阅读说明：本技术 一种三氮唑类化合物、制备方法及其在抗真菌药物中的应用 (Triazole compound, preparation method and application thereof in antifungal drugs ) 是由 娄红祥 王鑫 刘军 于 2020-07-21 设计创作，主要内容包括：本发明公开了一种基于三氮唑类药物骨架与多样性的亲脂性阳离子通过不同的链偶联,得到一系列新型三氮唑类化合物,还公开了这些化合物的制备方法以及在抗真菌方面的应用。研究发现,本发明所述的三氮唑类药物骨架与亲脂性阳离子偶联,能够克服外排泵对唑类药物的外排作用,从而克服唑类药物的耐药问题。(The invention discloses a series of novel triazole compounds obtained by coupling a triazole drug skeleton and diversified lipophilic cations through different chains, and also discloses a preparation method and application of the compounds in antifungal aspects. Researches show that the triazole drug skeleton is coupled with lipophilic cations, so that the efflux effect of an efflux pump on azole drugs can be overcome, and the drug resistance problem of the azole drugs is further solved.)

1. A triazole compound shown as a formula I,

wherein R is₁Is selected from

R₂Selected from carbon, oxygen or carboxyl;

R₃selected from different lipophilic cations;

m and n are independently selected from any value of 0-15.

2. The triazole compound of claim 1, wherein the lipophilic cation is selected from rhodamine 123,

Wherein X is attached/represents a substitution in one or more of the ortho, meta or para positions, X is selected from methyl, ethyl, propyl, tert-butyl, methoxy or phenyl, Y is selected from methyl, ethyl, propyl or tert-butyl, and Z is selected from fluorine, chlorine, bromine or iodine.

3. The triazole-based compound according to claim 1 or 2, selected from the following compounds:

4. the process for producing a triazole-based compound as claimed in claim 1 or 2, wherein R is₁When piperazine is selected, the synthetic route is as follows:

5. the process for producing a triazole-based compound as claimed in claim 1 or 2, wherein R is₁When the triazole is selected, the synthetic route is as follows:

6. the use of the triazole-based compound as claimed in claim 1 or 2 in an antifungal agent.

7. The use of the triazole-based compound of claim 6, wherein the fungus is a drug-resistant fungus.

Technical Field

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a series of triazole derivatives with novel structures, a preparation method thereof and application of the compounds in antifungal medicines.

Technical Field

The triazole medicine has the characteristics of high bioavailability, less adverse reaction, moderate price and the like, has obvious curative effect on deep fungal infection, is the most main medicine for treating systemic fungal infection, and is widely applied clinically. Representative drugs are fluconazole, itraconazole, voriconazole, posaconazole and the like. The action mechanism of the medicine is that the medicine is combined with CYP51 to competitively block the biosynthesis of the ergosterol of the fungus, so that the lanosterol is accumulated, thereby destroying the cell membrane of the fungus and playing a role in bacteriostasis. Because the ergosterol synthetic pathway does not exist in mammalian cells, the toxicity of the medicine to normal cells of a human body can be avoided, and the high selectivity is realized. However, with the long-term use of triazole drugs in large quantities and even abuse, more and more drug-resistant bacteria appear, and become one of the main reasons for the failure of clinical antifungal therapy. Therefore, the novel antifungal drug which can overcome drug resistance and is designed and synthesized based on the triazole drug skeleton has important research significance and development and application value.

Disclosure of Invention

Aiming at the problem of drug resistance of azole drugs, the invention provides a series of novel triazole derivatives, a preparation method thereof and application of the compounds in the antifungal aspect based on the coupling of a triazole drug skeleton and diversified lipophilic cations through different chains.

One of the purposes of the invention is to provide a triazole compound shown in a formula I,

wherein R is₁Is selected from

R₂Selected from carbon, oxygen or carboxyl;

R₃selected from different lipophilic cations, preferably: rhodamine 123,

Wherein, to X is attachedRepresenting a substitution in one or more of the ortho, meta or para positions, X being selected from methyl, ethyl, propyl, tert-butyl, methoxy or benzeneY is selected from methyl, ethyl, propyl or tert-butyl, Z is selected from fluorine, chlorine, bromine or iodine;

m and n are independently selected from any value of 0-15.

Further, m and n are independently selected from any value of 0-10

The triazole compound represented by formula I is preferably:

another object of the present invention is to provide a method for preparing a triazole compound represented by formula I, comprising the following steps:

preparation of piperazine series derivatives:

taking 2 ', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone as an initial raw material, and carrying out Johnson-Corey-Chaykovsky reaction under the conditions of trimethyl sulfoxide iodide and alkalinity to convert ketone carbonyl into a ternary oxygen ring; piperazine nucleophilically attacks an epoxy group, so that the epoxy is opened and a piperazine group is introduced; further connecting with dibromides with different chain lengths and in the form of saturated carbon chains or polyethylene glycol chains to form bromides; triphenylphosphine and diversified bromo-carboxylic acid firstly form a carboxyl compound, and then the carboxyl compound and the bromo-carboxylic acid are connected in an ester bond form to form an amphiphilic cationic compound. The synthetic route is as follows:

preparation of triazole series derivatives:

under the action of sodium azide, epoxy ring opening of the epoxy compound to generate an azide; the azide further reacts with alkynyl under the action of sodium ascorbate, copper sulfate, tertiary butanol and the like to generate 1,2, 3-triazole; further coupled with lipophilic cations such as triphenylphosphine and the like to form an amphiphilic cationic compound.

The invention also aims to provide application of the triazole compound shown in the formula I in preparing antifungal medicines. Further, the fungus is a drug-resistant fungus.

Fungal efflux pump overexpression is one of the most common mechanisms of resistance. Increased efflux pump activity prevents the drug from entering the cell and expels more of the drug from the cell, resulting in a decreased intracellular concentration of the drug, which can lead to drug resistance by the candida species. The compound is based on the coupling of triazole drug skeletons with lipophilic cations, and the electron-shifted lipophilic cations are a class of cationic compounds with oleophylic and hydrophilic amphiphilicity, can penetrate cell membranes to enter cells under the pushing of membrane potential, and can avoid the efflux function of an efflux pump. Researches show that the triazole drug skeleton is coupled with the lipophilic cation, so that the efflux action of an efflux pump on azole drugs can be overcome, and the drug resistance problem of the azole drugs can be further overcome. The invention has the beneficial effects that:

(1) because an ergosterol synthesis path does not exist in animal cells, the azole drug has small side effect and high selectivity on a human body, and is economic and rapid and has strong pharmacy property when being developed based on an azole drug framework;

(2) by introducing diversified side chains such as aromatic rings, heterocycles and the like, the space conformation of the whole molecule is improved, the acting force with an enzyme activity pocket is enhanced, and the activity is improved;

(3) azole drugs, as substrates for fungal efflux pumps, are sensitive to efflux pumps. By coupling with lipophilic cations, the efflux action of an efflux pump on azole drugs can be overcome, and the problem that the azole drugs are easy to resist drugs is solved;

(4) the alkyl carbon chains and the polyethylene glycol chains with different lengths can change the electrical property, the lipid-water distribution coefficient and the like of the whole molecule, and influence the binding force with a target spot. Wherein the oxygen atom in the polyethylene glycol chain can participate in the formation of hydrogen bond, thereby enhancing the biological activity of the molecule.

Detailed Description

It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.

In order to make the technical solutions of the present application more clearly understood by those skilled in the art, the technical solutions of the present application will be described below in conjunction with specific embodiments and details.