209 ХИМИЯ ГЕТЕРОЦИКЛИЧЕСКИХ СОЕДИНЕНИЙ. — 2014. — № 2. — С. 209—218 V. A. Risley 1 , S. Henry 1 , M. V. Kosyrikhina 2 , M. R. Manzanares 2 , I. Payan 2 , C. D. Downer 2 , C. C. Hellmann 2 , S. Van Slambrouck 2 , L. V. Frolova 1 * 4-AMINO-2-ARYL-3-CYANO- 1,2-DIHYDROPYRIMIDO[1,2-a]BENZIMIDAZOLES AND THEIR PYRIMIDINE ANALOGS AS NEW ANTICANCER AGENTS A multicomponent condensation between 2-aminobenzimidazole, malononitrile, and an aryl or heteroaryl aldehyde was used for the synthesis of 4-amino-2-aryl-3-cyano- 1,2-dihydropyrimido[1,2-a]benzimidazoles. In addition, a new method of synthesis of corresponding pyrimido[2,1-a]benzimidazole derivatives was developed. These syntheses were used to prepare a library of 4-amino-2-aryl-3-cyano-1,2-dihydropyrimido[1,2-a]benz- imidazoles and their corresponding pyrimido[2,1-a]benzimidazole derivatives. This library of compounds was then tested against pancreatic and breast cancer cell lines. A number of compounds were found to possess notable anticancer activity. Keywords: benzimidazole, 1,2-dihydropyrimidine, 1,2-dihydropyrimido[1,2-a]benz- imidazoles, pyrimidine, pyrimido[2,1-a]benzimidazoles, anticancer activity, multi- component reactions. Multicomponent reactions (MCRs) are significant and important synthetic tools, which refer to a chemical reaction where three or more components react to form a single product [1, 2]. MCRs have become popular in modern synthetic chemistry due to their efficiency and convenience in the construction of multiple new bonds in a one- pot process, and are especially useful for the synthesis of heterocyclic compounds [3]. Heterocycles are found throughout medicinal chemistry, with examples including natural and synthetic drugs such as quinine, atropine, morphine, diazepam, barbiturates, and antipyrine. Many biologically active molecules, including those previously mentioned, typically feature five- and six-membered rings containing one or more nitrogen atoms. Such privileged medicinal scaffolds, benzimidazole and pyrimidine heterocycles being perfect examples, are frequently used in the development of new drugs. These heterocycles play the roles of key pharmaco- phores in many different drugs expressing anticancer and antibacterial activity. It is noteworthy that the pyrimidine core is a structural constituent of critically important anticancer drugs like fluorouracil, tegafur, methotrexate, and cytabine [4]. Likewise, compounds on the basis of the benzimidazole core are used in anticancer therapy alone, or in the mix with other drugs [5–7]. One of the most rapidly developing areas in modern medicinal chemistry is the design of new medicinal agents using the combination of different pharmaco- phores in one molecule [4, 8]. Such hybrid agents could offer several potential advantages over traditional drug combinations, such as improvement of activity against multidrug resistant cell lines, improvement of pharmacokinetic profile, and synergistic activity between the pharmacophores. There are two different approaches for the design of hybrid molecules: 1) merging two different pharmocophoric moieties; 2) linking of two or more pharmacophores together [9]. The first approach is based on the ability to combine pharmacophoric groups in a new molecular structure and to retain their affinity for the biological targets. A fusion of benzimidazole and pyrimidine cycles can be a good opportunity for creating a new scaffold with anticancer properties (Scheme 1).