Antibacterial applications of spiro three-membered ring and spiro five-membered ring peptide deformylase inhibitors

Abstract

The invention discloses antibacterial activities and antineoplastic activities of novel spiro three-membered ring and spiro five-membered ring containing peptide deformylase inhibitors. The spiro three-membered ring and spiro five-membered ring containing peptide deformylase inhibitors can be used as a novel antibacterial agent, are effective for multiple antibiotic-resistant Gram-positive bacteria strains by inhibiting activities of the peptide deformylase required in bacterial protein synthesis, and do not influence the protein synthesis process of the human body, thereby selectively killing the bacteria. The spiro three-membered ring and spiro five-membered ring containing peptide deformylase inhibitors can also be used as a novel anticancer drug, and can influence the energy balance of cells by inhibiting the peptide deformylase in cancer cell mitochondria; and therefore, mitochondrial membranes are depolarized, ATP is exhausted, cell apoptosis is promoted, so that the peptide deformylase inhibitors have favorable inhibition activities for multiple cancer cell strains, such as colorectal cancer, lung cancer, stomach cancer and liver cancer.

Description

technical field [0001] The invention belongs to the technical research field of antibacterial and anticancer drugs, and relates to a class of peptide deformylase inhibitors, in particular to novel spiro three-membered ring and spiro five-membered ring-like peptide deformylase inhibitors. Background technique [0002] Antibiotics refer to a series of chemical substances that can inhibit and kill pathogens at a certain concentration, including metabolites produced by microorganisms, animals and plants, as well as chemically synthesized or semi-synthesized compounds. Antibiotics not only refer to antibacterial substances, but also antitumor, antiviral, antiparasitic and other substances also belong to the category of antibiotics. Antibiotics are an important pillar enabling us to live longer, healthier lives and benefit from modern medicine. [0003] With the emergence and widespread use of antibiotics, the problem of antibiotic resistance has become increasingly prominent, an...

AI Technical Summary

Problems solved by technology

[0009] Although many PDF inhibitors have been developed for preclinical research, and even some compounds have entered the clinic (such as formula (b) ~ (d)), but due to the nature of the compound itself, the activity is not good, or it shows Clinical toxicity, ultimately failed to market

For example: actinomycin Actinonin is the first PDF inhibitor discovered, which shows good activity against Gram-positive bacteria and negative bacteria, but due to the instability of metabolism in the body, it eventually has no activity in vivo

LBM415, which has entered the Phase I clinical trial of antibacterial activity, has broad-spectrum activity, but it was found that high doses can cause methemoglobinemia (Clin.Pharmacol.Ther.2011, 90, 256); GSK1322322, also terminated by the FDA antibacterial activity Phase I clinical study of the same reason, the occurrence of metabolically active compounds, causing toxicity to the body (see the project number NCT01818011 in ClinicalTrials.gov for reasons for termination of clinical trials)

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