Synthesis and antimycobacterial activity of 1-(β-D-Ribofuranosyl)-4-coumarinyloxymethyl-/-coumarinyl-1,2,3-triazole

被引:39
|
作者
Srivastava, Smriti [1 ]
Bimal, Devla [1 ]
Bohra, Kapil [1 ,2 ]
Singh, Balram [1 ]
Ponnan, Prija [1 ]
Jain, Ruchi [1 ]
Varma-Basil, Mandira [3 ]
Maity, Jyotirmoy [1 ]
Thirumal, M. [1 ]
Prasad, Ashok K. [1 ]
机构
[1] Univ Delhi, Dept Chem, Delhi 110007, India
[2] Univ Delhi, Deen Dayal Upadhyaya Coll, Dept Chem, Delhi 110078, India
[3] Univ Delhi, VP Chest Inst, Dept Microbiol, Delhi 110007, India
关键词
Antimycobacterial; Click chemistry; 1,2,3-Triazole; Cytotoxicity; In silico pharmacokinetics; Docking study; CARRIER PROTEIN REDUCTASE; RAPID COLORIMETRIC ASSAY; BIOLOGICAL EVALUATION; DNA GYRASE; COUMARIN DERIVATIVES; CLICK CHEMISTRY; TRIAZOLE DERIVATIVES; MOLECULAR DOCKING; DRUG DISCOVERY; TUBERCULOSIS;
D O I
10.1016/j.ejmech.2018.02.067
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of beta-D-ribofuranosyl coumarinyl-1,2,3-triazoles have been synthesized by Cu-catalyzed cycloaddition reaction between azidosugar and 7-O-/7-alkynylated coumarins in 62-70% overall yields. The in vitro antimycobacterial activity evaluation of the synthesized triazolo-conjugates against Mycobacterium tuberculosis revealed that compounds were bactericidal in nature and some of them were found to be more active than one of the first line antimycobacterial drug ethambutol against sensitive reference strain H37Rv, and 7 to 420 times more active than all four first line antimycobacterial drugs (isoniazid, rifampicin, ethambutol and streptomycin) against multidrug resistant clinical isolate 591. Study of in silico pharmacokinetic profile indicated the drug like characters for the test molecules. Further, transmission electron microscopic experiments revealed that these compounds interfere with the constitution of bacterial cell wall possibly by targeting mycobacterial InhA and DNA gyrase enzymes. Study conducted on the activities of the test compounds on bacterial InhA and DNA gyrase revealed that the most bactericidal test compound, N-1-(beta-D-ribofuranosyl)-C-4-(4-methylcoumarin-7-oxymethyl)-1,2,3-triazole (6b) and its corresponding directly linked conjugate N-1-(beta-D-ribofuranosyl)-C-4-(4-methylcoumarin-7-yl)-1,2,3-triazole (11b) significantly inhibited the activity of both the enzymes. The results were further supported by molecular docking studies of the compound 6b and 11b with bacterial InhA and DNA gyrase B enzymes. Further, the cytotoxicity study of some of the better active compounds on THP-1 macrophage cell line using MIT assay showed that the synthesized compounds were non-cytotoxic. (C) 2018 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:268 / 281
页数:14
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