US-12622974-B2 - Siderophore-dihydrofolate reductase inhibitor conjugate and application thereof

US12622974B2US 12622974 B2US12622974 B2US 12622974B2US-12622974-B2

Abstract

A conjugate provided. The conjugate is a compound represented by Formula (I), or the conjugate is a stereoisomer, tautomer, homologue, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the compound represented by Formula (I): where A is a linker, and B is a dihydrofolate reductase inhibitor; R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from H or C 1-6 alkyl; and n1, n2, and n3 are each an integer selected from 0 to 6.

Inventors

Yun He
Yan Guan

Assignees

JASAN BIO MEDICINE (JIAXING) CO., LTD

Dates

Publication Date: 20260512
Application Date: 20220413
Priority Date: 20200123

Claims (3)

1 . A conjugate, being a compound represented by Formula (I), or being a stereoisomer, tautomer, homologue, solvate, or pharmaceutically acceptable salt of the compound represented by Formula (I): wherein A is a linker selected from heteroatom-containing alkane, amino acid, or amide, and B is a dihydrofolate reductase inhibitor, the dihydrofolate reductase inhibitor being methotrexate; R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from H or C 1-6 alkyl; and n1, n2, and n3 are each an integer selected from 1 to 3.
2 . The conjugate according to claim 1 , wherein the conjugate is any one of the following compounds, or a stereoisomer, tautomer, homologue, solvate, or pharmaceutically acceptable salt of any one of the following compounds:
3 . A pharmaceutical composition comprising the conjugate according to claim 1 and a pharmaceutically acceptable excipient, wherein the conjugate is a compound represented by Formula (I), or is a stereoisomer, tautomer, homologue, solvate, or pharmaceutically acceptable salt of the compound represented by Formula (I): wherein A is a linker selected from heteroatom-containing alkane, amino acid, or amide, and B is a dihydrofolate reductase inhibitor, the dihydrofolate reductase inhibitor being methotrexate; R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from H or C 1-6 alkyl; and n1, n2, and n3 are each an integer selected from 1 to 3.

Description

CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation of International Application No. PCT/CN2021/071142, filed on Jan. 11, 2021, which claims priority to and the benefits of Chinese Patent Application No. 202010076507.0 filed with China National Intellectual Property Administration on Jan. 23, 2020. The disclosures of the aforementioned applications are hereby incorporated by reference in their entireties. FIELD The present disclosure relates to the field of compounds, and specifically, to a siderophore-dihydrofolate reductase inhibitor conjugate and an application thereof. BACKGROUND The discovery of natural siderophore antibiotics provides an approach to develop new antibiotics. However, only a few types of siderophore antibiotics exists in nature. Therefore, chemists have developed a series of siderophore-antibiotic conjugates through artificial synthesis to enrich the types of siderophore antibiotics. In 1977, the first synthetic siderophore-antibiotic conjugate was produced. It drew on the structural characteristics of Ferrimycin and apomycin to connect a siderophore with sulfonamide drugs. It was found through the antibacterial activity test that the antibacterial spectrum of this class of antibiotics is closely related to siderophores. The author also found that the link arm connecting the siderophore with the drug plays a pivotal role in antibacterial activity, and the release of antibiotics is controlled through an appropriate design of the link arm. This research has opened up the development of antibiotics from siderophore-antibiotic conjugates, and provides guide for subsequent research. Many artificially synthesized siderophores-antibiotic conjugates have been reported one after another. They contain distinctive siderophores, link arms and antibiotic targets. β-lactam antibiotics, fluoroquinolone antibiotics, Lactivicin, macrolide antibiotics, aminocoumarin, 5-fluorouracil, artemisinin, cyanuric acid, gallium, antimicrobial peptide antibiotics, etc. have been used to artificially synthesize the siderophore-antibiotic conjugates. The most suitable drugs for synthesizing the siderophore-antibiotic conjugates are β-lactam antibiotics and fluoroquinolone antibiotics. Among them, the β-lactam antibiotics target at cell wall mucopeptide synthetase, i.e., penicillin binding proteins (PBPs), which are exposed on the outer surface of gram-positive bacteria and exist in the periplasm of gram-negative bacteria. The fluoroquinolone antibiotics target at the DNA gyrase that exists in the cytoplasm of gram-positive bacteria and gram-negative bacteria. All the β-lactam antibiotics and fluoroquinolone antibiotics contain sites to which larger side chain substituents can be introduced. That is, they can be attached to siderophores without affecting their binding to the corresponding targets. Therefore, scientists have employed the β-lactam antibiotics and fluoroquinolone antibiotics in the artificial synthesis of siderophore-antibiotic conjugates, in order to develop antibiotics with market potential. In 2013, Professor Miller reported on the synthesis of a conjugate of a chain-like siderophore, Danoxamine, with ciprofloxacin (a fluoroquinolone antibiotic) and a conjugate of Danoxamine with loracarbef (a β-lactam antibiotic) and tested their activities against Staphylococcus aureus. Danoxamine-loderacarbef conjugate only exhibited significantly lower activity against Staphylococcus aureus than loracarbef alone. The loss of antibacterial activity may be caused by that the target cell wall mucopeptide synthetase of loracarbef exists on the outer surface of Staphylococcus aureus, and the drug is transferred by the Danoxamine-loracarbef conjugate into the bacterial body to be far away from the target. The Danoxamine-ciprofloxacin conjugate against Staphylococcus aureus stain SG511 has an MIC value of 1 μM, which is equivalent to the antibacterial efficacy of ciprofloxacin. The affinity of ciprofloxacin for DNA gyrase may be weakened to a certain extent by modifying ciprofloxacin with a relatively large siderophore. The active transport of siderophores allows the drug to be enriched in the bacterial body, thereby compensating for the decrease in the affinity for DNA gyrase. These two factors simultaneously lead to that the Danoxamine-ciprofloxacin conjugate and ciprofloxacin alone have the similar activity against Staphylococcus aureus. In terms of antibacterial spectrum, ciprofloxacin itself is a broad-spectrum antibacterial drug and has a significant inhibitory effect on both gram-positive and gram-negative bacteria; while the Danoxamine-ciprofloxacin conjugate only has an inhibitory effect on gram-positive bacteria, and the antibacterial spectrum is significantly narrowed. The reason thereof may be in that the siderophore conjugate enters the bacteria through an active transport of the siderophore transport system, different siderophores are only recognized by the corresponding siderophore tr