Synthesis and biological evaluation of a series of 2-(((5-akly/aryl-1-pyrazol-3-yl)methyl)thio)-5-alkyl-6-(cyclohexylmethyl)-pyrimidin-4(3)-ones as potential HIV-1 inhibitors

A series of 2-(((5-akly/aryl-1-pyrazol-3-yl)methyl)thio)-5-alkyl-6-(cyclohexylmethyl)-pyrimidin-4(3)-ones were synthesized and their anti-HIV-1 activities were evaluated. Most of these compounds were highly active against wild-type (WT) HIV-1 strain (IIIB) with EC values in the range of 0.0038-0.4759 μmol/L. Among those compounds, had an EC value of 3.8 nmol/L and SI (selectivity index) of up to 25,468 indicating excellent activity against WT HIV-1. anti-HIV-1 activity and resistance profile studies suggested that compounds and displayed potential anti-HIV-1 activity against laboratory adapted strains and primary isolated strains including different subtypes and tropism strains (ECs range from 4.3 to 63.6 nmol/L and 18.9-219.3 nmol/L, respectively). On the other hand, it was observed that those two compounds were less effective with EC values of 2.77 and 4.87 μmol/L for HIV-1A (K103N + Y181C). The activity against reverse transcriptase (RT) was also evaluated for those compounds. Both and obtained sub-micromolar IC values showing their potential in RT inhibition. The pharmacokinetics examination in rats indicated that compound has acceptable pharmacokinetic properties and bioavailability. Preliminary structure-activity relationships and molecular modeling studies were also discussed.

Study on Vitro Anti-HIV-1 Activity ofTaiqi PeiyuanGranules / 中国中医药信息杂志

ObjectiveTo evaluate the vitro anti-HIV-1 activity ofTaiqi Peiyuan Granules.MethodsMTT was used to detect cytotoxicity ofTaiqi Peiyuan Granules; cytopathy method was used to detect the inhibitory activity of Taiqi Peiyuan Granules on acute infection of HIV-1; HIV-1 p24 antigen ELISA detection was used to detect inhibitory activity ofTaiqi Peiyuan Granules for virus replication of HIV-1 acute infection cells, and count the medical therapeutic indexes.ResultsCC50ofTaiqi Peiyuan Granules in cytotoxicity test was 3.761±0.370 mg/mL; the EC50 of inhibition syncytial test was 0.454 5±0.204 6 mg/mL; the therapeutic index was between 5.84 and 12.97; p24 ofTaiqi Peiyuan Granules in inhibition experiments was 0.56±0.27 mg/mL, and the therapeutic index was between 5.30 and 8.74.ConclusionAnti-HIV-1 activity ofTaiqi Peiyuan Granules is relatively weak.

Screening of Active Compounds Against HIV-1 Reverse Transcriptase Based on Molecular Docking / 广州中医药大学学报

Objective To screen the non-nucleoside compounds against HIV-1 reverse transcriptase by molecular modeling and bioactivity assay. Methods Surflex-Dock module of Tripos SYBYL software was used to simulate the binding pattern of 22 000 compounds in SPECS database with the active pocket of HIV-1 reverse transcriptase. Based on the simulation results, the interaction mode between the above compounds and the crystal structure of HIV-1 reverse transcriptase was analyzed. The compounds with higher docking scores and better binding pattern were determined by anti-HIV-1 ac tivities test in vitro. Results The virtual screening results showed that the docking conformation of 1- (4-fluorophenyl) -3- [2- (1H-indol-3-yl) ethyl] thiourea was similar to the embedded ligand in Rilpivirine crystal structure. 1- ( 4-fluorophenyl) -3- [ 2- ( 1H-indol-3-yl) ethyl] thiourea was held together with the key residue Lys101 in docking pocket of HIV-1 reverse transcriptase by hydrogen bonds, and hadπ-πstacking action together with the conservative residue Trp229 and the aromatic residue Tyr181 respectively. The bioassay in vitro results showed that when the proliferation rate of C8166 lymphocyte syncytium infected by HIV-1ⅢB arrived 50% ( EC50) , the concentration of 1- ( 4-fluorophenyl) -3- [ 2- ( 1H-indol-3-yl) ethyl] thiourea was 5.45μg/mL. Conclusion Molecule docking technology is an effective approach to reducing the screening of candidate compounds with micromolecular activity, and can be used to predict the interaction mode between the compound and the target receptor. In the study, active compound 1- (4-fluorophenyl) -3- [2- (1H-indol-3-yl) ethyl] thiourea has been screened out by molecule docking technology.

Establishment and optimization of a method for screening HIV-1 integrase 3′-processing inhibitor / 中国药理学通报

Aim To establish and optimize a method for screening HIV-1 integrase 3′-processing inhibitor. Methods Fluorescence resonance energy transfer ( FRET) was used to create an assay for screening in-tegrase 3′-processing inhibitors; wavelength was de-fined by DNaseⅠ; factors affecting IN activity were optimized, including buffer composition, substrate con-centration, enzyme concentration, metal ion concentra-tion. Results Integrase 3′-processing optimizing reac-tion conditions were buffer 1 , 500 nmol · L-1 sub-strate, 1 μmol·L-1 integrase, 20mmol·L-1 magne-sium ion. Positive drug raltegravir and myricetin could effectively inhibit integrase 3′-processing activity using this assay. Two integrase 3′-processing inhibitors were screened by this method. Conclusion The method for screening HIV-1 integrase 3′-processing inhibitor is successfully established and optimized.

Determination of the Concentrations of Ceftriaxone in Blood and Bile of Patients During Perioperative Period / 中国药房

OBJECTIVE:To study the anti-infective effect of ceftriaxone in perioperative period METHODS:28 cases of cholelithiasis complicating infections who had to undergo laparoscopic cholecystectomy were enrolled in this study Ceftriaxone,1g,im,was injected 1h～1 5h before anesthesia,and blood and bile were sampled before,during and after operation The concentration of ceftriaxone was determined by UV-spectrophotometry RESULTS:The concentrations of ceftriaxone in blood before,during and after operation were(37 59?16 13)?g/ml,(49 68?10 51)?g/ml and (27 09?12 38)?g/ml respectively The drug concentration in blood peaked 2h after drug administration,at this time,the drug concentration of bile was 4 times that of blood (201 77?20 16)?g/ml CONCLUSION:The drug concentration in blood was 49 times as high as MIC,which indicates that ceftriaxone has preventive and therapeutic effects on possible infections during perioperative period