Structure-based linker optimization of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with diverse structures,a series of novel S-DACO analogues of 6-(2-cyclohexyl-1-allkyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)pyrimidin-4(3 H)-ones were designed,synthesized and evaluated for their antiviral activities in MT-4 cells.Most of these new compounds showed moderate to good activities against wild type HIV-1 with IC_(50) values ranging from 7.55 μmol/L to 0.018 μmol/L.Among them,compound 5 c was identified as the most promising inhibitor against HIV-1 replication with an IC_(50)=0.018 μmol/L,CC_(50)=194 μmol/L,and SI=12791,which was much more potent than the reference drugs NVP and DLV and comparable to AZT and EFV.In addition,5 c also exhibited improved activity against double mutant HIV-1 strain RES056 compared to that of the reference drugs NVP/DLV and DB02.The preliminary structure-activity relationship(SAR) and molecular modeling studies were also discussed,which provides some useful indications for guiding the further rational design of new S-DACO analogues.     

Synthesis of 2-oxazolidinones from (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol

A series of isomeric 2-oxazolidinones has been synthesized from (1S, 2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 579–584, April, 2006.     

Diastereoselective reaction of (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol with aromatic aldehydes. Synthesis of (1R,2R,4S,5S,8S)-2,8-diaryl-4-(4-nitrophenyl)-1-aza-3,7-dioxabicyclo[3.3.0]octanes

We have synthesized a series of (1R,2R,4S,5S,8S)-2,8-diaryl-4-(4-nitrophenyl)-1-aza-3,7-dioxabicyclo[3.3.0]octanes as a result of reaction of (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol with aromatic aldehydes. The structure of the compounds obtained was established on the basis of ¹H NMR data. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 757–763, May, 2006.     

Synthesis of 3S-methylundec-1-ylbromide, a key synthon in the synthesis of (S,S,S)-diprionylacetate, from L-(-)-menthol

Three new approaches to the synthesis of 1-bromo-3S-methylundecane, a key synthon in the synthesis of (S,S,S)-diprionylacetate, a sex pheromone of pine sawflies of the genera Diprion and Neodiprion, were proposed based on chemo-and stereoselective transformations of L-(-)-menthol derivatives. __________ Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 73–76, January–February, 2006.     

Synthesis of derivatives of (S)-2-alkanols, components of pheromones ofDrosophila mulleri andRhyzopertha dominica, from (S)-(+)-3,7-dimethylocta-1,6-diene

Effective routes for the synthesis of (S)-2-acetoxytridecane, the sex pheromone of the fruit flyDrosophila mulleri, and (S)-1-methylbutyl 2-methyl- and 2,4-dimethylpent-2E-enoates, components of the aggregation pheromone of the lesser grain borerRhyzopertha dominica, were developed on the basis of (S)-4-methylhex-5-en-1-yl tosylate accessible from (S)-(+)-dihydromyreene. Published inIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1929–1931, November, 2000.     

Synthesis and biological activity of (Z) and (E) isomers of 3-(3,4-diaryl-1,2,4-triazole-5-yl)prop-2-enoic acid

Abstract  (Z)-3-(3,4-diaryl-1,2,4-triazole-5-yl)prop-2-enoic acid derivatives were obtained in the course of the reaction of N ³-substituted amidrazones with maleic anhydride, and isomerized into the (E) isomers by heating under reflux in acetic acid solution. The molecular structure of the compounds obtained was confirmed by IR and ¹H NMR spectroscopy, and by X-ray crystallography for (2E)-3-(4,5-diphenyl-4H-1,2,4-triazol-3-yl)prop-2-enoic acid. The antiviral and immunomodulating activity of several of the compounds was examined. Graphical abstract        

Asymmetric Synthesis of （R）- and （S）-Moprolol

A simple and effective procedure for the enantioselective synthesis of （R）- and （S）-moprolol was described. The key step was the asymmetric synthesis of enantiopure （R）- and （S）-guaifenesin, which were synthesized from enantioenriched （R）-3-chloro-l,2-propanediol and （S）-epichlorohydrin via kinetics of hydrolysis resolution of racemic epichlorohydrin by chiral Salen-Co^Ⅲ complex. The e.e. values of both the optical compounds were above 98%, and the chemical structures of the target compounds were confirmed by ^1H NMR, ^13C NMR, IR, and MS.     

Synthesis and Stereochemistry of (1S,3S,4S,7R11R)-3-(4-Nitrophenyl)-11-aza-2,6-dioxatricyclo[5,3,1,04,11]undecane

The reaction of (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol with glutaraldehyde has been studied. It has been established on the basis of AM1 and PM3 calculations and ¹H NMR spectra recorded in the presence of the shift reagent Eu(fod)₃ that (1S,3S,4S,7R,11R)-3-(4-nitrophenyl)-11-aza-2,6-dioxatricyclo[5,3,1,0^4,11]undecane is formed as the result of the reaction.     

L-(-)-Menthol in the Synthesis of Key Synthons for Optically Active Methyl-Branched Insect Pheromones

A synthesis of optically active 4S-methylhexanal, 1-bromo-3S-methylheptane, and 1-bromo-3S-methylundecane, which are key synthons for several methyl-branched insect pheromones, that is based on chemically selective transformations of 6-tosyloxy- and 6-iodoisopropyl-4R-methylhexanoates that are available from L-(-)-menthol was proposed. __________ Translated from Khimiya Prirodnykh Soedinenii, No. 6, pp. 592–593, November–December, 2005.     

(S)-N-Boc-α-氨基庚(辛)二酸单酯和双酯的制备

以(S)-N-Boc焦谷氨酸乙酯为原料, 经DIBAL-H还原得到半缩醛, 然后经Wittig反应得到相应的烯烃, 最后氢化制得(S)-N-Boc-α-氨基庚二酸二(单)酯, 总收率为85.1%(二酯)和86.1%(单酯). 另外, 以(S)-N-Boc-哌啶-2-甲酸为原料经酯化和氧化得内酰胺, 然后经还原、Wittig反应、氢化得到(S)-N-Boc-α-氨基辛二酸二(单)酯, 总收率为72.5%(二酯)和72.4%(单酯). 产品用¹H NMR, MS表征.     

X-ray structural analysis of (1R,2R,4S,5S,8S)-2,8-bis(4-chlorophenyl)-4-(4-nitrophenyl)-1-aza-3,7-dioxabicyclo[3,3,0]octane

The configuration of the asymmetric atoms in the molecule of (1R,2R,4S,5S,8S)-2,8-bis(4-chlorophenyl)-4-(4-nitrophenyl)-1-aza-3,7-dioxabicyclo[3,3,0]octane has been determined using X-ray analysis. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 930-934, June, 2006.     

Synthesis of 1-(9-butylcarbazol-3-yl)-5-oxopyrrolidine-3-carboxylic acid derivatives

A series of condensation products of 1-(9-butylcarbazol-3-yl)-5-oxopyrrolidine-3-carbohydrazide with 2-propanone, 2-butanone, 2,4-pentanedione, 2,5-hexanedione, ethyl 3-oxobutanoate, and aromatic aldehydes was obtained. Substituted oxadiazoles were synthesized from carbohydrazide or the corresponding hydrazone. Spectral properties of the synthesized compounds were examined. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1009–1017, July, 2008.     

Molecular docking studies on tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepinone (TIBO) derivatives as HIV-1 NNRT inhibitors

At present, chemotherapy seems to be the main weapon in the arsenal of remedies for the ongoing crusade against AIDS. The mode of binding of the TIBO family of inhibitors has been of interest because these compounds do not fit the two-hinged-ring model as generally observed in the NNRTIs. Flexible docking simulations were performed with a series of 53 TIBO derivatives as NNRTIs. Binding preferences as well as the structural and energetic factors associated with them were studied. A good correlation (r ² = 0.849, q ² = 0.843) was observed between the biological activity and binding affinity of the compounds which suggest that the identified binding conformations of these inhibitors are reliable. Further screening of PubChem database yielded novel scaffolds. Our studies suggest that modifications to the TIBO group of inhibitors might enhance their binding efficacy and hence, potentially, their therapeutic utility.     

Synthesis and antiemetic activity of 1,2,3,9-tetrahydro-9-methyl-3-(4-substituted-piperazin-1-ylmethyl)-4H-carbazol-4-one derivatives

5-HT₃ receptor antagonists, such as Ondansetron, are used for anti-emesis after chemotherapy, radiotherapy and operations. Some Ondansetron analogs possessing piperazine ring as side chains were synthesized in our lab. Thus, one of the two carbonyl groups of starting material 1,3-cyclohexandione (1) was condensed with phenylhydrazine hydrochloride to form monophenylhydrazone (2). 1,2,3,9-Tetrahydro-4H-carbazol-4-one (3) was prepared from 2 via cyclization and rearranged in the presence of ZnCl₂. Through a methylation reaction, compound 3 was converted to 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (4). 3-Dimethylaminomethyl substituted compound (5) was synthesized from 4 by a Mannich reaction in glacial acetic acid. Nine novel 1,2,3,9-tetrahydro-9-methyl-3-(4-substituted-piperazin-1-ylmethyl)-4H-carbazol-4-one derivatives (6a–6i) were synthesized through nucleophilic substitution reaction of 5 with piperazines. The structures of all the target compounds were determined by elemental analysis, IR, MS, ¹H NMR and ¹³C NMR spectra. The results of preliminary pharmacological test show that part of the novel compounds have antiemetic activity comparable to that of the control Ondansetron. __________ Translated from Chinese Journal of Organic Chemistry, 2008, 28(2) (in Chinese)     

Synthesis of isomeric 2-oxazolidinones from (1<Emphasis Type="Italic">R</Emphasis>,2<Emphasis Type="Italic">R</Emphasis>)-and (1<Emphasis Type="Italic">S</Emphasis>,2<Emphasis Type="Italic">S</Emphasis>)-2-amino-1-(4-nitrophenyl)-1,3-propanediols

A synthesis is reported for (4R,5R)-and (4S,5S)-4-hydroxymethyl-5-(4-nitrophenyl)oxazolidin-2-ones and (1′R,4R)-and (1′S,4S)-4-[hydroxy(4-nitrophenyl)methyl]oxazolidin-2-ones from (1R,2R)-and (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediols. The effect of the experimental conditions on the formation of these compounds was studied. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1562–1570, October, 2007.     

Synthesis, structure and biological activity of 1-(1-methoxy-1-ferrocenyl-3-arylpropan-2-yl)-1H-1,2,4-triazole derivatives

A total of eleven new 1-(1-methoxy-1-ferrocenyl-3-arylpropan-2-yl)-1H-1,2,4-triazole derivatives have been synthesized from acetylferrocene. The structures of the title compounds have been determined by elemental analysis, ¹H-NMR and single crystal X-ray diffraction analysis. Bioassay showed that some of the title compounds had high plant-growth regulatory activity. __________ Translated from Chinese Journal of Organic Chemistry, 2005, 25(8) (in Chinese)     

Synthesis of Cytotoxic 1,3,4-trisubstituted 2-azetidinones

A series of 1,3,4-trisubstituted and 3,4-disubstituted 2-azetidinones were synthesized in order to study the relation between their structure and biological characteristics. Study of the cytotoxic activity of these compounds revealed an anticancer effect in (3S,4S)-1-(4-methoxyphenyl)-3-methyl-2-azetidinones containing 2-acetoxybenzoyloxymethyl and 2,2-dicyanovinyl substituents at position 4 in vitro with respect to a wide range of monolayer cultures of cancer cells.