Triazole CYP51-HDAC double-target antifungal compound as well as preparation method and application thereof

A compound, dual-target technology, applied in the field of medicine

Active Publication Date: 2020-06-30
THE NAVAL MEDICAL UNIV OF PLA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these drugs have made great progress in the prevention and treatment of systemic fungal infections, the emergence of drug-resistant fungi poses a great challenge to the treatment of systemic fungal infections

Method used

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  • Triazole CYP51-HDAC double-target antifungal compound as well as preparation method and application thereof
  • Triazole CYP51-HDAC double-target antifungal compound as well as preparation method and application thereof
  • Triazole CYP51-HDAC double-target antifungal compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0119] Preparation of Compound A:

[0120]

[0121] Reagents and conditions: (a)Br(CH 2 ) mCN, K 2 CO 3 , DMF, 80°C, 12h; (b) (i) HCl, anhydrous MeOH, anhydrous Dioxane rt, 1h; (ii), HCONHNH 2 ,Et 3 N, MeOH, rt, 18h; (c), K 2 CO 3 , DMF, 80℃, 4h; (d), NH 2 OH, KOH, MeOH, rt, 5h.

[0122] The preparation method of compound A1:

[0123] In the first step, 0.5 g of compound 1 (n=0) was dissolved in 5 mL of dry DMF solution, and 0.73 g of reagent Br(CH 2 ) 3 CN, 1.36g K 2 CO 3 , react at 80°C for 12h, filter the filtrate, add 100mL ethyl acetate to dilute and wash three times with saturated aqueous sodium chloride solution, take the ethyl acetate layer, anhydrous Na 2 SO 4 Dry, filter, remove the organic solvent from the filtrate under reduced pressure, and use n-hexane / ethyl acetate (10 / 1, v / v) as the mobile phase to purify the residue by silica gel column chromatography to obtain compound 2 (n is 0, m is 3) .

[0124] In the second step, dissolve 0.5g of compou...

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Abstract

The invention discloses a triazole CYP51-HDAC double-target antifungal compound, which has a structural general formula disclosed in the invention, wherein R is selected from one of the structures disclosed in the invention. According to the triazole CYP51-HDAC double-target antifungal compound disclosed by the invention, an HDAC inhibitor fragment is introduced into a traditional triazole drug structure; a series of CYP51-HDAC double-target inhibitors are obtained, and the CYP51-HDAC double-target inhibitors are effective to azole sensitive fungi, and more importantly, have excellent in-vitroand in-vivo activity to azole drug-resistant fungi.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a triazole CYP51-HDAC dual-target antifungal compound and a pharmaceutically acceptable salt thereof, and a preparation method. The compound has antifungal activity and can be used for treating fungal infection diseases . Background technique [0002] In recent years, the incidence of systemic fungal infections has shown an upward trend, especially in patients with organ transplantation, tumors, HIV, etc., and the mortality rate remains high. Mold (Aspergillus fumigates) is currently the three most pathogenic fungi with the highest morbidity and mortality. [0003] Currently, there are four types of drugs clinically used to treat systemic fungal infections: polyenes (amphotericin B), nucleic acids (5-fluorocytosine) and azoles (fluconazole, itraconazole, etc.). Among them, azole drugs such as fluconazole, itraconazole, and voriconazole are the first-line drugs for t...

Claims

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Application Information

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IPC IPC(8): C07D249/08C07D249/12A61K31/4196A61K31/496A61P31/10
CPCC07D249/08C07D249/12A61P31/10
Inventor 盛春泉刘娜韩贵焱李成兰涂杰黄亚辉
Owner THE NAVAL MEDICAL UNIV OF PLA
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