- Synthesis of novel 1,2,4-oxadiazoles and analogues as potential anticancer agents
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A library of 3,5-disubstituted-1,2,4-oxadiazoles 7-9 and their bioisosters, 1,3,4-oxadiazole 14 and 1,3,4-thiadiazole 16, were synthesized and evaluated in vitro for their anticancer potential against a panel of six human cancer cell lines. The key step in the synthesis of oxadiazoles 7-9 involve coupling of amidoxime 6 with an appropriate carboxylic acid followed by thermal cyclization. The bioisosteres, 1,3,4-oxadiazole 14 and 1,3,4-thiadiazole 16 were prepared from the reaction of a common precursor diacylhydrazine 13 with thionyl chloride and Lawesson′s reagent, respectively. The anticancer studies on the synthesized compounds revealed that presence of a cyclopentyloxy or n-butyloxy on the C-3 aryl ring and piperdin-4-yl or trichloromethyl at the C-5 position of 1,2,4-oxadiazole is essential for good activity. In particular, 1,2,4-oxadiazole 7i and analogue 1,3,4-thiadiazole 16 exhibited significant activity against DU145 (IC50: 9.3 μM) and MDA-MB-231 (IC 50: 9.2 μM) cell lines, respectively.
- Kumar, Dalip,Patel, Gautam,Chavers, Angela K.,Chang, Kuei-Hua,Shah, Kavita
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- Design and Synthesis of 3,5-Disubstituted-1,2,4-Oxadiazoles as Potent Inhibitors of Phosphodiesterase4B2
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A series of 3,5-disubstituted-1,2,4-oxadiazoles has been prepared and evaluated for phosphodiesterase inhibition (PDE4B2). Among the prepared 3,5-disubstituted-1,2,4-oxadiazoles, compound 9a is the most potent inhibitor (PDE4B2 IC50=5.28μm). Structure-activity relationship studies of 3,5-disubstituted-1,2,4-oxadiazoles revealed that substituents 3-cyclopentyloxy-4-methoxyphenyl group at 3-position and cyclic ring bearing heteroatoms at 5-position are important for activity. Molecular modeling study of the 3,5-disubstituted-1,2,4-oxadiazoles with PDE4B has shown similar interactions of 3-cyclopentyloxy-4-methoxyphenyl group; however, heteroatom ring is slightly deviating when compared to Piclamilast. 3-(3-Cyclopentyloxy-4-methoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole (9a) exhibited good analgesic and antiinflammatory activities in formalin-induced pain in mice and carrageenan-induced paw edema model in rat.
- Kumar, Dalip,Patel, Gautam,Vijayakrishnan, Lalitha,Dastidar, Sunanda G.,Ray, Abhijit
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p. 810 - 818
(2012/06/18)
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