Novel Imidazole‐based Hydrazonoyl Cyanides and Amidrazones Containing N(N,O)‐Heterocycles: Selective Synthesis, Reaction Mechanisms and Preliminary Anticancer Evaluation

Two series of novel hybrid heterocyclic compounds that combine the imidazole ring with bioactive piperidine, morpholine or piperazine heterosystems, through a hydrazone unit, were easily obtained by two competitive pathways. Starting from 5‐amino‐4‐cyanoformimidoyl imidazoles and 1‐aminopiperidine,...

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Bibliographic Details
Published in:	European journal of organic chemistry Vol. 27; no. 22
Main Authors:	Fernandes, Soraia P. S., Gonçalves, Jorge M., Silva, Bruna F., Pereira, Eva Q., Coutinho, Paulo J. G., Pereira‐Wilson, Cristina, Dias, Alice M.
Format:	Journal Article
Language:	English
Published:	Weinheim Wiley Subscription Services, Inc 10-06-2024
Subjects:	amidrazone anticancer Chemical synthesis Heterocyclic compounds hetrocycloalkylhydrazine Hydrazones hydrazonoyl cyanide Imidazole Piperidine Reaction mechanisms
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Summary:	Two series of novel hybrid heterocyclic compounds that combine the imidazole ring with bioactive piperidine, morpholine or piperazine heterosystems, through a hydrazone unit, were easily obtained by two competitive pathways. Starting from 5‐amino‐4‐cyanoformimidoyl imidazoles and 1‐aminopiperidine, 4‐aminomorpholine or 1‐amino‐4‐methylpiperazine under mild acidic media led to the selective synthesis of 5‐aminoimidazole 4‐carboxamidrazones, whereas the corresponding 4‐hydrazonoyl cyanide derivatives were obtained under stronger acidic conditions. These highly functionalized imidazoles provide convenient synthetic precursors to a vast array of heterocycles with potential pharmaceutical applications. The reaction mechanisms were elucidated on the basis of experimental assays and in silico calculations. The compounds were screened against colorectal cancer HCT116‐p53 wt cell line, and significant IC50 values of 3.69 μM and 4.83 μM were obtained. Novel imidazole‐based hydrazonoyl cyanides and amidrazones containing morpholine, piperidine and N‐methylpiperazine heterocycles were obtained by two competitive pathways, starting from the same imidazole precursors and corresponding heterocycloalkylhydrazines. These imidazoles provide convenient synthetic precursors to a vast array of heterocycles with pharmaceutical applications. The compounds were screened against colorectal cancer cell line HCT116‐p53 wt and significant IC50 values were obtained.
Bibliography:	These authors contributed equally.
ISSN:	1434-193X 1099-0690
DOI:	10.1002/ejoc.202400253