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Heterocyclic peptide deformylase inhibitor and preparation method and application thereof

A peptide deformylase and inhibitor technology, applied in the field of heterocyclic peptide deformylase inhibitors and their preparation, can solve the problem of late start of research, and achieve the effect of good inhibitory effect, novel structure and inhibition of proliferation

Active Publication Date: 2019-06-07
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, anti-tumor research based on HsPDF started relatively late, and no good HsPDF inhibitors have been reported except for Actinonin.

Method used

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  • Heterocyclic peptide deformylase inhibitor and preparation method and application thereof
  • Heterocyclic peptide deformylase inhibitor and preparation method and application thereof
  • Heterocyclic peptide deformylase inhibitor and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] The preparation of embodiment 1 compound 1 to 3

[0049] Concrete preparation route is as follows:

[0050]

[0051] 1. The preparation method of intermediate A:

[0052] Step 1: Carboxylic acid (1 equiv), anthranilic acid (1.3 equiv), N,N-diisopropylethylamine (2 equiv) and propylphosphonic anhydride (1 equiv) were added in a sealed tube. Put the sealed tube into a microwave reactor and react at 100°C for 10 minutes. After the reaction was completed, water was added to dilute the reaction solution, alkalized with saturated sodium bicarbonate solution, ethyl acetate was added, the upper organic phase was separated, and the aqueous phase was extracted once. The organic phases were combined, washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a pure product.

[0053] Step 2: The product obtained in Step 1 was dissolved...

Embodiment 2

[0074] The preparation of embodiment 2 compound 4 to 7

[0075] The preparation route is as follows:

[0076]

[0077] 1. The preparation method of intermediate D:

[0078] Step 1: Weigh carboxylic acid (8.3g, 30mmol) into a reaction flask, dissolve in tetrahydrofuran, and stir in an ice-water bath. HOBt (1.5 eq) and DIPEA (3 eq) were added, EDCI (1.5 eq) was added after reacting at 0°C for 15 minutes, and ammonia (1.1 eq) was added half an hour later. After the raw materials have reacted, the reaction solution is spin-dried. Water and ethyl acetate were added to extract. The aqueous phase was back-extracted once more, and the organic phases were combined. The organic phase was washed once with saturated sodium bicarbonate solution and saturated brine once, then dried over anhydrous sodium sulfate, filtered and concentrated to obtain an oily product.

[0079] Step 2: Weigh the reaction product of the previous step (590 mg, 2.1 mmol) into a reaction flask, dissolve it i...

Embodiment 3

[0112] The preparation of embodiment 3 compound 8

[0113] The preparation route of compound 8 is as follows:

[0114]

[0115] Preparation of Intermediate H:

[0116] Step 1: Dissolve aldehyde (1 equivalent) in 15ml of methanol and stir under ice-water bath. Solid sodium bicarbonate (1.2 eq) and hydroxylamine hydrochloride (1.2 eq) were added, allowed to warm to room temperature, and stirred overnight. After the reaction was complete, the methanol was spin-dried, ethyl acetate was added, the organic phase was washed once with saturated brine, dried with anhydrous sodium sulfate, filtered and spin-dried to obtain the product.

[0117] Step 2: Put the reaction product of the previous step (1 equivalent) in a reaction bottle, dissolve it in 10 mL of DMF, stir in an ice-water bath, first add N-chlorosuccinimide (0.2 equivalent), and remove the ice-water bath after half an hour of reaction , add the remaining NCS (0.8 eq) and react at room temperature for 10 hours. Water an...

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Abstract

The invention discloses a heterocyclic peptide deformylase inhibitor and a preparation method and application thereof. The structure of the inhibitor is shown in formula (I), wherein A is a five-membered nitrogen-containing aromatic heterocycle, X, Y and Z are C, O, S or N independently, and R is a single substituent, multiple substituents or forms a ring with A. The peptide deformylase inhibitordisclosed by the invention is novel in structure, good in activity and low in toxicity, has obvious inhibition effects on gram-positive bacteria and gram-negative bacteria, and even has good inhibition effects on bacteria with multiple drug resistance; and meanwhile, the compound has remarkable inhibition effect on tumor cells such as colorectal cancer, lung cancer and osteosarcoma, can inhibit proliferation of the tumor cells, and can be prepared into antibacterial drugs or antitumor drugs for application.

Description

technical field [0001] The invention relates to the technical research field of antibacterial and anticancer drugs, and more specifically, relates to a class of heterocyclic peptide deformylase inhibitors and a preparation method and application thereof. Background technique [0002] While humans are fighting against bacteria, the widespread use of antibiotics has led to the emergence of bacterial resistance. Bacterial drug resistance has become a global health problem, but the speed of new drug development is still not enough to alleviate the serious health threat brought by bacterial drug resistance. In the face of "super bacteria", humans have no drugs available. Therefore, it is imperative to gain an in-depth understanding of bacterial resistance, find new drug targets and treatments, and develop new tools to fight bacteria. [0003] Since the "golden age" of antibiotic development, only a few antibiotics with completely new mechanisms of action have been marketed. Alt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/04C07D403/04C07D413/04C07D413/14A61P35/00A61P35/02A61P31/04
Inventor 胡文浩蔡星胡柳钱宇袁艳秋胡吉迪徐新芳
Owner SUN YAT SEN UNIV
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