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antifungal activity was observed [15]. In 2007, Desai et al. synthesized some aliphatic thiourea and aryl urea derivatives 17 incorporating 1,3,5-triazine moiety by ...

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Current Organic Synthesis, 2016, 13, 484-503 ISSN: 1570-1794 eISSN: 1875-6271

Current Organic Synthesis

Recent Advances in Synthesis and Antifungal Activity of 1,3,5-triazines

Impact Factor: 2.05

BENTHAM SCIENCE

Amit Sharmaa, Sarbjit Singhb and Divya Utrejac,* a

Department of Chemistry, Guru Nanak Dev University, Amritsar 143 005, India; bCollege of Life Sciences and Biotechnology, Korea University, Seoul, 136-701, Korea; cDepartment of Chemistry, Punjab Agricultural University, Ludhiana 141 004, India

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Keywords: Antifungal, Aspergillus, Candida, Cyanuric chloride, Triazine.

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Abstract: In the armamentarium of antifungal agents, appropriately functionalized triazines and their derivatives have received considerable attention in the recent past. In this focus review, we have highlighted the investigations regarding antifungal activities of triazines and their derivatives.

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Because of the large volume of work in this area, it is highly important to cover all those reports in which 1,3,5-triazines have been synthesized and explored as antifungal agents. This review article will cover the recent advancements made in the synthesis and antifungal activities of 1,3,5-triazine derivatives reported after 2000 to the present. 1.1. Antifungal Activity

In 2001, Modha et al. synthesized a series of dihydropyrimidinone derivatives 5 from 5-cyano-2-mercapto-6-phenyl-3,4dihydropyrimidin-4-one 1 [12]. Treatment of compound 1 with methyl iodide afforded compound 2 which on further treatment with hydrazine hydrate furnished hydrazine derivative 3. Condensation of 3 with 2,4-bis alkyl/arylamino-6-chloro-s-triazine 4 gave the corresponding s-triazines 5 in quantitative yield (Scheme 1). All the compounds were evaluated in vitro for their antifungal activity against Aspergillus niger using cup-plate method. It was concluded that the presence of halogen and methoxy group at 3 and/or 4 position, in 1H aryl ring of the arylamino substituted s-triazinyl group increase the activity (upto 27 mm zone of inhibition) towards A. niger.

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Most of the pharmacologically active compounds reported in literature contain the heterocyclic ring as an integral part of their structures. Many heterocyclic rings such as indole, benzothiazole, triazole, pyrrole, imidazole, thiophene, pyrrolidine, tetrazole, benzimidazole, quinoline, isoquinoline, benzoxazole, triazine etc. are significant constituents of many drugs [1]. Among these heterocyclic moieties, the triazine ring is one of the most important frameworks found in many pharmacologically active compounds. Triazine exists in three isomeric forms: 1,2,3-triazine, 1,2,4-triazine and 1,3,5-triazine, but the last one is a most common isomer of triazine, which exists as an integral component of many natural products and pharmacologically active compounds [2]. Interestingly, many 1,3,5triazine rings containing compounds exhibited a broad range of biological activities such as antibacterial [3], antimicrobial [4] and antitumor [5], and muscle relaxants [6].

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hydroxide or tertiary amines have made this reagent very useful for selective preparation of mono-, di- and tri-substituted-1,3,5triazines. The substitution pattern also depends on the structure of the nucleophile, its basic strength, steric factors, the substituent already present in the triazine ring and the nature of the solvent used.

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1. INTRODUCTION

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Among various 1,3,5-triazine based antimicrobial agents, those showing antifungal activities have gained a special attention in medicinal chemistry because many species of Candida, Cryptococcus and Aspergillus fungi are associated with high morbidity and mortality in immuno-compromised patients [7]. The clinical relevance of fungal diseases has increased dramatically over the second half of 20 th century primarily due to the higher number of immune compromised patients, which include cancer patients, transplant recipients, patients receiving broad-spectrum antibacterial drugs or those facing long hospital stays, and/or on parenteral nutrition [8-9]. But, because of the tremendous increase in AIDS and cancer chemotherapeutic agents, current interest in the development of new antifungal agents is not up to the mark. Thus, there is a grave need to discover new antifungal drugs with low cytotoxicity and high potency. The search of such drugs is difficult because both host and pathogen are eukaryotic organisms with similar metabolism, and due to lack of detailed biochemical information about the infecting organism. Henceforth, there is an urgent need to develop novel and effective antifungal drugs against drug resistance and other species of fungi [10].

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Current Organic Synthesis

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Cyanuric chloride, a chlorinated derivative of 1,3,5-triazine is known since 1827. It was considered as trichloride of cyanogens for a long time [11]. The ease of displacement of chlorine atoms in cyanuric chloride by a variety of nucleophiles in the presence of hydrochloride acceptors such as sodium carbonate, bicarbonate,

*Address correspondence to this author at the Department of Chemistry, Punjab Agricultural University, Ludhiana 141 004, India; Tel: +91-94638-52716; E-mail: [email protected] 1875-6271/16 $58.00+.00

In 2002, Ghaib et al. synthesized triazine derivatives 9-10 by addition of 5,5-dialkyl-6-aminopyrimidine-2,4(3H,5H)-dione 6 to variously substituted anilines 7 and formaldehyde 8 in absolute ethanol as shown in scheme 2 [13]. All the synthesized compounds were tested for antifungal activity in vitro against Tricophyton mentagrophytes (B70554), Aspergillus fumigates (B42928), Candida albicans (B59630 and B63195), Candida glabrata (B63155), Candida crusei (B68404), Candida parapsilosis (B66126), Candida kefyr (81/018), Candida tropicalis (CDC44), Cryptococcus neoformans (B66663), Sporothrix schenckii (B64284) and Microsporum canis (B68128). All compounds displayed poor to moderate antifungal activity (MIC = 0.4