Synthesis, characterization of some benzazoles bearing pyridine moiety: Search for novel anticancer agents

Thirteen novel benzazole derivatives were synthesized as possible anticancer agents. The first intermediate 1,3-benzothiazol-2-ylacetonitrile (2) was synthesized via cyclodeamination reaction of o-aminothiophenol (1) with malononitrile. Also, the second intermediate 5,6-dimethyl-1H-benzimidazol-2-ylacetonitrile (10) was afforded via cyclocondensation reaction between 4,5-dimethyl-1,2-phenylenediamine (9) and ethylcyanoacetate. Nucleophilic reaction of benzimidazolyl NH of compound (10) with ethylcyanoacetate afforded benzimidazolyl-3-oxopropanenitrile (11). On the other hand, methylenation of CH2 function of compound (10) with dimethylformamide/dimethylacetal afforded benzimidazolylprop-2-enenitrile 12. The synthesis of benzothiazoylpyridines 5a,b and 8a,b as well as benzimidazolylpyridines, 14a,b and 17a–d was carried out through Michael addition of compounds 2 or 10 with arylidenemalononitriles 3a,b and 4a–d. The combination of pharmacophoric anticancer moieties, pyridine and benzazoles was the base on which target compounds 5a,b, 8a,b, 14a,b and 17a–d were designed. Among the synthesized compounds, four derivatives 10 and 17b–d were selected by National Cancer Institute (NCI), USA to be screened for their anticancer activity at a single high dose (10−5 M) against a panel of 60 cancer cell lines. Compound 17b 4-[p-chlorophenyl]pyridine and 17d 4-[p- methoxyphenyl] pyridine exhibited a broad and moderate antitumor activity against 41 tumor cell lines belonging to the nine subpanels employed and are selected for further evaluation at five dose level screening.

This article summarizes Micheal addition of benzazolyl-2-acetonitriles 2 and 10 with some arylidenemalononitriles, dicussing the different possible products of the reaction. Benzazolylpyridines 5a,b, 8a,b, 14a,b and 17a–d are confirmed as final products with excluding the reported fused pyridobenzazoles. Also, it handles the nucleophilic attack of different functional groups of 10 with ethylcyanoacetate and DMFDMA producing compounds 11 and 12 respectively. Four compounds selected for one dose assay as anticancer agents, two of them e.g. 17b and 17d passed to five dose assay. TGI, LG50, LC50 were recorded and comparatively studied for the tested cancer cell lines. Figure optionsDownload as PowerPoint slideHighlights
► Benzazoles 2 or 10 reacted with arylidenemalononitriles to afford benzazolylpyridines.
► Nucleophilic reaction of 10 with ethylcyanoacetate afforded oxopropanenitrile 11.
► Methylenation of 10 with DMFDMA afforded Benzimidazolylprop-enenitrile 12.
► Compounds 17b, 17d are selected by NCI to five dose assay as anticancer agents.