CN100519540C - S-DABO compound, synthesizing method and usage - Google Patents
S-DABO compound, synthesizing method and usage Download PDFInfo
- Publication number
- CN100519540C CN100519540C CNB2007100656059A CN200710065605A CN100519540C CN 100519540 C CN100519540 C CN 100519540C CN B2007100656059 A CNB2007100656059 A CN B2007100656059A CN 200710065605 A CN200710065605 A CN 200710065605A CN 100519540 C CN100519540 C CN 100519540C
- Authority
- CN
- China
- Prior art keywords
- alkyl
- hiv
- reaction
- dabo
- ring
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Abstract
S-DABO composition and its synthesis method and function belong to medicine technical medicine. The invention relates to a 5-alkyl-6-phenyl-2-(substituted arylcarbonylmethylsulfur)uracil composition, having following general formula: wherein, R1 is C1-3 alkyl; R2=C1-6 alkyl, substituted furan ring, thiofuran ring, benzene ring (substituent on the benzene ring is H, OH, Cl3 alkoxy), having the 5-alkyl-6-phenylthiouracil as reagent, reacting with alpha-halogen ketone to get the inventive product which is catalyzed by K2CO3. The synthesis method is easy to operate. The product has an obvious anti-HIV virus activity, a low toxicity, a high selectivity index and can be an anti-HIV medicine candidate.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to dihydro alkoxy benzyl pyrimidine dione (S-DABO) compounds as inverase.
Background technology
Inverase design at present mainly is that each link with the HIV virus replication cycle is a target spot, design various inhibitor with the duplicating of blocking virus, mainly contain efabirenz (NRTIs), non-nucleoside reverse transcriptase inhibitor (NNRTls), proteinase inhibitor, fusion enzyme inhibitors etc. by its mechanism of action.Though these medicines have anti-HIV to infect and the clinical efficacy of AIDS, exist simultaneously toxic side effect greatly, defective such as cost an arm and a leg.Especially HIV is a height variability virus, is easy to produce resistance, and this becomes the difficult problem that current all inverases face.Comparatively effective clinically at present therapy-combination treatment, thereby allow patient take several medicines that act on different target spots simultaneously duplicating of virus produced more effective inhibition, but in the face of so many patient population, existing inverase does not all satisfy demand far away on quantity still is kind.Therefore design and develop have the new texture type, new role mechanism, new role target spot or have strong inhibiting inverase of new generation particularly important to the drug-fast virus of tool.
Dihydro alkoxy benzyl pyrimidine dione (S-DABO) belongs to NNRTIs, its mechanism of action is and some amino-acid residue effects formation stabilized complex on reversed transcriptive enzyme (RT) reactive site surface, makes enzyme lose the normal function of retrovirus DNA by conformation that changes RT and then the conformational change that influences the substrate-function position.This compounds becomes an important series seeking the HIV medicine because of characteristics such as its high-efficiency low-toxicity, synthetic facilities.Chen Fener etc. are based on the theory action model of dihydro alkoxy benzyl pyrimidine dione (S-DABO) with HIV-RT, synthesize a series of 2-(aryl carbonyl methyl sulphur)-5-alkyl-6-menaphthyl-uracil compounds, demonstrated HIV (human immunodeficiency virus)-resistant activity (seeing that the patent No. is the Chinese patent file of Z L 200410017802.1) preferably.Find that through structure activity study though this compounds 6-naphthalene nucleus has big cloud density, help the pi-pi accumulation effect of amino-acid residue in small molecules part and the RT enzyme binding cavity cave, the naphthalene nucleus rigidity is bigger simultaneously, to unfavorable with combining of RT enzyme.
Summary of the invention
The objective of the invention is to replace 6-position naphthalene nucleus to reduce molecular volume with the less phenyl ring of volume, increase molecular flexibility, the synthetic a series of 5-alkyl of design-6-phenyl-2-(substituted aryl carbonyl methyl sulphur) uracil derivative, promptly obtain a kind of S-DABO class reverse transcriptase inhibitors 2-substituted aryl-5-alkyl-6-phenyluracils, compare with existing compound, HIV (human immunodeficiency virus)-resistant activity can obviously improve, and cytotoxicity reduces.
The present invention also aims to obtain the preparation method of above-claimed cpd.
Purpose of the present invention also is to obtain the purposes of above-claimed cpd.
Product S-DABO compounds of the present invention is 5-alkyl-6-phenyl-2-(substituted aryl carbonyl methyl sulphur) uridylic, is the compound that a class has following general formula:
Wherein:
R
1Be C
1-3Alkyl;
R
2=C
1-6Alkyl, substituted furan ring, thiphene ring, phenyl ring (substituting group on the aromatic ring is H, OH, C
1-3Alkoxyl group).
The preparation method of this compound is as follows:
With 5-alkyl-6-phenyl thiouracil 1 is raw material, with alpha-brominated ketone 2 in solvent, K
2CO
3Under the catalysis, heated and stirred is carried out the S-alkylated reaction, and getting target molecule 3 is compound of the present invention, and its reaction formula is as follows:
Wherein:
(1) 5-alkyl-6-phenyl thiouracil press document (Mai, A., Artico, M.et.al.J.Med.Chem.1995,38,3258-3263) method preparation, reaction formula is as follows:
(2) R
1=C
1-3Alkyl; R
2=C
1-6Alkyl, substituted furan ring, thiphene ring, phenyl ring (substituting group on the aromatic ring is H, OH, C
1-3Alkoxyl group).
(3) mol ratio of 5-alkyl-6-phenyl-2-thiouracil and various alpha-brominated ketone is 1:1.2~2, and it is between 25~80 ℃ that temperature of reaction is controlled at, and the reaction times is 4-12 hour.
(4) used solvent can be a kind of in toluene, methylene dichloride, the N-N dimethyl formamide or their mixture.
The purposes of invention product is as anti-AIDS drug.
The beneficial effect of the invention: The compounds of this invention is synthetic convenient, HIV virus is had very strong restraining effect, and cytotoxicity is very little, has very high selectivity index, therefore can be used as anti-AIDS drug candidates purposes.In addition, the mechanism of action of this compounds and HIV is different from classical NNRTIs, and further research might search out the novel targets of anti-AIDS medicine.
Embodiment
To help to understand the present invention by following embodiment, but can not limit the scope of the invention.
Synthesizing of 5-alkyl-6-phenyl-2-(substituted aryl carbonyl methyl sulphur) uridylic.The general operation of reaction: with 5-alkyl-6-phenyl-2-thiouracil (3mmol) and K
2CO
3Place flask, add the dry DMF of 15ml, stirring at room is reacted half an hour, adds alpha-brominated ketone R
1COCH
2Br (3.6mmol) continues stirring reaction under optimal temperature, and TLC follows the tracks of raw material point disappearance stopped reaction, and reaction solution is poured in the 30mL frozen water, precipitation is separated out in stirring, filters, and washes precipitation with water, the suction filtration oven dry gets crude product, and further column chromatography purification can get various white powders.Can get the white crystal of 5-alkyl-6-phenyl-2-(substituted aryl carbonyl methyl sulphur) uridylic with the appropriate solvent recrystallization.
Respectively obtain target product with different alpha-brominated ketone with aforesaid method with different 5-alkyl-6-phenyl-2-thiouracil, partial results is as shown in table 1:
Table 1.
The C8166 cell and the HIV-1RT enzyme that adopt HIV-1 to infect carry out cell levels and the anti-HIV biological activity test of enzyme level.Method is described below.
RT suppresses experiment: testing sample is diluted to 3 times of final concentration, HIV-1RT (2ng/ μ l ,-70 ℃ frozen) with lysate, be diluted to 2ng/20 μ l with lysate, take out the reaction bar, every hole adds 20 μ lRT, 20 μ l dilute good sample, and 20 μ l reaction mixture 3a mix back 37 ℃ of reaction 2h.(RT operation and on carry out).Positive control hole 20ulPFA (300 μ g/ml) is set, joins the 1X washing lotion, confide all liquid after, every hole adds the 250ml washing lotion to be washed 5 times, 1min/ time, confides all washing lotion.Coupling diluent 100X dilution resists-digoxin-peroxidase (anti-DIG-POD), every hole 200 μ l, 37 ℃ of reaction 1h, after confiding all liquid, every hole adds 250 μ l washing lotions to be washed 5 times 1min/ time, confides all washing lotion, every hole adds 200 μ lABTs substrate reactions liquid, 37 ℃ of room temperature reactions, green up to occurring, measure the OD value with BIO-TEK ELx800ELISA instrument behind the mixing and (measure wavelength: 405nm; Reference wavelength: 490nm), calculate IC
50(HIV-1RT to 50% produces the drug level that suppresses).
Cytotoxicity experiment: compound adopts mtt assay to measure to the toxicity of C8166 cell.In 96 porocyte culture plates, compound is carried out five times of doubling dilutions, every hole adds 4 * 10
5Each concentration of/ml C8166 cell suspension is provided with 3 multiple holes.The cell contrast and the contrast of AZT medicine that do not contain medicine are set simultaneously.37 ℃, 5%CO
2Cultivated three days in the incubator, every hole adds 37 ℃ of MTT solution and hatched 4 hours.Every hole adds 10%SDS-50%DMF again, and 37 ℃, 5%CO
2Overnight incubation in the incubator.Measure the OD value with BIO-TEK ELx800ELISA instrument behind the mixing and (measure wavelength: 595nm; Reference wavelength: 630nm), draw Dose-Response Curve, calculate CC according to experimental result
50(compound concentration during 50% cell toxigenicity)
Synplasm suppresses experiment: with 4 * 10
5/ ml C8166 cell suspension inoculation adds HIV-1 in the 96 porocyte culture plates that contain five times of doubling dilutions of compound
IIIBDilution supernatant liquor (MOl=0.04), each concentration gradient are established 3 multiple holes.The HIV-l that does not contain compound is set simultaneously
IIIBNegative control hole that infects and the positive control hole that contains the AZT medicine.37 ℃, 5%CO
2Cultivated three days in the incubator, under the inverted microscope (100 *), choose 5 nonoverlapping visuals field, counting synplasm number.Draw Dose-Response Curve according to experimental result, press Reed﹠amp; The Muench method calculates the 50% effective concentration (EC that compound suppresses virus
50, 50% effective concentration).Calculation formula: cytopathogenic effect inhibiting rate (%)=(1-experimental port synplasm number/control wells synplasm number) * 100%
The present invention compares product with AZT, and the part target compound is to HIV-l
IIIBThe inhibition activity the results are shown in Table 2:
Table 2. anti-HIV-1
IIIBActive
aSI (selectivity index)=CC
50/ EC
50
The existing compound of such compound activity of HIV (human immunodeficiency virus)-resistant activity test shows obviously improves, and cytotoxicity reduces, and wherein active maximum compound can and suppress the HIV virus replication at nmole, and selectivity index is up to 36364.In addition, the C8166 cell inhibitory activity that this compounds infects HIV is apparently higher than its inhibition to RT, shows that this compounds is compared with classical NNRTIs with the effect of HIV virus might have new target spot.
Claims (3)
2, a kind of preparation method of S-DABO compounds as claimed in claim 1 is characterized in that: with 5-alkyl-6-dibenzylsulfide uridylic is raw material, respectively with alpha-brominated ketone in solvent, K
2CO
3Under the catalysis, heated and stirred is carried out the S-alkylated reaction, makes the S-DABO compounds, and its reaction formula is as follows:
Wherein:
R
1Be C
1-3Alkyl;
R
2For quilt-H ,-OH ,-C
1-3The furan nucleus that alkoxyl group replaced, thiphene ring or phenyl ring,
5-alkyl-6-dibenzylsulfide uridylic and α bromo ketone mol ratio are 1:1.2~2, and temperature of reaction is controlled to be between 25-80 ℃, and the reaction times is 4-12 hour, and solvent is toluene or methylene dichloride or N, a kind of in the dinethylformamide or their mixture.
3, the application of S-DABO compounds as claimed in claim 1 in the medicine of preparation anti-AIDS.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB2007100656059A CN100519540C (en) | 2007-01-09 | 2007-01-09 | S-DABO compound, synthesizing method and usage |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB2007100656059A CN100519540C (en) | 2007-01-09 | 2007-01-09 | S-DABO compound, synthesizing method and usage |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101037415A CN101037415A (en) | 2007-09-19 |
CN100519540C true CN100519540C (en) | 2009-07-29 |
Family
ID=38888618
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2007100656059A Expired - Fee Related CN100519540C (en) | 2007-01-09 | 2007-01-09 | S-DABO compound, synthesizing method and usage |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN100519540C (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101638391B (en) * | 2009-08-21 | 2011-04-27 | 山东大学 | 2-[(substituted aminobenzene)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-3H-pyrimidyl-4-ketone derivative and preparation method and application thereof |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102399197B (en) * | 2011-11-14 | 2014-04-16 | 云南大学 | 2-(2-hydroxy - substituted phenethyl sulfenyl]-3H-pyrimidin-4-ketone compounds and synthesis method and application thereof |
CN102558072B (en) * | 2012-01-13 | 2014-12-31 | 昆明理工大学 | 2-(4-alkylformyloxyphenylcarbonylmethylthio)pyrimidine compounds and application thereof |
CN106866548B (en) * | 2017-04-26 | 2019-08-27 | 云南大学 | 6- ring methylpyrimidine ketone hiv reverse transcriptase inhibitor, preparation method and use |
CN111303136B (en) * | 2020-04-10 | 2021-10-01 | 云南大学 | 6- (1, 3-benzodioxy-5- (methyl) -substituted uracil derivative, synthetic method, application and medicine |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996010565A1 (en) * | 1994-10-04 | 1996-04-11 | Istituto Superiore Di Sanita' | Substituted 6-benzyl-4-oxopyrimidines, process for their preparation and pharmaceutical compositions containing them |
CN1309647A (en) * | 1998-07-17 | 2001-08-22 | 诺沃瑞尔制药有限公司 | Substd. 6-benzyl-4-oxopyrimidines, process for their preparation and pharmaceutical compositions contg. them |
RU2238269C1 (en) * | 2003-04-21 | 2004-10-20 | Волгоградский государственный технический университет | Method for preparing 6-substituted 2-(alkylsulfanyl)-4(3h)-pyrimidinones |
CN1562978A (en) * | 2004-04-15 | 2005-01-12 | 复旦大学 | Compound of multiple substituted uracil class, preparation method and usage |
-
2007
- 2007-01-09 CN CNB2007100656059A patent/CN100519540C/en not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996010565A1 (en) * | 1994-10-04 | 1996-04-11 | Istituto Superiore Di Sanita' | Substituted 6-benzyl-4-oxopyrimidines, process for their preparation and pharmaceutical compositions containing them |
CN1309647A (en) * | 1998-07-17 | 2001-08-22 | 诺沃瑞尔制药有限公司 | Substd. 6-benzyl-4-oxopyrimidines, process for their preparation and pharmaceutical compositions contg. them |
RU2238269C1 (en) * | 2003-04-21 | 2004-10-20 | Волгоградский государственный технический университет | Method for preparing 6-substituted 2-(alkylsulfanyl)-4(3h)-pyrimidinones |
CN1562978A (en) * | 2004-04-15 | 2005-01-12 | 复旦大学 | Compound of multiple substituted uracil class, preparation method and usage |
Non-Patent Citations (2)
Title |
---|
5-Alkyl-2-[(aryl and alkyloxylcarbonylmethyl)thio]-6-(1-naphthylmethyl) pyrimidin-4(3H)-ones as an unique HIVreverse transcriptase inhibitors of S-DABO series. Yanping He, et al.Bioorganic & Medicinal Chemistry Letters,Vol.14. 2004 * |
Synthesis and Anti-HIV-1 Activity of Thio Analogues ofDihy droalkoxybenz yloxop yrimidines. Antonello Mai, et al.J. Med. Chem,Vol.38 No.17. 1995 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101638391B (en) * | 2009-08-21 | 2011-04-27 | 山东大学 | 2-[(substituted aminobenzene)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-3H-pyrimidyl-4-ketone derivative and preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN101037415A (en) | 2007-09-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100519540C (en) | S-DABO compound, synthesizing method and usage | |
AU2016250976B2 (en) | Imidazo isoindole derivative, preparation method therefor and medical use thereof | |
CN100488504C (en) | Novel coumarin-amide derivatives and its preparation, its drug composition and use | |
CN106831605B (en) | A kind of substituted diaryl pyridine derivatives and the preparation method and application thereof | |
Murugesan et al. | Lead optimization at C-2 and N-3 positions of thiazolidin-4-ones as HIV-1 non-nucleoside reverse transcriptase inhibitors | |
Ibrahim et al. | Design, synthesis and biological evaluation of novel 5-((substituted quinolin-3-yl/1-naphthyl) methylene)-3-substituted imidazolidin-2, 4-dione as HIV-1 fusion inhibitors | |
CA3075062A1 (en) | Rad51 inhibitors | |
Liang et al. | Synthesis and anti-HIV activity of 2-naphthyl substituted DAPY analogues as non-nucleoside reverse transcriptase inhibitors | |
CN104926829A (en) | Thieno miazines derivatives and preparation method and application thereof | |
CN101367749A (en) | A set of mesidino mesitoyl derivant, preparation and application thereof | |
CN102202737A (en) | Disubstituted phthalazine hedgehog pathway antagonists | |
CA3143716A1 (en) | Methods of using rad51 inhibitors for treatment of pancreatic cancer | |
CN112920208B (en) | Boric acid-containing indole aryl sulfone derivative and preparation method and application thereof | |
Zhu et al. | Preliminary SAR and biological evaluation of potent HIV-1 protease inhibitors with pyrimidine bases as novel P2 ligands to enhance activity against DRV-resistant HIV-1 variants | |
CN103450176A (en) | Naphthalimide compound containing 2-(4-aminophenyl) benzothiazole and application thereof | |
CN103159695A (en) | Thiazole compound capable of restraining human immunodeficiency virus (HIV) replication and effective against drug-resistant HIV virus strains and preparation method and purpose thereof | |
CN111518104B (en) | 1,2, 4-triazolo [1,5-a ] pyrimidine compound containing thiourea pyrimidine and preparation method and application thereof | |
CN106866548B (en) | 6- ring methylpyrimidine ketone hiv reverse transcriptase inhibitor, preparation method and use | |
CN101638391B (en) | 2-[(substituted aminobenzene)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-3H-pyrimidyl-4-ketone derivative and preparation method and application thereof | |
El-Sharief et al. | Synthesis, characterization, and derivatization of some novel types of fluorinated mono-and bis-imidazolidineiminothiones with antitumor, antiviral, antibacterial, and antifungal activities | |
CN104876860B (en) | A kind of diaryl pyrazole piperidine derivatives and preparation method and application | |
CN103483272B (en) | Between two aromatic hydrocarbons-polysubstituted pyrimidine analog derivative and preparation method thereof and application | |
CN103275023B (en) | 1-aryl-1,2,3-triazole compound and Synthesis and applications thereof | |
CN101475536A (en) | Polysubstituted S-DACO derivative, synthesizing method and use thereof | |
CN101602733A (en) | A kind of Diarylmiazines derivatives and its production and use |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090729 Termination date: 20110109 |