Spiro three-membered ring, spiro five-membered ring peptidyl deformylase inhibitor

Abstract

The invention discloses novel peptide deformylase inhibitors containing spiro three-membered rings or spiro five-membered rings, and the inhibitors have antimicrobial activity and antineoplastic activity. The peptide deformylase inhibitors containing spiro rings such as the spiro three-membered rings or the spiro five-membered rings provided in the invention can be taken as a class of novel antibacterial agents, by inhibiting activity of peptide deformylase required in synthesis of bacterial proteins, the inhibitors have effects on gram-positive bacterium strains which have drug resistance to a plurality of antibiotics, and have no influences on synthetic processes of human proteins, thus the bacteria are selectively killed; and the peptide deformylase inhibitors containing the spiro rings such as the spiro three-membered rings or the spiro five-membered rings provided in the invention can also be taken as a class of novel anti-cancer drugs, by inhibiting peptide deformylase in mitochondria of cancer cells, the inhibitors can have influences on energy balance of the cells, thus mitochondrial membranes are depolarized, ATP is depleted and apoptosis is promoted, and the inhibitors have relatively-good inhibition activity on a plurality of cancer cell bacterial strains such as colorectal cancer cell bacterial strains, lung cancer cell bacterial strains, stomach cancer cell bacterial strains and liver cancer cell bacterial strains under relatively-low concentrations.

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. Th...

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, entered Phase I clinical (Phase I) trial of antibacterial activity, has broad-spectrum activity, but found that high doses can cause methemoglobinemia (Clin.Pharmacol. Ther.2011, 90, 256); GSK1322322, also terminated antibacterial activity by FDA 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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