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Synthesis method of glycogen synthase kinase-3 inhibitor for treating plasmodium falciparum causing malaria

A technology for synthesis of Plasmodium falciparum and glycogen, which is applied in drug combination, resistance to vector-borne diseases, organic chemistry, etc., can solve the problem of decreased sensitivity to artemisinin, and achieve the effect of short production cycle and simple operation

Inactive Publication Date: 2018-05-04
杨文思
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Recently reported decreased susceptibility of P. falciparum to artemisinin at the Cambodia-Thailand border is of concern

Method used

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  • Synthesis method of glycogen synthase kinase-3 inhibitor for treating plasmodium falciparum causing malaria
  • Synthesis method of glycogen synthase kinase-3 inhibitor for treating plasmodium falciparum causing malaria
  • Synthesis method of glycogen synthase kinase-3 inhibitor for treating plasmodium falciparum causing malaria

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] The synthesis conditions of 4-(2-chlorophenyl)-3-cyano-1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridine-2-thione 2 are:

[0021] Mix cyclopentanone (34.5g), piperidine (12.7g) and dioxane (350mL), heat to 60-80°C and stir for 1-2 hours; add (E)-3-(2 -Chlorophenyl)-2-cyanothioacrylamide 1 (83.0g), stirred for 2-5 hours, cooled to room temperature, filtered to obtain 4-(2-chlorophenyl)-3-cyano-1,5 , 6,7-Tetrahydro-2H-cyclopenta[b]pyridine-2-thione 2 (89.4 g, 84%).

[0022] m.p.:234-238℃; IR(KBr):3225cm -1 (NH),2925cm -1 and 2861cm -1 (aliphatic CH), 2231cm -1 (C≡N); 1 H NMR (DMSO-d6, 500MHz): δ (ppm) = 1.55-1.66 (m, 2H, CH2), 1.90-1.99 (m, 2H, CH2), 2.75-2.85 (m, 2H, CH2), 7.25 ( m,1H,ArH),7.31(m,2H,ArH),7.58(m,2H,ArH),8.02(m,1H,ArH), 14.14(brs,1H,NH); 13 C NMR (DMSO-d6, 125MHz): δ (ppm) = 20.3, 24.8, 27.0, 128.0, 128.9, 130.7, 138.9, 96.3, 113.9, 115.6, 120.1, 140.0, 152.9, 159.0, 175.4.m / z (MS -ESI):287.65[M+1] + .

[0023] Synthesis conditions of 3-amino-4-(2-chl...

Embodiment 2

[0026] Example 2 Kinase Analysis

[0027] By mixing the protein with buffer A (pH 7.5, 10mM MgCl 2 , 1 mM EGTA, 1 mM DTT, 25 mM Tris / HCl, pH 7.5, 50 μg / mL heparin, 0.15 mg / mL BSA) in 40 μM GS-1 peptide substrate (YRRAAVPPSPSLSRHSSPHQpSEDEEE, where pS represents phosphorylated serine; Proteogenix, Oberhausbergen, France) at 15 μM γ- 33 Incubate in the presence of P-ATP in a final volume of 30 μL for the measurement of recombinant kinase activity. With the exception of DdGSK3 (30 min at room temperature), 25 [mu]L of the reaction was spotted on Whatman P81 phosphocellulose paper after incubation at 30[deg.] C. for 30 min. The filter was washed 5 times (at least 5 minutes each) in a 1% phosphoric acid solution. Wet filters were counted in the presence of 1 mL of ACS (Amersham) scintillation fluid. Blank values ​​were subtracted and activity was calculated as picomoles of phosphate incorporated during the 30 min incubation. Activity is usually expressed as a percentage of maxim...

Embodiment 3

[0028] Example 3 In Vitro Antimalarial Activity Determination

[0029] Plasmodium falciparum erythroid stage stably expressing the luciferase gene using the hrp2 promoter (NF54:LUC) from a chromosomal locus. These parasites constitutively express high levels of luciferase. Cultures in a total volume of 20 mL were grown in 75 mL tissue culture flasks (Costar brand, NUNC, Denmark). When 3% parasitaemia was reached, the medium was aspirated and 100 μL of 25% hematocrit-cultured parasite multichannel pipettes were transferred to a sterile 96-well plate (100 μL per well). Drug diluted in complete RPMI-1640 containing 1% DMSO (10 µM, 100 µL / well) was added to each well. Each drug was tested in triplicate. As a control (NF54:LUC) three wells without drug in regular medium and another three (NF54:LUC) wells exposed to 1% DMSO only were seeded. An additional 3 wells were inoculated with NF54 "wild type" parasites not expressing luciferase and used as "blanks". Plates were incubate...

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Abstract

The invention discloses a synthesis technology of a glycogen synthase kinase-3 inhibitor for treating plasmodium falciparum causing malaria. The synthesis method has the advantages of simple operationand short production period, and can massively prepare the glycogen synthase kinase-3 inhibitor, namely 3-amino-4-(2-chloromethyl)-6,7-dihydro-5H-cyclopentene[b]thieno[3,2-e]pyridine-2-ylphenyl ketone.

Description

technical field [0001] The field of the invention belongs to the field of drug synthesis, in particular to a Plasmodium falciparum glycogen synthase kinase-3 inhibitor 3-amino-4-(2-chloromethyl)-6,7-dihydro- Synthesis of 5H-cyclopentenen[b]thieno[3,2-e]pyridin-2-ylphenylmethanone. Background technique [0002] Malaria is one of the world's most serious infectious diseases, mainly affecting the poor in developing countries, especially young children in tropical African countries threatened by Plasmodium falciparum. Plasmodium falciparum is the most virulent parasite that causes malaria. Although the use of insecticide-treated bed nets led to a dramatic reduction in the number of infections in several countries, there were still 225 million malaria cases reported in 2009, including 771,000 deaths. A major problem in malaria treatment is the limited number of suitable drugs and the development of drug resistance. While larger drugs such as chloroquine or pyrimethamine have b...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61P33/06
CPCC07D495/04Y02A50/30
Inventor 杨文思
Owner 杨文思
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