5]. 1,2,3-Triazines fused with *Address correspondence to this author at the Dr. K.N. Modi Institute of heterocyclic moiety show high reactivity, chemical and Pharmaceutical Education and Research, Inside Cotton Mill Compound, biological effects [6]. Modinagar, Ghaziabad, Pin-201201, U.P., India; Tel: +91-9528204982; Fax: +91-9045217932; E-mail: [email protected]

HO O O HN HN O O N HN S N N N N O O N N HO O HN 14 O

8 (IC = 0.52 M) 50 O H2N N NH2

The 1,2,4-triazine and their condensed analogs with one N O N or more heterocycles have found application in many fields N N as pharmaceuticals, herbicides, pesticides, dyes and agriculture N N Cl [7]. The 6-Azacytosine (9) and 6-azauracil (10) show antiviral Cl and antitumor activities [8-11]. Azaribine (11) is used as 15 16 effective antiviral, antifungal agents, and also in management of H psoriasis [12]. Tirapazamine (TPZ, 12) is currently O N O OH undergoing various phase of the clinical trial for the treatment N of different human cancers. Anticancer activity of TPZ is O O N S N shown by inducing DNA damage in poorly oxygenated O NH2 tumor cells [13]. Dihydromethyl furalazine (13) showed a N S N wide spectrum antibacterial activity against various H H S pathogenic organisms. Gram-negative rods such as Shigella O N and Salmonella, in particular, are found to be extremely 17 sensitive to this drug [14]. Vardenafil (14), phosphodiesterase inhibitor, is useful in the treatment of male erectile 1,3,5-Triazine is a class of well known compounds due to dysfunctions. Apazone (15) exhibits anti-inflammatory and their applications in different fields [19]. Hexamethyl analgesic activities. Lamotrigine (16), a phenyl-1,2,4-triazine melamine (Altretamine, HMM, 19) is an effective anticancer derivative is used as anticonvulsant agent and in the agent for breast, lung and ovarian cancers. Altretamine treatment of bipolar disorders. Ceftriaxon (17) is a well- damages tumor cells by the formation of weakly alkylating known third generation parenteral cephalosporin antibiotic. It species, formaldehyde, a product of CYP450-mediated N- is highly efficacious in a wide range of serious life threatening demethylation [16, 20-23]. The 2-amino-4-morpholino-s- infections including bacterial meningitis, multiresistant typhoid triazine (20) is used clinically due to its antitumor properties fever, complicated urinary tract infections, abdominal sepsis against lung, breast and ovarian cancers. Hydroxy methyl and septicaemias [15, 16]. Pymetrozine (18) represents a new pentamethyl melamine (21) is a hydroxylated metabolite, chemical class of insecticides [17]. N-Methyl derivatives of which corresponds to the major active form of HMM [20]. 1,2,4-triazines like fervenulin (Planomycin), reumycin and Triethylenemelamine (Tretamine, 22) is used as an adjuvant toxoflavin (Panthothricin) are some naturally occurring to radiation therapy of retinoblastoma and injected into the antibiotics [18]. carotid artery. It is also used in the palliative treatment of malignant neoplasms [24]. Dioxadet (23), trisadet and furazil N N N NH have a pronounced therapeutic effect against a broader spectrum of tumors grafted in mice and rats. Antitumor H2N N O O N O H H activity of dioxadet is comparable with activity of cisplatin 9 10 against intraperitoneal therapy of the ascitic ovarian tumor O [25-27]. Irsogladine (24) is commonly used as anti-gastric ulcer agent in Japan [28]. Irsogladine has anti-tumor activity HN in murine xenograft models of epidermoid cancer and glioma N O N [21, 23]. Cycloguanil (25) is a cyclic metabolite of antimalarial O- drug proguanil which is plasmodial dihydrofolate reductase O O N+ inhibitor in preference to the mammalian enzyme [15]. N O Almitrine (26), a triazinylpiperazine analog currently being O O + used for respiratory insufficiency, moderately sensitized the N NH2 O - highly resistant cell line DC-3F/AD to actinomycin D. The O O 11 12 compound S9788 (27) is currently under Phase 1 clinical

O2N trial. The compound S9788 was shown to have comparable calcium channel affinity to that of verapamil and markedly O higher than that of almitrine [29]. Compound DW1865 (28) N CH2OH is a novel Rho kinase inhibitor, which exhibits significant N antihypertensive properties both in in vitro and in vivo, N N CH2OH presumably via inhibition of intracellular Rho kinase 13 activation. DW1865 blocks angiotensin-II induced stress 74 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 Kumar et al.

O H N N O N OH N N N N N N N N N N NN N N N N N N N N N N N N NH2 18 19 20 21 22

NH2 N N O NH2 N N F N N N H Cl N N O H2N N N NH N N

HO N NH2 NN Cl N Cl F 24 23 25 26

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

F 28 27 fiber formation and cellular hypertrophy in the rat heart- against chronic myeloid leukaemia and non-hodgkin lymphoma derived H9c2 cell line [30]. human cells in vitro. Compound (29) showed the most effective antiproliferative activity against human chronic Several medicinal scientists like Abdel-Rahman, Prashant myeloid leukaemia. The cytotoxicity of compound was Gahtori, Krzysztof Kaminski, Tarun kumar M. Patel, James strongest against human chronic myeloid leukaemia cells C. A. Hunt and G.L. Viswanatha are still working on these and less against non-hodgkin lymphoma cells. Screening triazines and their fused nucleus to explore out the detailed data revealed that the presence of bulky hydrophobic chemical and pharmacological properties, which will be substituents like benzyl, butane, cyclopropane, cyclohexane, definitely a bench-mark for its clinical use. Fusion of the 2-chloroethane, 3-chloropropane and ter-butyl at the 3-position heterocyclic nuclei like benzene, indole, indeno[2,1 b] of indole-triazinone show decrease antiproliferative activity thiophene and pyrazolo rings to the 1,2,3-triazine nucleus against chronic myeloid leukaemia and non-hodgkin lymphoma enhances pharmacological activities than its parent nucleus. human cells in vitro. The lower activity of compound (29), In a search of novel therapeutic agents, various versatile with regard to daunorubicin, and the greater selectivity of heterocyclic moieties were appended in the 1,2,3-triazine action, against chronic mieloid leukaemia, might be used in nucleus via the interaction between functionalized 1,2,3- polychemotherapy protocols. triazines with various nucleophilic and electrophilic reagents. This review is an systematic attempt to compile the chemical and pharmacological aspects of various synthesized 1,2,3- 1 2 triazine analogs reported till date. N N NH 3 SYNTHETIC ANALOGS OF 1,2,3-TRIAZINE, SHOW- ING VARIOUS PHARMACOLOGICAL ACTIVITIES N O H Anticancer activity 29 Laura Garuti et al. [6] synthesized and evaluated Ali M. M. et al. [31] synthesized some new indeno[2,1b] antiproliferative activity of 3-substituted lH-indole[3,2-d]- thiophenes, and indeno[1,2:4,5]thieno[2,3d][1,2,3]triazines. 1,2,3-triazin-4(3H)-ones. They compared antiproliferative The prepared compounds showed antitumor activity, partly activity of the synthesized compounds with daunorubicin 1,2,3-Triazine Scaffold as a Potent Biologically Active Moiety Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 75 by increasing free radicals production and partly by depletion of antifungal activity. Compounds 38, 39, and 40 displayed intracellular catalase, glutathione peroxidase, glutathione most potent antibacterial activity. SAR studies revealed that reductase, reduced glutathione. Among the synthesized maximum in vitro antitumor activity correlates with the compounds, compound (30) was most potent with IC50 of 6 presence of either a chlorine atom at position 10 (34) or a g/mL. This compound lead to an increased level of NO methyl group at position 2 (35). Furthermore the absence of with decrease in the level of total protein, RNA and DNA. substituents at positions 10, and 2 (36), or the substitution of a chlorine atom for a methoxy (39) or nitro (40) group at position 10 or the substitution of a methyl group for a O chlorine atom (38) at position 2 significantly decreased the activity. Moving the chlorine atom from position 2 to 3 (37) NH partially restores the antitumor activity in vitro. Maximum N S N potency of antifungal activity correlates with the absence of substituents (36) or the presence of a chlorine atom at 30 (IC = 6 g/mL) 50 position 3 (37). Compound 37 was found to be the only Jin-Ling Lv et al. [32] synthesized a series of substituted compound capable of potently inhibiting the proliferation of 1,2,3-benzotriazines based on the structures of vatalanib both animal and fungal cells, whereas the derivatives succinate (PTK787) and vandetanib (ZD6474). The endowed with the highest in vitro antitumor activity (34-35) antiproliferative effects of synthesized compounds were were totally ineffective on the fungal growth. The potent and tested on microvascular endothelial cells (MVECs) using the selective antibacterial activity is correlated with the presence MTT assay. Compounds 31(bearing 3'-chloro, 4'-fluoro of a chlorine atom at position 2 (38) or with a methoxy (39) aniline group) and 32 (bearing 3’, 4’-dichloro aniline group) or nitro (40) group at position 10. were the potent compounds in inhibiting proliferation of R MVECs with GI50 values of 7.98 M and 11.02 M, 10 11 respectively. Most of the synthesized compounds (GI value NO 50 9 12 1 range = 7.98-42.64 M) were more effective than PTK787 2 R 8 N 1 (GI50 value of >80 M) in inhibiting proliferation of MVECs 7 N except compound 33 (GI50 value = >80 M). Compound 31 6 rd th N 3 R2 containing chloro group at 3 and flouro at 4 position was 5 4 more effective than PTK787 to inhibit cell growth in all the 34 R=Cl, R =R =H, (IC range = 0.08-0.7 M); tested cell lines. 1 2 50 35 R= R2=H, R1=CH3, (IC50 range = 1.9-9.5 M); 36 R=R1=R2=H; 37 R=R1=H, R2=Cl; 38 R= R2=H, R1=Cl; 39 R=OCH3, R1=R2=H, R 3 40 R=NO2, R1=R2=H HN

R2 Thierry Le Diguarher et al. [34] prepared 5-substituted 2- N bisarylthiocyclopentane carboxylic acids as specific matrix N metalloproteinase (MMP) inhibitors. They reported that R1 N compound (41) is found to be a very potent and specific

31 R1=Cl(CH2)3O, R2=CH3O, R3=3-Cl,4-F, (GI50 = 7.98 M), inhibitor of MMP-2, -3, -9, and -13. However, this compound 32 R1=Cl(CH2)3O, R2=CH3O, R3= 3,4-di-Cl, (GI50 =11.02 M), has only modest bioavailability (<30%), a fact attributed to 33 R1=Cl(CH2)3O, R2=CH3O, R3=4-Cl, (GI50 = >80 M) the presence of the hydroxamate function. Conformational analysis of compound (41) modeled in the three-dimensional Girolamo Cirrincione et al. [33] synthesized some indolo structure of MMP-2 suggested that the P1 and P1’ groups [1,2-c]benzo[1,2,3]triazine analogs. Synthesized compounds adopt a trans/trans orientation relative to the zinc binding were evaluated for their in vitro antitumor activity against a group. Compound (1R,2S,5R)- (42) was most active compound panel of leukemia-, lymphoma-, carcinoma and neuroblastoma against MMP-2, -3, -9 and -13 than the other diastereoisomer. derived cell lines. Some of the synthesized compounds inhibited The profile is comparable to those for the hydroxamates the proliferation of T and B cell lines at submicromolar CGS 27023A and trocade but with better selectivity versus concentrations and their activity against solid tumor cell MMP-1. The calculated distances of the sulfur atom and the lines was in the micromolar range. Indolobenzotriazine carbonyl of the triazine moiety are compatible with hydrogen analog 34 showed most potent antitumor activity with IC in 50 bonding interaction with the amide proton of Ala192/Leu191 range of 0.08-0.7 M. This compound was fully inhibitory to and Ala194, respectively. Replacement of the 4-chlorophenyl all the resistant cell lines thus suggesting that it neither is ring of 42 with the heteroaryl groups 4-pyridyl (43), 2-thiazolyl subject to the pump mediating the efflux of many antitumor (44), 2-benzothiazolyl (45), and 4-triazolyl (46) increased drugs nor interferes with the DNA synthesis. The compounds IC values across the board by 1 or 2 orders of magnitude. 34 (IC range = 0.3-2.7 M) and 35 (IC range = 1.9-9.5 50 50 50 Replacement of the 4’-chloro of 42 by 4-methylthio (47) and M) displayed lower antiproliferative activity against cell 4-cyano (48) group showed substantial improvement in lines derived from solid tumors than that of Doxorubicin. All potency. In these cases, IC values for MMP-2, -3, -9, and - the synthesized compounds were also screened for antimicrobial 50 13 are shifted into the nanomolar range. Compounds (42), activity. All indolobenzotriazines were proved to be fairly (49) and (50), administered intraperitoneally (i.p.) led to the potent and selective inhibitors of Streptococcus and significant dose-dependent reduction in the number of Staphylococcus. Compounds 36 and 37 showed most potent 76 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 Kumar et al. metastases (>60% at 200 mg) and marked reduction of their organisms. Antimicrobial results of the synthesized compounds size (100% inhibition of the occurrence of metastases with concluded that lipophillic groups like chloro, fluoro diameter over 1 mm). On the basis of their in vivo activities in a substitutions on the phenyl ring play an important role in mouse metastasis model and their good oral bioavailabilities, enhancing the antimicrobial properties of this class of compounds (1R,2S,5R)- (42) and (49) were identified as compounds. suitable candidates for the further development.

O O S R N N NH N NN O OH S N Cl 41 51 R=4-fluorophenyl, 52 R=2-chlorophenyl, R 53 R=3-chlorophenyl, 54 R=4-chlorophenyl, 55 R=H, 56 R=ethyl, 57 R=ethyl, 58 R=phenyl, 59 R=2-methylphenyl, 60 R=3-methylphenyl, O 61 R=4-methylphenyl, S N James C. A. Hunt et al. [35] synthesized a new series of N N OH pyridothieno-1,2,3-triazines and screened them for antifungal O activity against Erysiphe graminis. Compounds 62 with R1= Morpholino, R = OC H and 63 with R = Pyrrolidino, R = 42 R=4-chlorophenyl, 43 R=4-pyridyl, 2 3 7 1 2 44 R=2-thiazolyl, 45 R=2-benzothiazolyl, OCH3 groups displayed significant antifungal activity with 94% 46 R= 4-triazolyl, 47 R= 4-methylthio, 48 R= 4-cyano and 92% inhibition, respectively. Compound 64 exhibited potent antifungal activity (with 100% inhibition). Compounds F O 65 with R1= Morpholino, R2= OC2H5, 66 with R1= Morpholino, R2= SCH3, 67 with R1= Morpholino, R2= SC2H5 and 68 with N S R1= Morpholino, R2=MeOCH2CH2O groups also showed potent antifungal activity (with 100% inhibition). Compounds O OH O 69 with R1= N(C2H5)2, R2= OCH3, 70 with R1= PhCH2(Me)N, 49 R2= OCH3, 71 with R1= MeOCH2CH2(Me)N, R2= OCH3 and 72 with R1= MeOCH2CH2(Me)N, R2= MeOCH2CH2O groups O Cl also showed potent antifungal activity. Compounds 64-72 (with 100% inhibition) showed more antifungal activity as N S compared standard drug Fenpropimorph with 97% inhibition. N They concluded that incorporation of oxygen atoms into the N OH O side chains of the pyridothieno-1,2,3-triazines has increased 50 the solubility of the compounds by 10-fold whilst retaining biological activity. Antimicrobial Activity

Janardhanan Saravanan et al. [3] synthesized some 3- N N substituted amino-4,5-tetramethylene thieno[2,3-d][1,2,3]- N triazin-4(3H)-ones. Synthesized compounds were evaluated S R2 for their antimicrobial activity by agar diffusion method R1 N using Ampicillin and Miconazole nitrate as standard drugs. The compounds (51-54) showed considerably greater 62 R1 = Morpholino, R2 = OC3H7, antimicrobial activity than the compounds (55-61). 63 R1 = Pyrrolidino, R2 = OCH3, Screening data showed that the compound (51) with 64 R1 = Morpholino, R2 = OCH3, 4-fluorophenyl substitution exhibited excellent inhibition 65 R1 = Morpholino, R2 = OC2H5, against tested Gram positive bacteria (MIC=6.75 g/mL) 66 R1 = Morpholino, R2 = SCH3, and Gram negative bacteria (MIC=12.5 g/mL). Compound 67 R1 = Morpholino, R2 = SC2H5, (54) with 4-chlorophenyl substituent at R on triazin-4-one 68 R1 = Morpholino, R2 = OCH2CH2OCH3, nucleus, was potent against all types of bacterial (MIC range 69 R1 = N(C2H5)2, R2 = OCH3, =12.5-25 g/mL) and fungal employed (MIC range = 12.5-37.5 70 R1 = PhCH2(Me)N, R2 = OCH3, g/mL). The MIC study of synthesized compounds confirmed 71 R1 = MeOCH2CH2(Me)N, R2 = OCH3, that the potency of the title compounds is based on the 72 R1 = N(CH3)CH2CH2OCH3, R2 = OCH2CH2OCH3 substituents attached to the phenyl group. The tested Samir Bondock et al. [36] synthesized a series of compounds having methyl, ethyl, phenyl, 2-methyl phenyl, pyrazolo[3,4-d]triazine and screened them for in vitro 3-methyl phenyl, 4-methylphenyl, 2-chlorophenyl, antimicrobial activity against Bacillus thuringiensis, Klebsiella 3-chlorophenyl and 3-chloro-4-flurophenyl substituent’s at pneumonia, Botrytis fabae and Fusarium oxysporum by the the 3-position were less active against all the tested agar diffusion method. Compound 73 exhibited significant 1,2,3-Triazine Scaffold as a Potent Biologically Active Moiety Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 77 antifungal activity. It was concluded that incorporation of Antiprotozoal Activity antipyrine to the coumarin nucleus at position 3, via a Jose M. Quintela et al. [39] synthesized a series of carboxamide linker produces a high antimicrobial activity. pyridothienotriazines and evaluated them for antiprotozoal H activity against Philasterides dicentrarchi. Pyridothienotriazines N N incorporating a piperazine group is directly related to the N N O antiprotozoal activity of the compounds against P. dicentrarchi. N Pyridothienotriazine (79) showed the activity (0.8 mg/L in HN N O physiological phosphate-buffered saline and 1.5 mg/L in sea N water) which is comparable with standard drugs niclosamide and oxyclozanide (0.8 mg/L). Pyridothienotriazines (80-85) showed significant antiparasitic activity. Comparison of the 73 compounds (80) and (81) indicated that substitution of the th Tarun M. Patel et al. [37] synthesized some 1-(4-(1H- ethoxy group at the 7 position by a phenyl and the cyano th naphtho[1,8-de][1,2,3]triazin-1-ylsulfonyl)phenyl)-3-chloro- group at the 8 position by a hydrogen atom produces 4-fold 4-arylazetidin-2-one derivatives. Antibacterial activity of all increase of the lethal dose values. All the compounds of this the compounds was studied against Gram-positive bacteria series, particularly 79, possess significant antiprotozoal activity. (Staphylococcus aureus and Bacillus subtilis) and Gram- negative bacteria (E.coli and klebsiella promioe) at 50g/mL by agar cup plate method. Compounds 74, 75 and 76 bearing N N N N chloro, methoxy and hydroxy groups at 4-position showed NC N NC N significant antibacterial activity. Compounds containing S N hydrogen, methyl and bromo substitutions at 4-position and N N O N S N hydroxy at 2-position were found to be less or moderate NH NH active than standard drug (Tetracycline). Compound 74 also 79 80 exhibited maximum antifungal activity as compared to other tested compounds at 1000 ppm. N N R N N NC N N S N N N N N S N O O N NH N S N Cl NH 81 82 O O N N N N NC N NC N 74 R=4-Cl, 75 R=4-OCH3, 76 R=4-OH N N S N Tarun kumar M. Patel et al. [38] synthesized some 1-(4- N N S N S (1H-naphtho[1,8-de][1,2,3]triazin-1-ylsulfonyl)phenyl)-5- NH NH oxo-2-arylpyrrolidine-3-carboxylic acid derivatives. The 83 84 antibacterial activity of all the synthesized compounds was studied against Gram-positive bacteria (Staphylococcus N N aureus and Bacillus subtilis) and Gram-negative bacteria NC N (E.coli and klebsiella promioe) at 50 g/mL by agar cup O plate method. Compounds 77 and 78 bearing 4-chloro and 4- N N S N N methoxy groups respectively, showed significant antibacterial N NH N activity. Compounds containing hydrogen, methyl and N bromo substitutions at 4-position were found to be less or moderate active than standard drug (Tetracycline). Compound 85 77 also exhibited maximum antifungal activity as compared 86 other tested compounds at 1000ppm. Nematocidal Activity R F. Kiuchi et al. and J. Feldmesser et al. [40-41] observed structure–activity tendencies of N-acyl cyclic amines and N- O substituted amides. They concluded that the hydrophobic/ N hydrophilic balance of the compounds controls the NO OH N S N nematocidal activity. Keiji Nishiwaki et al. [42] synthesized O some tetrahydrobenzotriazines as a new class of nematocide. O Compound (86), having acetyl group, showed the strongest activity (100% of the revised death rate). Decanoyl derivative 77 R=Cl, 78 R=OCH3 78 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 Kumar et al.

(87), having long acyl chain, also showed high nematocidal [human foreskin fibroblasts, (HFF's)]. They reported that the activity (97%). Nematocidal activity of the compound (88) unsubstituted compound (99) was slightly active against was 5 times stronger than that of the compound (89). HCMV in plaque and it was not cytotoxic to stationary Compounds 86, 88 and methyl isothiocyanate (standard HFF's at the highest tested concentration. Thiomethyl- drug), killed all the nematodes within 24 hours. They substituted analog (100) was the most active compound and revealed that this may be due to the hydrophobic nature or comparable to ganciclovir albeit with greater cytotoxicity. bulkiness of the methyl group. Nematocidal activity of the tested compounds gradually decreased as the length of the N acyl chains increased. In the phenylurea and phenylthiourea N N substituted tetrahydrobenzotriazines, introduction of a methyl CN group on the nitrogen atom increased the nematocidal activity. N N N N O O O N O N O O N O O

S S 91 N N N N N N H HN R N NH2 O N NH2 NH2

N N 88 89 N N N N N N O O O NH2 NH2 HO OH N HO OH HO N HO N N O 92 93 R= NNH , 94 R= O, O 2 O 95 R= NOH, 96 R= NCN, O O O S O NH2 NH2 N N N N N N N N N O O 90 HO OH HO OH Antiviral Activity HO HO Michael T. Migawa et al. [4] synthesized some new 4,5- 97 98 disubstituted 7-(-D-ribofuranosyl)pyrrolo[2,3-d][1,2,3] triazines as analogs of triciribine. Synthesized compounds S (90-98) were evaluated for their antiviral activity. Most of the pyrrolotriazine analogs (90-92, 96-98) were inactive or N N weakly active against human cytomegalovirus (HCMV) and N N N O herpes simplex virus type 1 (HSV-1). The 2-aza analog of O sangivamycin (94) was active against HCMV and HSV-1. N Activity of the compound (94) was most likely due to its HO OH N S N high cytotoxicity. Compound (98) shown modest activity HO against HCMV and was cytotoxic at the concentrations of 99 100 only two to three times of antiviral concentrations. They concluded that in comparison to triciribine, the newly Analgesic, Anti-inflammatory and Antiarthritic activities synthesized analogs were less active against HIV-1 and more GL Viswanatha et al. [1] synthesized some bicyclothieno cytotoxic. 1,2,3-triazine analogs and screened them for analgesic, anti- Steven Krawczyk et al. [43] synthesized some inflammatory and antiarthritic activities. All the tested 4-substituted imidazo[4,5-d][1,2,3]triazine(2-azapurine) analogs showed significant analgesic, anti-inflammatory and nucleoside derivatives. Synthesized compounds were tested antiarthritic activities. Compound 101 (50 mg/kg, i.p.) was for their activity against human cytomegalovirus (HCMV) found to be more potent than pentazocin (4 mg/kg i.p) in hot and for cytotoxicity in the cells used to propagate the virus plate test. In the motor coordination test, using rotarod 1,2,3-Triazine Scaffold as a Potent Biologically Active Moiety Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 79 apparatus, compound 101 (100 mg/kg, i.p.) exhibited significant of histamine in some assays. The screening data showed that sedative effect that was evidenced by reduction in the the replacement from ethoxy to aminobenzyl did not produce endurance time. They revealed that the mechanism of analgesic any change in the activity. They revealed that a common effect of tested compounds could be due to blockade of the mechanism of action of the compounds was perhaps related effect or the release of endogenous substances that excite the to the alkylating properties of the masked imminium ion. pain nerve endings similar to that of standard drug pentazocin Pyridotheino- (110) and pyridodithieno-(111) compounds and other NSAIDs. showed remarkable activity against several human and mouse tumoral cell lines. O

N N N N S N NC N 101 O N S N Antidepressant Activity N Srinath R. et al. [44] synthesized some new thieno 1,2,3- triazin-4-ones. All the synthesized compounds were screened for antidepressant activity by using tail suspension, reserpine induced hypothermia and forced swim models. Compounds O (102) and (103) showed significant activity against all models 107 at 50 mg/kg. Compound (102) also exhibited significant activity against all models 25 mg/kg. At both dose levels (25 mg/kg and 50 mg/kg), Anti-depressant activity of both the compounds (102) and (103) was comparable to standard drug Imipramine N N (20 mg/kg). N N N N

O N S N N O N S N N NH O N 109 N S 108 N N N S 102 103

N N N N N N NC N N N

N N N N O N S Cl Cl S S Cl NC N N N N N N

O O N S 110 (IC50 = 0.25g/mL) 111 (IC = 0.05g/mL) R S N S R 50

104 105 R=OC2H5, 106 R=NHNH2 Antihistaminic Activity N N N N NC N NC N Jose Maria Quintela et al. [45] synthesized some N pyridotheino and pyridoditheinotriazines and evaluated them O N S N O N S for antihistaminic and cytotoxic activities. Compounds (104) and (105) were found to be strong inhibitors under all the N conditions tested, while compound (106) was found to be a 112 113 good inhibitor under all the conditions except the condition when it was preincubated with ovoalbumin. Compounds F3C (107), (108) and (109) were found to be good inhibitors in the immunological experiments but were practically inactive Gollapalle L. Viswanatha et al. [46] synthesized some under chemical stimulus. Compounds (110) (IC50 = 0.25g/mL) 3H-benzo[4,5]thieno[2,3-d][1,2,3]triazin-4-ones and evaluated and (111) (IC50 = 0.05g/mL) showed in vitro cytotoxic their antihistaminic activity. All the compounds showed very activity against several human and mouse tumoral cell lines. good in vitro antihistaminic activity. Sedative action of the The nitrogen-substituted compounds (112) and (113) also synthesized compounds was found to be less in comparison showed significant inhibitory action. The oxygen-substituted to standard drug chlorpheniramine maleate. Compounds analog (114) surprisingly acted as an inducer of the liberation (115) and (116) were found to possess competitive antagonism 80 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 Kumar et al. as compared to the standard drug. Compound (117) was N N NC N N N found to possess non-competitive antagonism at H1-receptor NC N site and showed very low sedative potential as compared to N N S Cl the standard drug. N N N N S O O 119 118 N N O NC N Raymond D. Youssefyeh et al. [48] synthesized a new N series of pyrido[3',2':4,5]thieno[3,2-d]-N-triazines and evaluated S O 3 O N N them for antiallergic activity. Most of the synthesized S N 2 compounds showed significant antiallergic activity with a 1 mechanism of action similar to that of disodium cromoglycate 114 115 (DSCG) for the prophylaxis of asthma. DSCG is a well- Cl established drug that inhibits release of the mediators of anaphylaxis and thus provides a prophylactic treatment of O O asthma. Compounds (120-123) were found to be more potent N N inhibitors of AIR (antigen-induced release of histamine) than 3 3 N N disodium cromoglycate (I50 value = 3 M) when added S N 2 S N 2 simultaneously with antigen. The potent compound 121 (I 1 1 50 value = 0.05 M) was 60 times more potent than DSCG as 117 116 an inhibitor of AIR in the rat peritoneal mast cells (RMC) assay. Compounds of this series were also tested orally for Miscellaneous Activities inhibition of passive cutaneous anaphylaxis (PCA) in the rat, Jose Ma Quintela et al. [47] synthesized some 8- either at a single dose (122, 124 and 125, 25 mg/kg PO) or at cyanopyrido[3’,2’:4,5]thieno[3,2-d]triazine derivatives as multiple dose levels (120, 121, 123, 126,and 127). Compound inhibitors of nitric oxide and eicosanoid biosynthesis. Most 129 was an orally potent inhibitor of the IgE-mediated passive of the synthesized compounds exhibited considerable activity. cutaneous anphylaxis in the rat (ED50 = 1.5 mg/kg PO); SAR study of the synthesized compounds reveals that the 8- however, it was virtually inactive in vitro, suggesting in vivo cyanopyridothieno-1,2,3-triazines with a chloro substituent metabolism to an active form. Compounds with reasonably low oral ED50 values were 120 (5.2 mg/kg) and 126 (3.6 (R2 = Cl) at position C-4 of the triazine nucleus and a mg/kg). Substitution of the hydrogen in the 4-position by nitrogen heterocycle at C-7 (R1) are found to be good hydroxy (120), amino (122), ethoxyethyl (125), methylamino inhibitors of PGE2 production, and reductions of about 50% of the control value are obtained in most cases. Compound (128), or a sulfhydryl groups (123) resulted in compounds that inhibited AIR from RMC. However, replacement of the with an N-(p-acetylphenyl)piperazine group at C-7 (R1), is found to be much more effective (95% inhibition), practically 4-hydrogen by an ethoxy, chloro, methyl carbazate, or methylthio groups did not result in compounds capable of suppressing the generation of PGE2. Presence of an amino group or a linear amine at C-7 and a bromo instead of a inhibiting AIR. Replacement of the 7-methyl (120)with a chloro substituent atom at C-4 is associated with a total loss phenyl group (121) resulted in a compound that was also an of activity on PGE2 production. Compounds carrying a active inhibitor of PCA (ED50 = 3 mg/kg). Compound (121) morpholine substituent at C-7 and different heterocycles at was potent as an inhibitor of AIR from RMC and also oral C-4 (R2), a moderate decrease (30-40%) in accumulation of PCA. both metabolites at 10 M. At 10 M concentration, compound bearings morpholine at C-7 and 4-methylpiperidine at C-4 is R2 N N an active compound inhibiting around 90% production of N NO and PGE2. While compounds containing heterocycles other than morpholine at C-7 position show 50% inhibitory S R3 R1 N action on both metabolites generation. The presence of acyclic amines in C-7 position does not improve the effectiveness of 120 R1=CH3, R2=H, R3=OH; these compounds. 8-Cyanopyridothieno-1,2,3-triazines (118) 121 R1=C6H5, R2=H, R3=OH (ED50 = 3 mg/kg); and (119) were the potent inhibitor with IC50 values of 11.2 122 R1=CH3, R2=H, R3=NH2; and 3.4 M on nitrites and 0.9 and 0.6 M on prostaglandin 123 R1=CH3, R2=H, R3=SH; E2 production on murine macrophages, respectively. They 124 R1=CH3, R2=H, R3=NHNHCOOCH3; concluded that the effect of compounds (118) and (119) 125 R1=CH3, R2=H, R3=O(CH2)OC2H5; could be due to their action on the degree of induction/ 126 R1=CH3, R2=CH3, R3=OH; expression of NOS and COX proteins caused by LPS in 127 R1=CH3, R2=H, R3=OC2H5; macrophages. These compounds might be of benefit for the 128 R1=CH3, R2=H, R3=NHCH3, prevention and treatment of autoimmune diseases, septic 129 R1=CH3, R2=H, R3=H (ED50 = 1.5 mg/kg). shock, and different inflammatory pathologies. 1,2,3-Triazine Scaffold as a Potent Biologically Active Moiety Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 81

DISCUSSION unsubstituted at the C-6 and C-7 positions. The compounds with a 3-chloropropoxy group at the C-7 position are more Azoles and azines are ubiquitous heterocycles which active than compounds with an ethoxy group or a pentyloxy display versatile pharmacological activities [49]. Originated group. By comparing the activities of compounds with a from various plant products and synthetic products, 1,2,3- methoxy group at the C-6 position and a 3-chloropropoxy triazine analogs display potent antibacterial and cytotoxic group at the C-7 position, but with a different substituted activities. Fusion of 1,2,3-triazine with heterocyclic moiety group at the C-4 anilino group, it revealed that compounds like indolo-benzo, pyridine, indole, thieno, pyrazolone, with different substitution at the aniline group increase the triazole and 1,2,4-triazine moieties have been reported to antiproliferative activity in MVECs as compared to show improved chemical and pharmacological activities. The compound with unsubstituted anilino group. Compounds heterocyclic system containing indole and triazine rings with disubstituents at the 3’ and 4’ positions of the anilino alone and in fused form together exhibit significant antitumor group are more active than compounds with disubstituents at activity against leukaemia and broad spectrum antimicrobial the 3’ and 5’ positions or compounds with monosubstituent activity, while presence of benzene in the heterocyclic of the aniline group. The compounds with substituents (like system with 1,2,3-triazine shows significant antitumor activity fluoro, chloro, methyl, methoxy and trifluoromethyl at 3’ in the various cancer cell lines. Indolo-benzotriazine analogs and 4’ positions) at the anilino group are more effective reveal qualitative variability in their biological activities. than PTK787 in inhibiting growth of MVECs after the Substitution with chlorine in benzene ring or with methoxy introduction of a methoxy group at the C position and a 3- or nitro group in the indole ring at specific positions shows 6 chloropropoxy group at the C position. Recently, it was potent antibacterial activity, while chlorine substitution in 7 reported that 1,2,4-benzotriazines are inhibitors of Src and indole ring alone shows inhibitory activity against resistant the binding model of 1,2,4-benzotriazines with Src showed solid tumor cell lines. Significant biological activities are the importance of the N1 and N2 atoms [50-51]. They also associated with indole-fused 1,2,4-triazines. The further concluded that since there is high degree of similarity heterocyclic systems containing pyridine, thieno or pyrazolone between 1,2,3-benzotriazine and 1,2,4-benzotriazine, the rings display potent antifungal activity. Another heterocyclic increased antiproliferative effects of the designed compounds in system comprising tetra substituted thieno group reveals that the tumor cells may be due to the inhibition of Src, or other substitution at nitrogen atom with lipophilic groups enhances tyrosine kinases which is not inhibited by PTK787 (130) its antimicrobial activity. Likewise pyridothienotriazine analogs [52]. PTK787 contains 2,3-benzodizine and ZD6474 (131) show promising antiprotozoal activity. Tetrahydrobenzotriazine contains 1,3-benzodizine. Replacement of the benzodizine analogs display nematocidal activity which varies according with 1,2,3-benzotriazine express significant increase in to the group present on the on the second nitrogen of 1,2,3- anticancer activity as compared to PTK787. Both PTK787 triazine. Bicyclothieno-1,2,3-triazin-4-one analogs containing and ZD6474 contain a substituted anilino group which might o-chloro phenyl, m-chloro phenyl, p-fluoro phenyl and phenyl be responsible for anticancer activity. ZD6474 contains a groups exhibit significant analgesic, anti-inflammatory and methoxy group at the C-6 position and a short side chain at antiarthritic activities. Analog with unsubstituted phenyl the C-7 position. Probably due to presence of substituted group showed maximum activity. Thieno-1,2,3-triazin-4-one anilino group, methoxy group at the C-6 position and a short analog bearing 3-cyclohexyl and 3-furfuryl groups reveals side chain at the C-7 position in 1,2,3-benzotriazine like good antidepressant activity. Thieno-1,2,3-triazin-4-one analog PTK787 and ZD6474 responsible for anticancer activity. having (furan-2-yl) methyl substitution at the third nitrogen Thus this analog can act as a lead for development of future shows potent antidepressant activity at low dose (25 mg/kg). anticancer agents. Extensive research is required on 1,2,3- Depending on the various substitutions on pyridotheino and triazine moiety to find novel analogs suitable for clinical pyridoditheinotriazine moieties, these analogs show variable applications in the cancer treatment. Indolo[1,2-c]benzo degree of antihistaminergic and cytotoxic activities. Above [1,2,3]triazine analogs 38, 39, and 40 are up to 80-times literature review showed that broad range of pharmacological more potent than streptomycin against Streptococcus and activities of triazines fascinates researchers to synthesize Staphylococcus and showed comparable potency against some potent 1,2,3-triazine analogs. However each segment penicillin-resistant strains of S. aureus. Hence these compounds of activity need to be further explored and a more may be considered as clinical candidates for the development comprehensive and organized structure activity relationship of future novel antimicrobial agents. will shed more light on its chemical arrangement and its correlation with its pharmacological activity. Cl SUMMARY AND FUTURE DIRECTIONS F Br 4-(3-Chloro-4-fluoroanilino)-7-(3-chloropropoxy)-6- HN methoxy-1,2,3-benzotriazine (62) has shown potent N HN antitumor activity. This analog is found to be 4-10 fold more N O potent than PTK787 to inhibit the growth of T47D breast N cancer cells, DU145 and PC-3 prostate cancer cells, LL/2 O N murine lewis lung cancer cells and B16F0 melanoma cells. N N The SAR study of the substituted 1,2,3-benzotriazine compounds reveals that compounds with a methoxy group 130 131 at the C-6 position and an alkoxy group at the C-7 position increase in activity as compared to compound with 82 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 Kumar et al.

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Received: September 13, 2013 Revised: September 30, 2013 Accepted: November 18, 2013

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