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1, 3, 5-Triazine and 2, 4, 6-trichloro-1, 3, 5-triazine as Antimicrobial Drugs

3 Jan

Summary

Antimicrobial drugs are used widely by the medical practitioners and doctors in the hospitals. The use of antimicrobial agents is comes under the chemotherapy. At present, fewer brand new antimicrobial agents are coming onto the market, considering this situation together with the increasing awareness of drug safety; we are facing a situation of severely limited options among antimicrobial agents. 1, 3, 5-Triazine and 2, 4, 6-trichloro-1, 3, 5-triazine are the two widely used antimicrobials with their derivatives.

 Introduction

Antimicrobial drugs had caused a dramatic change not only of the treatment of infectious diseases but of a fate of mankind. Antimicrobial chemotherapy made remarkable advances, result in the overly optimistic view that infectious diseases would be conquered in the near future [1].However, in reality, emerging and reemerging infectious diseases have left us facing a counter charge from infections. Infections with drug resistant organisms remain an important problem in clinical practice that is difficult to solve. If an improper antimicrobial agent happens to be chosen for the treatment of infection with drug-resistant microorganisms, the therapy may not achieve beneficial effect and more over, may lead to a worse prognosis. In addition, in a situation where multidrug-resistant organism shaves spread widely, there may be quite a limited choice of agents for antimicrobial therapy.

 

1, 3, 5-Triazine

The symmetrical triazine ring system is ordinarily abbreviated as s-triazine, although the designation 1, 3, 5-triazine is also common, particularly in the British literature [2]. In this convention the numbers refer to positions of the ring-nitrogen atoms. In the early German literature, the s-triazine system was known as kyanidine (cyanidine) or γ-triazine. The designation s-triazine is preferred by both chemical abstracts and the ring index. Ring nitrogen positions 1, 3 and 5 are equivalent, as are ring-carbon positions 2, 4 and 6. s– Triazine is an extremely volatile crystalline solid which melts, at 86°C and boils at 114°C at one atmosphere. It is easily soluble in ether and in ethanol at -5°C. The relatively high melting point and extreme volatility are in accord with a highly symmetrical molecular structure. Because of its volatility, s-triazine can be isolated from reaction mixtures by entrainment in a stream of nitrogen or dry air. The density of the highly refracting rhombohedral crystals has been determined to be approximately 1.38 g/cm3. The heat of combustion for s-triazine has been calculated to be 424.4, the heat of fusion, the heat of vaporization, 12.15 and the resonance energy, 20.0  kilo.cal./mole. s-Triazine exhibits a high degree of thermal stability; it can be purified without appreciable loss by repeated distillation over metallic sodium. Introduction of ring-nitrogen atoms has little effect on the boiling points but causes a linear increase in the melting points.

Fig. 1: 1,3,5 triazine

2, 4, 6-trichloro-1, 3, 5-triazine

The ease of displacement of chlorine atoms in 2,4,6-trichloro-1,3,5-triazine by various nucleophiles, in the presence of a hydrochloride acceptor usually sodium carbonate, bicarbonate, hydroxide or tertiary amines, makes this reagent useful for the preparation of mono-, di- and tri-substituted 1,3,5-triazines. The substitution of chlorine can be controlled by temperature to run in a stepwise manner.  Mono-substitution of chlorine occurs below or at 0°C di-substitution at 40-45°C and tri-substitution above 120°C. The substitution pattern also depends on the structure of the nucleophile, its basic strength and steric factors, the substituent already present in the s-triazine ring and the nature of solvent used. By controlling the temperature, time and optimization of variables, such as solvent and base, the substitution of chlorine in 2, 4, 6-trichloro-1, 3, 5-triazine with different substituent can be accomplished in one pot, if the correct order of addition of nucleophiles.

 

Justification

As resistance towards various available antimicrobial drugs is the major world-wide problem facing today. In this era there is a need for the synthesis of advanced compound showing effective activities against various existing microorganism. A considerable part of research carried out in the development of new drugs is devoted to the study of heterocyclic compounds. There are vast numbers of pharmacologically active nitrogen containing heterocyclic compounds, among the known, s-Triazine is of immense importance. Triazine shows various pharmacological actions such as antibacterial, antitubercular, antifungal, antimalarial, antiplasmodial, antiviral, antitumor, respiratory stimulant, CNS depressant and herbicidal etc. Different substitutions on triazine moiety on different position are found to posse’s different activity. It is promoted for sequential introduction of various piperazine and piperidine substituent into the triazine ring by many investigators [1, 3, 5]. Literature survey reveals that piperazine ring is important for biological activity [3-5]. Currently important antibiotics used for the treatment of microbial infections contain a piperazine ring in their structures. The piperidine structure is found in paroxetine, risperidone, methylphenidate, raloxifene, minoxidil and thioridazine pharmaceuticals. In this project work triazine is taken as a parent moiety for its antimicrobial activity. To fulfill the need of various substitutions on triazine, various piperazine derivatives are used to obtain advanced antimicrobial drugs.

Ravikumar et al. (2008) [6] showed the 3D-QSAR and molecular docking studies of 1, 3, 5-triazine-2, 4-diamine derivatives against r-RNA and reported it as a promising antibacterial translational inhibitor.

 

 

 

 

Fig. 2: Structure of 1, 3, 5-triazine and 2, 4-diamines

 Srinivas et al. (2006) [7] reviewed the antibacterial activity of a series of mono-, di-, tri-substituted 4-benzyloxy and 4-imidazoloaniline-[1,3,5]-triazine derivatives  and found that all the [1,3,5]-triazine derivatives exhibited significant to moderate activity (MIC 12.5-50 µg/ ml) against gram positive and gram negative bacteria.

 

 

 

Fig. 3: tri-substituted 4-imidazoloaniline-[1,3,5]-triazine.

 

Desai et al. (2005)[8] synthesized and studied in-vitro antimicrobial activities of 2-coumarin, 4-imidazole, 6-aryl thiourea substituted [1,3,5]- triazine derivatives. These compounds were found to possess promising activity against S. paratyphi and Enterobector. Thore et al. (2005)[9] synthesized 2, 4-bisanilino-6-[2’(3”-phenyl pyrazolin-5”-yl)   4’chlorophenyloxy-[1,3,5]-triazine. The synthesized compounds showed their antimicrobial activity against a. brassicicola, staphyloccous and lactobacillus.

 

Fig. 4: Synthesis of amino substituted [1, 3, 5]-triazine derivatives

 

 

Fig. 5: 2-coumarin, 4-imidazole, 6-aryl thiourea substituted [1, 3, 5]- triazine.

 

Zhou Y. et al. (2005) [10] assessed the synthesis of 3,5-diamino-piperidinyl triazine (DAPT)  as a novel translation inhibitor class that targets bacterial rRNA which exhibited broad spectrum antibacterial activity.

 

Fig. 6: 3, 5-diamino-piperidinyl triazine compound.

 

 Guo Zhiqiang et al. (2004)[11] assessed the synthesis of some new biologically active bis-(thiadiazolotriazines) in presence of 1,4-dioxane as solvent. Chikhalia et al. (2002)[12] synthesized and studied morpholine, pyridine and phenyl    thiourea substituted-[1, 3, 5]-triazine. The synthesized compounds were found to possess antibacterial activity against e. coli, s. aureus, s. paratyphi , p.vulgaris.

 

 

 

Fig. 7: 2-[4-(-4-chlorophenyl)-6-(3, 4, 5 trimethoxyphenyl) pyrimidin-2ylamino]-4-(morpholino)-6-(arylthioureido)-[1, 3, 5]-triazine.

 

Modha et al. (2001) [13] reported the antibacterial activity of 3, 4-dihydropyrimidin-4-ones and alkyl/aryl amino substituted [1, 3, 5]-triazine. It was found that aryl amino substituted [1,3,5]-triazine showed maximum antibacterial activity against s. albus, B. mega, S. typhosa and E.coli.

 

Fig. 8: 2,4-Bis alkyl/aryl amino-6-[5’-cyano-3’-N-methyl]-6-phenyl/p-chlorophenyl-3, 4-dihydropyrimidin-4-one-2’-yl-hydrazino)-[1,3,5]-triazine

 

Baldaniya e. al (2009) [14] several compounds viz. N’-{4-[(3-chloro-4-fluorophenyl) amino]-6-[(-aryl) amino] -1, 3, 5-triazin-2-yl} isonicotinohydrazides and N2-(Aryl)-N4, N6-dipyrimidin- 2-yl-1, 3, 5-triazine-2, 4, 6-triamines were prepared. All newly synthesized compounds had been tested for their antibacterial activity against gram (+)ve and gram (-)ve bacteria and also on different strains of fungi. Introduction of -OH, -OCH3, -NO2, -Cl and –Br groups to the heterocyclic frame work enhanced antibacterial and antifungal activities.

 

Fig. 9: Structures of substituted 1, 3, 5-triazine

Acknowledgements

The author is most grateful to K.P. Rathoure (Mrs.) for her technical and valuable comments.

 

References

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  2. 2.      Walsh C, Wright G., Introduction: Antibiotic Resistance. Chemical Reviews. (2005), Vol. 105(2): 391-392.
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  4. 4.      Elzbieta W; Monika K; Bogdan, Eur. J. Med. Chem. (2006), 41(4):519-525.
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  6. 6.      Ravikumar M, Mahmood SK, Sivakumari N., 3D-QSAR and molecular docking studies of 1, 3, 5-triazene-2, 4-diamine derivatives against r-RNA: Novel bacterial translation inhibitors. J of Mole Graph and Model. (2008), 26(8):1338-1352.
  7. 7.      Srinivas U, Hara Kishore K, Murthy U S N, Jayatirtha Rao V., Synthesis and Antibacterial Activity of 2,4,6-trisubstituted s-triazines. Bioorg Med Chem Lett. (2005), 15:1121–1123.
  8. 8.      Desai PS, Patel M, Chikhalia KH., Synthesis of Pyrimidine Thiazolidones and Azetidinones: Antibacterial and Antitubercular agents. J of Indian Chem Soc Jan (2005), 82: 83-85.
  9. 9.      Thore SN, Synthesis and Antimicrobial Study of Triazolo Pyrazolines and Isoxazolines Derivatives Asian J Chem. (2005), 17(4):2463-2466.
  10. 10.  Zhou Y, Gregar VE, Sun Z., Structure Guided Drug Discovery of Novel Aminoglycoside Mimetics as Antibacterial Transational Inhibitors Antimicrobial Agents and Chemother. Feb 2005, 4942-4949.
  11. 11.  Zhiquiang G, Koci J, Pour M, Stachel J, Waisser K., Synthesis, evaluation of benzimidazole derivative as antimicrobial agents. Eur. J. Med. Chem. (2002), 37:409-418.
  12. 12.  Patel RB, Desai PS, Desai KR, Chikhalia KH, J of Indian Chem Soc., Vol-45, 711-719.
  13. 13.  Modha J.J., Antibacterial Activity of Various Substituted s-triazines. Eur J Med Chem. (2006), 41:1240–1246.
  14. 14.  Mukesh M. Jotani, Bharat B. Baldaniya and Edward R. T. Tiekink., Ethyl 2-(2-acetoxy­benzyl­idene)-7-methyl-3-oxo-5-phenyl-2,3-dihydro-5H-1,3-thia­zolo[3,2-a] pyrimidine-6 carboxyl­ate. Pubmed central. (2010), 66:762–763.

About the Author:

Ashok Kumar*

Dept of Biotechnology, Himachal Institute of Life Sciences Rampurghat Road, Paonta

Sahib -173025, Himachal Pradesh, INDIA

*Corresponding Author’s Email: asokumr@gmail.com

 

Address for Correspondences:

Dr. Ashok Kumar C/O Mr. G.K. Rathoure, MAYASHIVRAJ SADAN, Gupta Colony, Railway Ganj Hardoi-241001 (UP) INDIA, Email- asokumr@gmail.com

Phone- 05852-223447, Mob- +919450501471, +919548080680

 

 

क्लिनिकल ट्रायल या क्लीनिकल रिसर्च – Dr Mahesh Sharma

30 Jun

Author: Dr. Mahesh Sharma —M.D.(Ay. Medicine)

About: Dr.Mahesh Sharma is an expert of Ayurveda by profession. He is a practicing as a consulting Ayurvedic physician since 1977. Having practiced as a general practitioner for a short stint of 3 years, he opted to be a specialist and hence, pursued specialization in “Internal Medicine” and completed M.D. in the year 1983 from Osmania University. Besides his own consultancy clinic, he was invited on board by different institutes/organizations to render his services. Dr. Mahesh Sharma has a website from WebsiteForDoctors

Contact: http://www.ayursharma.com

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