Cancer is a worldwide health problem according to the American Cancer Society report 2014, with lung, breast and central nervous system cancers being the most widespread. According to the Brain and Central Nervous System Cancer Agency (BC Cancer Agency), the incidence of central nervous system cancer is mostly due to metastasis from other sites e.g. lung and breast. That is why we focused on developing new antitumor agents against these types of cancers. Existing anticancer agents are not able to treat cancer effectively because of limited activity, rapid development of resistance and adverse effects. 1 To discover and synthesise novel compounds as antiproliferative agents, scaffold hopping theory suggests that modifying the central core structure of the biologically active molecules by combining two or more biologically active entities could be effective. 2 The benzimidazole ring system features in many bioactive heterocyclic compounds which exhibit diverse biological and clinical applications. Since benzimidazole derivatives are structural bioisosteres of naturally occurring nucleotides, they can interact with biological macromolecules such as proteins, enzymes and receptors. [3][4][5][6][7][8][9][10][11][12] Even quite simple 2-substituted derivatives of benzimidazole I-IV (Fig. 1) are known inhibitors of type I DNA topoisomerase. 5,7,[13][14][15] Furthermore, some benzimidazole derivatives cause downregulation of androgen receptor (AR) protein expression in vitro and in vivo. Recently, some benzimidazoles showed antiproliferative activity via destruction of DNA. [16][17][18] Therefore, we devised target compounds that were comprised of a 2-substituted benzimidazole and either a pyridazinyl, thienyl, thienopyridazinyl, thienopyrimidinyl, thienooxazinyl, thiazolyl or a guanidinyl moiety, each of which has featured structurally in some anticancer agents. In this paper, we report the synthesis and anticancer testing of twenty two new polycyclic compounds that have a core of a 2-substituted benzimidazole.
Results and discussionThe synthesis of the novel compounds is shown in Schemes 1-4. All of the new compounds described below were characterised by their IR, 1 H NMR, 13 C NMR and mass spectra as well as microanalyses. The key precursor compound 1 was synthesised by reacting 2-(2-(1-ethoxy-1,3-dioxobutan-2ylidene) hydrazinyl) benzoic acid 19 with o-phenylenediamine (Scheme 1). 20 The 1 H NMR spectrum of compound 1 showed a singlet signal at δ 2.44 ppm attributed to three protons of the CH 3 group. D 2 O exchangeable signals appeared at δ 11.63 and 13.71 ppm due to the protons of 2 NH groups. Also the triplet quartet signals of the ethyl group of the former compound disappeared. In addition, its mass spectrum displayed a molecular ion peak at m/z 322 (M ).Bromination of compound 1 with bromine in acetic acid afforded the target compound 2. The 1 H NMR of compound 2 showed a singlet at δ 3.38 ppm due to a CH 2 group. Compound 3 was synthesised via reacting compound 1 and cyanoacetohydrazide. The IR spectrum of compo...
