Imidazole derivatives and their antitumor activity (review)

Abstract

Bis(2-chloroethyl)amino derivatives of imidazole, 4(5)-aminoimidazol-5(4)-carboxamide, 4-nitro-5-thioimidazole, benzimidazole, and imidazolylpeptides are reviewed. Data are presented for active compounds, some of which have passed the preclinical testing stage. Structures under consideration are interesting with respect to both the search for new antitumor drugs and the synthesis of compounds with different biological properties.Key words: imidazole, 4(5)-aminoimidazol-5(4)-carboxamide, 4-nitro-5-thioimidazole, benzimidazole, imidazolylpeptides, bis(2-chloroethyl)amino derivatives, antitumor activity.Chemotherapy of tumors is one of the most important medical achievements of the 20th century. Chemotherapy of malignant neoplasms was identified as an independent area of oncology in the middle of the 1940s with the advent of alkylating agents.It is currently possible to treat patients with Burkitt's lymphoma, Hodgkin's disease, chorionepithelioma, germinogenic ovarian diseases, Ewing's sarcoma, Kaposi's sarcoma, osteosarcoma, breast and prostate cancer, and certain acute forms of leukemia and lymphosarcoma. However, any treatment method is ineffective at advanced stages of the disease in all instances.The ability to treat cancers with derivatives of bis(2-chloroethyl)amine was discovered serendipitously. The doctor on-board the transport ship John Harvey that was carrying mustard gas (1943) noticed the toxic effect of this compound on the blood of sailors. These and other observations signaled the beginning of studies on the effect of mustard gas and its derivatives on experimental and human tumors. Mustard gas itself is highly toxic and is not used in medical practice. A methyl analog of mustard gas, embichin, which was also one of the first antitumor preparations, was proposed in 1946 as a therapeutic. Searches in the next 20 -30 years in this direction discovered derivatives of bis(2-chloroethyl)-amine with aromatics such as novembichin, chlorambucil, paphencyl; with amino-acids, sarcolysine, asaline, lofenal; with hemi-alcohols, degranol; with phosphorylated amines, cyclophosphane; and with nitrogen-containing heterocycles, dopan and fluorodopan.A distinguishing feature of these preparations is the rather effective action on malignant systemic diseases of blood and hematopoietic organs.The presence of imidazole derivatives in man and their involvement in metabolism has drawn the attention of researchers. For example, a key compound in the biosynthesis of natural purine components of RNA and DNA is the ribotide 4(5)-aminoimidazol-5(4)-carboxamide [1,2]. Involvement of 4,5-aminoimidazolcarboxamide in metabolic processes can be used to synthesize its antimetabolites that can inhibit biosynthesis after biotransformations and thereby suppress tumor growth.The biological activity of bis(2-chloroethyl)amines is due to their interaction with carboxylic, sulfhydryl, and amino groups of proteins. They react with nucleic acids at the phosphoric-acid hydroxyls and DNA guanine at the 7-nitrogen atom [3].A characteristic of 2...

One-Pot Synthesis of 2,4,5-Triphenyl Imidazoles from 1,2-Diols as Key Reagents

“…Multicomponent reactions (MCRs) have emerged as a powerful tool for industrial and academic research groups because of their shorter reaction times as well as the avoidance of the isolation of intermediates, their purification, and characterization . Imidazoles have a privileged structure as they occur as fragments in drugs displaying a wide spectrum of pharmacological activities . A large number of compounds bearing substituted imidazole derivatives have entered preclinical and clinical trials over the last few years.…”