Triazines – a Comprehensive Review of Their Synthesis and Diverse Biological Importance

Curr Med Drug Res, 2017, 1 (1), Article ID 173 Review article Triazines – A comprehensive review of their synthesis and diverse biological importance Rajeev Kumar1*, Neeraj Kumar1, Ram Kumar Roy2 and Anita Singh3 1Devsthali Vidyapeeth College of Pharmacy, Lalpur, Rudrapur (U.S. Nagar)-283148, Uttarakhand, India. 2Innovative College of Pharmacy, Greater Noida, Uttar Pradesh, India. 3Department of Pharmacy, Kumaun University, Bhimtal, Nainital-263136, Uttarakhand, India. *Corresponding author: E-mail: [email protected]; Tel: +91-9528204982. Article history ABSTRACT Triazine is a heterocyclic aromatic ring structure, with three isomers distinguished by Received : May 09, 2017 positions of their nitrogen atoms. 1,2,3-triazine derivatives like tubercidin, toyocamycin, Accepted : May 28, 2017 sangivamycin, 2-azaadenosine and 2-aza-2-desamino-5,8-dideazafolic acid are the important active moieties in pharmaceutical field while 6-azacytosine, 6-azauracil, azaribine, tirapazamine, dihydromethyl furalazine, vardenafil, apazone, lamotrigine, Keywords ceftriaxone, pymetrozine, fervenulin (planomycin), reumycin and toxoflavin (panthothricin) are 1,2,4-triazine moieties used in clinical practices. The triazine ring Cycloguanil structure is also found in naturally occurring antibiotics like fervenulin, reumycin and Heterocyclic compounds toxoflavin. 1,3,5-Triazine isomer or s-triazine is an oldest known organic compound, Pharmacological activity broadly used as a lead structure in ammeline, aceto-guanide, acetoguanamine, cyanuric Synthesis acid and melamine. Some s-triazine containing drugs are hexamethylmelamine Triazine (altretamine), 2-amino-4-morpholino-s-triazine, hydroxymethyl-pentamethyl melamine, triethylenemelamine (tretamine), dioxadet, irsogladine, cycloguanil, almitrine, S9788 and DW1865. Triazines have a high significance in the field of pharmaceutical chemistry with wide-spectrum of pharmacological activities so useful for design and formation of novel drugs. Some triazine analogues are recently screened in clinical trials which may lead to potent type drugs with no side effects as presently available pharmacological agents. This review outlines the biological importance and synthesis of various types of triazine derivatives from various heterocyclic and drugs containing triazine moiety. © 2017 Global SciTech Ocean Publishing Co. All rights reserved. INTRODUCTION Triazines have a unique position in pharmaceutical chemistry. It is worked as Heterocycles are the ring compounds that protecting groups in natural chemistry. Triazines contain one or more diverse ring atoms (i.e. atom are reactive groups and flexible for different other than carbon like N, O, S, P, B, Si, As and Se). synthetic transformations (Dawane et al., 2010). Five and six-membered compounds are the most Triazine is a six-membered heterocyclic compound important heterocyclic systems. These are main with empirical formula C3H3N3. Its structure is class compounds which include more than 50% of analogous to the benzene ring in which three all well-known organic compounds. They can be carbons of the ring are substituted by nitrogen drugs, vitamins and natural products (Morrison et atoms. Due to different position of nitrogen atoms al., 2004). In the ancient times, synthesis of in the ring, triazine are found in three isomeric heterocyclic compounds was important because of forms (Fig. 1) its broad application. Heterocyclic compounds obtained from nature are important to life (Khalil et 1 1 1 N 6 N 2 N al., 2011). In life science industry and industrial 6 N 2 N 6 2 N 3 3 5 5 N 5 N N 3 field’s related to fine and special chemistry, 4 4 4 heterocyclic compounds showed important role 1 2 3 (Patel et al., 2007). They consist of a class of natural and synthetic products; some of them showed good Fig. 1. Isomeric forms of triazine: 1 (1,2,3- pharmacological property (Elgazwy et al., 2006). triazine); 2 (1,2,4-triazine); 3 (1,3,5-triazine) Curr Med Drug Res, 2017, 1 (1), Article ID 173 Page 1 Kumar et al. [Synthesis and biological importance of triazines] Pyridines (with one ring nitrogen atom), biological activity (Stevens et al., 1976). As a diazines (with two ring nitrogen atoms) and comparison with 1,2,4- and 1,3,5-triazine isomers, tetrazines (with four ring nitrogen atoms) are other the 1,2,3-triazine isomer is the least studied isomer aromatic nitrogen heterocyclic compounds. As because the nucleus of 1,2,3-triazine isomer is the compare to pyridine, Triazine compounds are least stable as compare to rest isomers and weaker bases (Yu et al., 2008). synthetic routes are also limited (Butler et al., 2006). Newly discovered 1,2,3-triazines are more 1,2,3-Triazine effective drugs along with less adverse effects (Biesele, 1952; Simons et al., 1963). Tubercidin, 1,2,3-Triazine derivatives are the new member toyocamycin, sangivamycin, 2-azaadenosine and 2- of heterocyclic compounds. In older literature, V- aza-2-desamino-5,8-dideazafolic acid are the 1,2,3- triazine or β-triazine are also found along with triazine moiety containing drugs which show 1,2,3-triazine isomer (Biesele, 1952, Simons et al., different pharmacological activities. The drugs 1963). Heterocyclic moiety fused with 1,2,3- containing 1,2,3-triazine moiety and their triazine-4-ones show high chemically-reactivity and biological activities are shown in Table 1. Table 1. Drugs containing 1,2,3-triazine moiety. S.No. Name of compound Structure Uses Reference 1. 2-Azaadenosine NH2 Cytotoxic agent Montgomery and Thomas, 1972 N N N N N O HO OH HO 2. 2-Aza-2-desamino-5,8- HO Thymidylate Roeowsky et al., dideazafolic acid O synthase inhibitor 1992 HN HN N O O N HO HN O NH 3. Sangivamycin 2 CONH2 Anticancer agent Brockman, 1983; Robins and N Revankar, 1985 N N N O HO OH HO 4. Tubercidin NH2 Antimicrobial Nishimura et al., activity by 1966; Bergstrom et N inhibiting DNA, al., 1984 N N N RNA and O protein synthesis HO OH HO 5. Toyocamycin NH2 CN Anticancer agent Cohen and Glazer, (Antibiotic) N 1985; Renau et al., 1994 N N N O HO OH HO 1,2,4-Triazine 2002). 6-Azacytosine, 6-azauracil, azaribine, tirapazamine, dihydromethyl furalazine, vardenafil, The 1,2,4-triazine derivatives, obtained from apazone, lamotrigine, ceftriaxone, pymetrozine, synthetic and natural sources, have different fervenulin (planomycin), reumycin and toxoflavin biological activity (Simons et al., 1953). 1,2,4- (panthothricin) are 1,2,4-triazine moiety containing Triazine compound and its condensed derivatives drugs which show different pharmacological with the heterocyclic ring, showed the application activities. Naturally occurring antibiotics like in various fields as pharmaceuticals, agriculture, fervenulin (planomycin), reumycin and toxoflavin dyes, pesticides, and herbicides (Diana et al., (panthothricin) are N-methyl derivatives of 1,2,4- Curr Med Drug Res, 2017, 1 (1), Article ID 173 Page 2 Kumar et al. [Synthesis and biological importance of triazines] triazines. The microwave assisted one-pot solvent- was carried out from fatty acid hydrazides together free synthesis of 3,5,6-trisubstituted-1,2,4-triazines with their antimicrobial activity (Rauf et al., 2007). Table 2. Drugs containing 1,2,4-triazine moiety. S.No. Name of compound Structure Uses Reference N 1. 6-Azacytosine N Antiviral and Sidwell et al., 1968; antitumor activities Falke and Rada, H2N N O H 1970; Creasey et al., 1963 N 2. 6-Azauracil NH Antiviral and Sidwell et al., 1968; antitumor activities Falke and Rada, O N O 1970; Creasey et H al., 1963 3. Apazone Anti-inflammatory and Tripathi, 2003; O analgesic activities Lemke et al., 2010 N O N N N 4. Azaribine O Antiviral, antifungal Negwer, 1987 NH agents and also in N treatment of psoriasis N O O O O O O 5. Ceftriaxone (Third H Broad spectrum Lemke et al., 2010; O N O OH generation N antimicrobial agent Ucherek et al., 2008 O cephalosporin O N S N O NH2 antibiotic) N S N H H S O N 6. Dihydromethyl O2N Wide spectrum Kobari et al., 1970 furalazine O antibacterial agent N CH2OH N N N CH OH 2 7. Lamotrigine H2N N NH2 Anticonvulsant drug Tripathi, 2003; and also in the Lemke et al., 2010 N N treatment of bipolar depression Cl Cl 8. Metribuzin O Herbicide Curran, 1999 NH N 2 N N S 9. Pymetrozine H Insecticide Ucherek et al., 2008 N O N N N N 10. Tirapazamine O- Anticancer agent by Sarkar et al., 2010 N+ inducing DNA N damage in poorly N+ NH2 oxygenated tumour O- cells 11. Vardenafil O Used for treatment of Arnold, 2004 HN erectile dysfunction O O N S N by inhibiting N N phosphor-diesterase- N O 5 Curr Med Drug Res, 2017, 1 (1), Article ID 173 Page 3 Kumar et al. [Synthesis and biological importance of triazines] 1,3,5-Triazine or s-triazine melamine are the 1,3,5-triazine moiety-containing compounds (Simons et al., 1953). Due to various 1,3,5-triazine isomer also called as s-triazine applications in different fields, 1,3,5-triazines are a due to the symmetry of three nitrogen in the ring. well-known class of compounds from a long time This isomer is an oldest known organic compound. and still continue of considerable interest (Afonso 1,3,5-Triazines represent a broadly used lead et al., 2006). Hexamethylmelamine (altretamine), 2- structure with remarkable applications in various amino-4-morpholino-s-triazine, hydroxymethyl- fields (Vora et al., 2009). s-Triazine derivatives are pentamethylmelamine, dioxadet, irsogladine, an important class of compounds showing many triethylenemelamine (tretamine), cycloguanil, pharmacological activities (like antimicrobial almitrine, S9788 and DW1865 are s-triazine activities) (Dawane et al., 2010). Ammeline, aceto- containing drugs. The drugs containing 1,3,5- guanide, acetoguanamine, cyanuric acid, and triazine moiety are given in Table 3. Table 3. Drugs containing 1,3,5-triazine moiety. S. No. Name of compounds Structure Uses Reference 1.

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