A SYNOPISIS on

SYNTHESIS AND ANTI-MICROBIAL EVALUATION OF TRIAZINE DERIVATIVES

Submitted to Submitted by Dr.R.K.Roy Abhilash Kumar Gupta

M.Pharm DR.K.N.MIPER

Director

DR.K.N.MIPER

INTRODUCTIONThe triazine structure is a heterocyclic ring, analogous to the six-

membered benzene ring but with three carbons replaced by nitrogen.(1)

General molecular formulae : C3H3N3

Cyanuric acid, melamine, ammeline, aceto-guanide, acetoguanamine are some of the important compounds under this class.1, 2, 4-triazines(2)

Drug comes under 1,2,4-triazines : lamotrigine

Literature Review Anti microbial activity Jumat Salimon et al. Synthesized and anti-

microbial activity of some new 1,2,4-triazine derivatives (3)

The title compound 2-(4-(anthracen-9(10H)-ylideneamino)-4-(1,6-dihydro-1,2,4-triazin-5(2 H)-one)pyridine molecular formula C29H43N5O,

All synthesized compounds were primary in vitro screened for their antibacterial activity against Gram-positive

These compounds showed in vitro growth inhibitory activities against the tested organisms comparable or higher than Streptomycin.

Marzena M. Chereket al synthesized and evaluated biological activity of methyl 2-[5-oxo-3,4-di-(2-pirydyl)-1,4,5,6 tetrahydro 1,2,4-triazine-6-ylidene] acetate (4)

The NCNN group is an essential part of various heterocycles bearing high biological activities. 1,2 ,4-Triazines and their condensed derivatives found applications as pharmaceuticals and in agriculture.

It was observed that the growth of only two strains of Candida albicans wasinhibited by compound 6 at a concentration of 256 g/mL. Surprisingly, this substance exhibited higher antifungal potency against three strains of Candida.

Baseer M.Shaikh et al synthesized and evaluated antimicrobial activity of 1, 2, 4-Triazin-6-(5H)-one derivatives (5)

The condensation of 4-(2-susbtituted benzylidine)-2-phenyloxazol-5(4H)-one with 4-(4-Chlorophenyl)2- Hydrazinylthiazol in presence of sodium acetate in acetic acid. The newly synthesized compounds were evaluated for their antimicrobial activity

The antibacterial and antifungal activity revealed that most of the compounds showed moderate to good activity. The substitution of hydroxyl group and presence of halo groups emerged as active in both antibacterial and antifungal screening

Bhaskar S. Dawane et al synthesized and evaluated anti-microbial activity of 1, 2, 4-triazine derivatives (6)

A simple and efficient synthesis of 1, 2, 4- triazine derivatives is described by the condensation of substituted 4-(2-chloro-quinoline-3yl methylene)-2-[phenyl-4H-oxazol-5-one and phenyl hydrazine an equimolar sodium. The newly synthesized compounds were evaluated for their antimicrobial activity

Compounds, 3b, 3c, 3g showed good activity comparatively active against B. subtillis. As compared with standard antibacterial compounds 3a, 3d, 3e, 3f, 3g, 3h were observed as active against S. typhi.

A. A. El-Barbary Synthesized and evaluated Biological Activity of Some 1, 2, 4-Triazine Derivatives(7)

Three series of novel fused nitrogen heterocyclic systems such as triazines linked with a chromone moiety were synthesized from the key intermediate 1,6-diamino-(6-chloro-4-oxo-4H-chromen-3-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile with some electrophilic reagents.

Anti anxiety activity

Pooja Mullick et al synthesized and evaluated anti-anxiety and anti-inflammatory activity of 1, 2, 4- triazine.(8)

Many of the triazine compounds were found to possess good activity.

Especially, compounds bearing the sulfur atom showed better activity than those bearing the oxygen atom.Secondly, compound with electronegative substituent at the para position showed better activity than other substituents.

Anti-convulsant activity B.P. Mallikarjuna, et al synthesized and evaluated

the anti -convulsant activity of 5,6-bis aryl 1,2,4-triazines(9)

A series of 5,6-bis aryl 1,2,4-triazines were synthesized by condensation of various benzils with aminoguanidine bicarbonate and were screened

Few Compounds were found to be potent molecules of this series, when compared with the reference drugs

The characteristic feature of these compounds is substitution of electron rich atom/group at different positions of aryl ring, which demonstrates potent anticonvulsant activity

Saurabh k Sinha et al Synthesized and evaluated biological activity of three new amide prodrugs of lamotrigine with reduced hepatoxicity (10)

Lamotrigine is an anti-epileptic drug used for the prevention of convulsion. Except several known side effects, hepatic dysfunction is also reported.

Three prodrugs of LTG was synthesized by its reaction with N-acetyl amino acids , viz , glycine ,glutamic acid and methionine.

ClCl

N

N N

NH2

HNC

O

CH

R

NHC

O

H3C

Anticonvulsant activity of LTG-Mt conjugate comparable to that of LTG and the significantly lower damage to liver .

Other activityHugo Cerecetto et al studied 1,2,4-Triazine N-

oxide Derivative as Potential Hypoxic Cytotoxins(11)New 5-(2-arylethenyl)-1,2,4-triazine N-oxide and N,N_-dioxide derivatives were

synthesized in order to obtain compounds as selective hypoxic cell cytotoxins. The desired products were obtained when the 5-methyl heterocycle reacted with the corresponding iminium electrophiles..Derivative 11, 6-methyl-5-[2-(5-nitrofuryl)ethenyl)-1,2,4-triazine N4- oxide, was the most cytotoxic compound, but it was non-selective.

Compound showed good cytotoxic activity, displaying excellent V79 cell-growth inhibition even at 1 μM being

M. A. El-Badawi Synthesized and Evaluated biological activity of Some Novel N , N '-Bis-(1,2,4-Triazin-4-Yl)Dicarboxylic Acid Amides and Some Fused Rings with 1,2,4-Triazine Ring (12)

Some of novel N,N0-bis-(1,2,4-triazin-4-yl)dicarboxylic acid amides and thiadiazolo[2,3-b][1,2,4]triazin-7-yl carboxylic acid derivatives were prepared by heating 4-amino-6-methyl-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine with different dicarboxylic acids (oxalic, malonic, fumaric, maleic, succinic, and phthalic acids respectively) in POCl3.

ANTI-HBV ACTIVITY used to evaluate theantiviral effect of the tested compounds against HBV Compound showed moderate inhibition of viral replication with a 50% inhibitory concentration and 50% cytotoxic concentration

NEERAJ K. SHARMA et al STUDIED 3D QSAR OF PYRROLO[2,1F][1,2,4] TRIAZINES AS TYROSINE KINASE INHIBITORS (13)

Recently several pyrrolo triazine derivatives were identified as potentially active anticancer agents against vascular endothelial growth factor receptor (VEGFR) tyrosine kinases

Neighbor Molecular Field Analysis (kNN‐MFA) combined with various selection procedures was performed

The presence of electronegative groups on molecule with less bulky substituents on other positions has shown better

activity.

Synthesis and antitumor activity of new 1,2,4-triazine and [1,2,4]triazolo[4,3-b][1,2,4]triazine derivatives and their thioglycoside and acyclic C-nucleoside analogs (14)

New 1,2,4-triazine and their derived 1,2,4-triazolo[3,4-b][1,2,4]triazine derivatives were synthesized starting from 5,6-diphenyl-1,2,4-triazine-3-thiol. Furthermore, the corresponding 1,2,4-triazolo[3,4-b][1,2,4]-triazine thioglycosides and acyclic C-nucleoside analogs were synthesized.

The newly synthesized compounds were evaluated for their antitumor activity and some of them showed high inhibition activities.

KRZYSZTOF SZTANKE et al. SYNTHESIZED AND BIOLOGICAL ACTIVITY OF NEW DERIVATIVESOF 8-ARYL-4-IMINO-2,3,7,8-TETRAHYDRO-IMIDAZO [2,1-c][1,2,4]TRIAZIN-3 (6H)-ONE (16)

Reaction of 1-aryl-2-hydrazono-imidazolidines with ethyl oxamate furnished novel derivatives of imidazo [2,1-c][1,2,4] triazine Imidazotriazines reported herein contain intheir chemical structure similar features .

4-imino-2,3,7,8-tetrahydro-imidazo [2,1- c][1,2,4] triazin-3 (6H)-one to be analgesic (83.2 %)is imperceptibly greater than for a molecule of similarstructure, having in 4 position the oxo-group

STEPHEN D. LINDELL Synthesized and evaluated 3-(Carboxyphenylethyl)-imidazo[2,1-f] [1,2,4] Triazines as Inhibitors of AMP Deaminase(17)

A combination of the aglycone with the ribose phosphate led to the evaluated 3-(Carboxyphenylethyl)-imidazo[2,1-f] [1,2,4] Triazines which represents a new class of AMP deaminase inhibitors . The best compound 3—[2-(3-Carboxy-5,6,7,8-tetrahydronapthyl)-ethylimidazo[2,1-f] [1,2,4] Triazine was good inhibitor of all the three human AMPD

N

NN

N

HO2C

ZHE JIN et al. Synthesized and evaluated Acetylcholinestrase activity of 3,6- diaryl -7H-thiazolo[3,2-b][1,2,4]triazin-7-one Derivatives (18)

In order to study on the influence of modification at different groups and side chains on the AChE inhibitory ability and the active sites of 7H-thiazolo[3,2-b][1,2,4]triazin-7-one derivatives

The AChE inhibitory activity was carried out, most of the target compounds exhibited more dan 50 % inhibition at 10 um, some compounds showed strong inhibition against AChE .

The compound which have hydroxyl group, exhibited more potent inhibitory because the hydroxyl group was able to form hydrogen bond

N

N

N

S

R1

ON

N

N

SO

O

O

R3

Rolf Paul et al. synythesized and evaluated anti asthma activity of Imidazo[1,5-d][1,2,4 triazines (19)

A potentially prophylactic drug for the treatment of asthma, a series of substituted imidazo[1,5-d][1,2,4]triazines were found which were active.

Those compound which have greatest basophil activity were tested for the mouse passive cutaneous anaphylaxis

The best compounds,1-ethyl-8-methyl-6 propylimidazo[1,5-d][1,2,4]triazin-4(3H)-one and 1,8-dimethyl-6-propylimidazo[1,5-d][1,2,4]triazine-4-(3H)-one

N

N

NHN

O

R2

R1

Ph

V.L RUSINOV Et Al Synthesized And Evaluate The Antiviral Activity Of Nucleoside Analogs Based On 1,2,4-Triazolo[3,2c][1,2,4]Triazin-7-Ones(20)Nucleosides analogs containing

hydroxybutyl ,hydroethoxymethyl, alloxymethyl and propylgalloxymethyl fragments were synthesized based on 1,2,4-Triazolo[3,2c][1,2,4]Triazin-7-Ones isoteric to purine bases.

Some of the compounds obtained inhibit in vivo reproduction of influenza and respiratory syncital virus infection.

N

N

N

HO

N

R1

R2

Long-Chih Hwang et al Synthesis and Molecular Structure of 6-Amino-3-benzylmercapto-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-one (8)(21)

Kung Ban et al synthesized and evaluated anti malarial activity of 3-Alkylthio-1,2,4-triazine dimmers(22)

Scheme of work

NO

O

R1

R2H2N

NH

X

NH2 NR1

R2

NNHCXNH2

O

1

2

AcOH,Reflux

3a-l

R3R3

R2 NH

HN

NX

O

4a-l

NHR1

NaOH,Reflux

R3

NR1

R2

NNHCXNH2

O

3a-l

R3

NN

NHNR2 X

R1

5a-l

AcOH,Reflux

R3

R2 NH

HN

NX

O

4a-l

NHR1R3

R3= Br, NO2

R1=H, CH3, COCH3 X=O,S

R2=H, Cl, Br,NO2

NN

NNR2 X

R1

6a-lR3

H2C N

HCHO

R4

R5

HNR5

R4

NN

NHNR2 X

R1

5a-lR3

HNR5

R4=

NH

HN

O

HN

HN

, ,

Step 1

Step 2

Step 3

Step 4

References Yu Q. and Schwidom D. (2008) ‘Synthesis of Novel Homo-N-Nucleoside

Analogs Composed of a Homo-1,4-Dioxane Sugar Analog and Substituted 1,3,5-Triazine Base Equivalents’, Molecules, Vol. 13, pp.3092-3106.

Srinath R et al. (2010) ‘Synthesis and Evaluation of Anti-Depressant like Activity of Some NovelThieno 1, 2, 3 – triazine 4 – ones’,Int. J. Res. Pharm. Sci., Vol-1, NO 2, pp 143-150.

Sailamon.J and Salih.N.(2010) ‘Synthesis, characterization and biological activity of some new 1,2,4-triazine derivatives’ International Journal of PharmTech Research. Vol.2, No.2, pp 1041-1045

UCHEREK MARZENA M. et al.(2008) ‘BIOLOGICAL ACTIVITY OF METHYL 2-[5-OXO-3,4-DI-(2-PIRYDYL)-1,4,5,6-TETRAHYDRO-1,2,4-TRIAZINE-6-YLIDENE] ACETATE’ Acta Poloniae Pharmaceutica. Vol. 65 No. 6 pp. 789-791

Shaikh BaseerM. et al .(2010) ‘An efficient synthesis and in vitro antimicrobial activity of 1, 2, 4-Triazin-6-(5H)-one derivatives’ Der Chemica Sinica , Vol-1 , NO-2, pp -86-91

Dawane B S.(2010) ‘An efficient synthesis of 1, 2, 4-triazine derivatives and their in vitroantimicrobial activity’ Der Pharmacia Lettre, ,Vol 2,No4, pp 126-131

- El-Barbary A. and A., Sakran M. A..(2005) ‘Synthesis, Characterization and Biological Activity of Some 1,2,4-Triazine Derivatives. J. Heterocyclic Chem.’, Vol 42, pp 935.

Mullick.P et al.(2009) ‘ Synthesis of 1,2,4-triazine derivatives as potentialanti-anxiety and anti-inflammatory agents’ Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 66 No. 4 pp. 379-385

Mallikarjuna.B.P.etal.I(2007) ‘Synthesis and anticonvulsant activity of some potent 5,6-bis aryl 1,2,4-triazines’ J Zhejiang Univ Sci B,Vol 8,No. 7,pp 526-532

Sinha .K .Saurabh et al (2010) ‘synthesis ,characterization and biological activity of three new amide prodrugs of lamotrigine with reduced hepatoxicity’ chemical papers,

El-Badawi M.A et al (2002) ‘Synthesis and biological evaluationOf some novel n,n0-bis-(1,2,4-triazin-4-yl)-Dicarboxylic acid amides and some fused rings with 1,2,4-triazine ring’ Phosphorus, Sulfur and Silicon, Vol.177 pp 587–596

Sztanke Krzysztof (2005) ‘Studies on the synthesis of new derivatives Of 8-aryl-4-imino-2,3,7,8-tetrahydro-imidazo [2,1-c][1,2,4]Triazin-3 (6h)-one with an expected biological activity’ Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 62 No. 3 pp. 221ñ226,

Lindell S.Stephen et al (2010) ‘synthesis and biochemical testing of 3-(carboxyphenylehtyl)-imidazo[2,1-f][1,2,4]triazines as inhibitor of AMP deaminas’ ASC Med. Chem, Vol 10 ,pp 286-289

Paul Rofel (1985) ‘imidazo[1,5-d][1,2,4]triazines as potential asthma agents’J.Med.Chem ,Vol 28,pp 1704-1716

Rasinov.V.L . Et al. (2010) ‘syntheis and anti-viral activity of nucleoside analogs based on 1,2,4-triazolo[3,2-c][1,2,4]triazine-7-ones’ Russian chemical bulletin,Vol 59,NO 1 , pp 136-143

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