Synthesis and antimicrobial activity of polyhalo isophthalonitrile derivatives Chao Huang a,b,  , Sheng-Jiao Yan a,  , Neng-Qin He a , Ya-Juan Tang a , Xing-Hong Wang c,⇑ , Jun Lin a,⇑ a Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China b Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan University of Nationalities, Kunming 650050, PR China c Institute of Microbiology, Yunnan University, Kunming 650091, PR China article info Article history: Received 21 October 2012 Revised 29 January 2013 Accepted 6 February 2013 Available online 16 February 2013 Keywords: 4-(Benzylamino)-5-chloro-2,6- difluoroisophthalonitrile Polyhalo isophthalonitrile Antimicrobial activity Gram-positive bacteria Anti-fungi abstract A series of polyhalo isophthalonitrile derivatives (3 and 4) that incorporate a variety of substituents at the 2-, 4-, 5- and/or 6-positions of the isophthalonitrile moieties have been designed and synthesized. These derivatives were evaluated for their antimicrobial activity against Staphylococcus aureus, Bacillus cereus (Gram-positive bacteria), Escherichia coli, Pseudomonas aeruginosa (Gram-negative bacteria); and Candida albicans (Fungi). Compounds 3 and 4 showed stronger inhibition of gram-positive bacteria and fungi growth, and the antimicrobial ability of compound 3j (a 4-(benzylamino)-5-chloro-2,6-difluoro analog, MIC[SA] = 0.5 lg/mL; MIC[BC] = 0.4 lg/ML; MIC[CA] = 0.5 lg/mL) were close to nofloxacin and fluconaz- ole and identified as the most potent antimicrobial agents in the series. The preliminary analysis of struc- ture–activity relationships is also discussed. Ó 2013 Elsevier Ltd. All rights reserved. It is well known that halogen plays an important role in living organisms. 1 As an important part of biological activity organic hal- ogenated compounds are widely used as antibacterial, antineoplas- tic, hormones, pheromones, pesticides. 2 Due to its special character, organic halide plays an important role in drug research. In particular, the antimicrobial activity of organic halide deriva- tives is also well documented in the literatures, 3,4 for example or- ganic chlorides (Vancomycin, Chlorotetracycline, Chloramphenicol, Calicheamycin, Rebeccamycin, and Ambigol A), bromides (Pyrolni- trin) and iodide (Calicheamicin). Recently, the use of fluorinated compounds as bioactive or functional molecules has increased in pharmaceutical research due to the unique effects of F-substitu- ents in pharmaceutical formulations. Fluorine incorporation into biologically-active compounds can alter drug metabolism or en- zyme substrate recognition. 5 The hydrophobic nature of fluori- nated compounds has also been cited for its ability to improve transport across the blood–brain barrier. Improved oral bioavail- ability is seen in some systems where fluorine substitution leads to improved hydrolytic stability. Moreover, polyhalo compounds are also widely present in nature, its anti-microbial activity is attracting more attention. A series of polyhalo compound deriva- tives have been identified as potent antimicrobial agents. 6,7 Organic cyanide is halogen isostere and often called virtual ana- log halogen. 8 The biological compatibility, stability of cyanoacrylate and ability to build relationship plays a key role. In particular, organ- ic cyanide and organic halogenated compounds were expected to have the similar effects of anti-bacterial active. Organic cyanide has an important role in the study of drugs and drug intermediates in the development, 9 cyanoacrylate derivatives can also generate further amine, aldehyde carboxylic acid, and such compounds, and more and more cyanide-containing drugs are being used for clinical treatment. Recently, isophthalonitrile derivatives, one of the most important organic cyanide compounds, have received much atten- tion. They are biologically active. For example, they are inhibitory of HIV-1 reverse transcriptase 10 and mPGES-1, 11 and they have anti-inflammatory 12 and insecticidal activity, etc. Such properties have been explored and a lot of preparation methods of this type of compounds have been developed. 13,14 Polyhalo isophthalonitriles, especially polyfluoro-isophthalonit- rile, have been widely used as anti-cancer, 15 anti-inflammatory 16 and insecticidal 17 agents, among other uses 18 in pharmaceuticals. Our previously works have explored the antitumor and anti-HIV activities of polyhalo isophthalonitriles, and all were found to have good bio-activities. 19–22 0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2013.02.033 ⇑ Corresponding authors. Tel./fax: +86 871 5033215 (J.L.). E-mail address: linjun@ynu.edu.cn (J. Lin).   These authors contributed equally to this work. Bioorganic & Medicinal Chemistry Letters 23 (2013) 2399–2403 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl