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3,5-Disubstituted Thiadiazine-2-thiones: New Cell-Cycle Inhibitors
Awwad A. Radwan,Tarek Aboul-Fadl,Abdullah Al-Dhfyan,Mohammed K. Abdel-Hamid,Abdullah A. Al-Badr 대한약학회 2012 Archives of Pharmacal Research Vol.35 No.1
Two series, a and b, of 3-cyclopentyl or (3-cyclohexyl)-5-substituted-3,4,5,6-tetrahydro-2H-1,3,5-thiadiazine-2-thiones (THTT) 2a-9a and 3b, 4b, 6b-9b, were synthesized to develop new cell cycle inhibitors. Variable and promising in vitro antiproliferative activities were shown with the synthesized THTT derivatives. Compound 5a with a 5-cyclopentyl group on position-3 and a glutamine residue on position-5 of the THTT moiety showed maximum activity (IC50 = 8.98 μM). Compound 5a possessed notable cell cycle disrupting and apoptotic activities with enhanced selectivity against cancer cells, suggesting the potential for the development of new selective cell cycle inhibitors. There is no evident relationship between the cytotoxic activity of the tested compounds and their lipophilicity. In addition, a pharmacophore based study was performed to explain the biological activity on structural bases. A successful model was generated with a good correlation with the observed activity.
Hajjaj H. M. Abdu-Allah,Bahaa G. M. Youssif,Mostafa H. Abdelrahman,Mohammed K. Abdel-Hamid,Rudraraju Srilakshmi Reshma,Perumal Yogeeswari,Tarek Aboul-Fadl,Dharmarajan Sriram 대한약학회 2017 Archives of Pharmacal Research Vol.40 No.2
The antitubercular drug; para-aminosalicylicacid (PAS) was used as the core scaffold for the design of aseries of 1H-1,2,3-triazolylsalicylhydrazones upon couplingwith triazole and arylhydrazone moietis to furnish asingle molecular architecture. The obtained derivativeswere screened against Mycobacterium tuberculosis H37Rvrevealing good to high activity for the active compounds(MIC values of 0.39–1.5 lg/mL) compared to the marketeddrugs isoniazid, rifampicin and ethambutol. Moreover, themost active analogue N-(1-(4-chlorobenzyl)-2-oxoindolin-3-ylidene)-2-hydroxy-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-benzohydrazide (20) was found to be ten-fold more potentthan PAS and equipotent to rifampicin (MIC 0.39 lg/mL),while exhibiting low cytotoxicity with a selectivity indexof[128. In addition, this compound was shown to beactive against persistent forms of mycobacteria comparableto standard drugs in nutrient starvation model. Accordingly,we introduce compound 20 as a valuable lead forfurther development. A 3D-QSAR study was also conductedto help in explaining the observed activity and toserve as a tool for further development.