ORIGINAL RESEARCH Regioselective synthesis and antibacterial evaluation of novel bis-pyrimidine derivatives via a three-component reaction Nosrat O. Mahmoodi • Sajede Shoja • Bahman Sharifzadeh • Mehdi Rassa Received: 5 June 2013 / Accepted: 15 August 2013 Ó Springer Science+Business Media New York 2013 Abstract A series of novel bis-2-phenylpyrimidines with alkyl linkages have been prepared by a three-component cyclo-condensation of benzamidine hydrochloride, b-keto- ester, and dihaloalkanes. The easy work-up of the products, rapid reaction, and mild conditions are notable features of this protocol. The reaction was efficiently catalyzed in one-pot by K 2 CO 3 as a base in N,N-dimethylformamide under optimized temperature (70 °C) conditions providing the title com- pounds in moderate to high yields. The antibacterial activities of the selected products were evaluated against some strains of Gram-positive and Gram-negative bacteria. Biological data indicated that some products exhibit promising activities. Keywords Three-component reaction Á Antibacterial activity Á Bis-pyrimidine Á Benzamidine hydrochloride Á b-ketoester Introduction The pyrimidine moiety turned out to be an important pharmacophor, interacting with the synthesis and function of nucleic acid like the cyctostaticum fluorouracil (Rose- meyer, 2004; Goette, 1981) or the anti-HIV drug zidovu- dine (Darbyshire et al., 2004) or potent antioxidant agents. Short-acting barbiturates like thiopental sodium (pentothal) (Dordoni et al., 2004) are frequently used as general anesthetics, while methylphenobarbital (Eadie and Hooper, 2002) even now is in use as antiepileptic. A survey of literature in the recent past reveals that some pyrimidines are building blocks for pharmaceutical agents (Deshmukh et al., 2009). They exhibit a wide spectrum of pharmacophore as it acts as microbicidal (Sedaghati et al., 2012), antihypertensive (Winter et al., 1962), anti-tumor and anticancer agents (Desai et al., 2011; Becan and Wagner, 2013) and DNA replication in eukaryotic cells (Sawa and Masai, 2008). It can be sug- gested that the bis-pyrimidine compounds would consider as bis-drugs, and are estimated to be capable of double therapeutic behavior. Influence and pharmacological properties of alkyl link- ages in the mono, and bis-compounds have been reported (Maletic et al., 2011; Levi et al., 1989; Perrey et al., 2000; Tanabe et al., 2011). For example, recently the relationship between alkyl chain length and the antifungal (Sortino et al., 2011), antimalarial (Fattorusso et al., 2011), anti- tubercular (Gao et al., 2013) and antibacterial (Xu et al., 2009) activity have been described. In addition to these, role of alkyl chain in activity of ligands for a 1 -adreno- ceptor subtypes is studied (Romeo et al., 2011). Also the effect of alkyl chain length on plasticizer and biodegra- dation properties was examined (Erythropel et al., 2013). Results and discussion Chemistry The most click procedure for the preparation of pyrimidi- nones has been reported by condensation of b-dicarbonyl compounds with the amidine or other analogs of them via N. O. Mahmoodi (&) Á S. Shoja Á B. Sharifzadeh Department of Organic Chemistry, Faculty of Sciences, University of Guilan, PO Box 41335-1914, Rasht, Iran e-mail: mahmoodi@guilan.ac.ir; nosmahmoodi@gmail.com M. Rassa Department of Biology, Faculty of Sciences, University of Guilan, PO Box 41335-1914, Rasht, Iran 123 Med Chem Res DOI 10.1007/s00044-013-0731-0 MEDICINAL CHEMISTR Y RESEARCH