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] 1875-5607/14 $58.00+.00 © 2014 Bentham Science Publishers 1,2,3-Triazine Scaffold as a Potent Biologically Active Moiety Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 73 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 HN 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 HN 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.