Synthesis of some new propanamide derivatives bearing 4-piperidinyl-1,3,4-oxadiazole, and their evaluation as promising anticancer agents

• Main Authors: Abbasi, M.A (Author), Ahtzaz, N. (Author), Aziz-Ur-Rehman (Author), Chohan, T.A (Author), Iqbal, J. (Author), Manzoor, S. (Author), Saleem, S. (Author), Shah, S.A.A (Author), Siddiqui, S.Z (Author), Virk, N.A (Author)
• Format: Article
• Language: English
• Published: University of Benin 2018
• Subjects: 1,3,4-Oxadiazole; 5 (1 [(4 methylphenyl)sulfonyl] 4 piperidinyl) 1,3,4 oxadiazole 2 thiol; Anti-cancer activity; antineoplastic activity; Article; carbon nuclear magnetic resonance; doxorubicin; drug synthesis; ethyl 1 [(4 methylphenyl)sulfonyl] 4 piperidine carbohydrazide; ethyl 1 [(4 methylphenyl)sulfonyl] 4 piperidinecarboxylate; Ethyl isonipecotate; IC50; in vitro study; mass spectrometry; MTT assay; n (2 ethylphenyl) 2 [[5 [1 [(4 methylphenyl)sulfonyl] 4 piperidinyl] 1,3,4 oxadiazol 2 yl]thio] propanamide; n (2 methoxyphenyl) 2 [[5 [1 [(4 methylphenyl)sulfonyl] 4 piperidinyl] 1,3,4 oxadiazol 2 yl]thio] propanamide; n (2 methylphenyl) 2 [[5 [1 [(4 methylphenyl)sulfonyl] 4 piperidinyl] 1,3,4 oxadiazol 2 yl]thio] propanamide; n (2 phenylethyl) 2 [[5 [1 [(4 methylphenyl)sulfonyl] 4 piperidinyl] 1,3,4 oxadiazol 2 yl]thio] propanamide; n (2,3 dimethylphenyl) 2 [[5 [1 [(4 methylphenyl)sulfonyl] 4 piperidinyl] 1,3,4 oxadiazol 2 yl]thio] propanamide; n (2,4 dimethylphenyl) 2 [[5 [1 [(4 methylphenyl)sulfonyl] 4 piperidinyl] 1,3,4 oxadiazol 2 yl]thio] propanamide; n (2,5 dimethylphenyl) 2 [[5 [1 [(4 methylphenyl)sulfonyl] 4 piperidinyl] 1,3,4 oxadiazol 2 yl]thio] propanamide; n (2,6 dimethylphenyl) 2 [[5 [1 [(4 methylphenyl)sulfonyl] 4 piperidinyl] 1,3,4 oxadiazol 2 yl]thio] propanamide; n (4 ethylphenyl) 2 [[5 [1 [(4 methylphenyl)sulfonyl] 4 piperidinyl] 1,3,4 oxadiazol 2 yl]thio] propanamide; n (phenylmethyl) 2 [[5 [1 [(4 methylphenyl)sulfonyl] 4 piperidinyl] 1,3,4 oxadiazol 2 yl]thio] propanamide; n [2 (4 methoxyphenyl)ethyl] 2 [[5 [1 [(4 methylphenyl)sulfonyl] 4 piperidinyl] 1,3,4 oxadiazol 2 yl]thio] propanamide; n phenyl 2 [[5 [1 [(4 methylphenyl)sulfonyl] 4 piperidinyl] 1,3,4 oxadiazol 2 yl]thio] propanamide; Propanamides; propionamide derivative; proton nuclear magnetic resonance; spectroscopy; thin layer chromatography; unclassified drug
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 Purpose: To sequentially synthesize piperidine-4-carboxylic acid ethyl ester-appended 1,3,4-oxadiazole hybrids and to evaluate them as anticancer agents. Methods: Ethyl 1-[(4-methylphenyl)sulfonyl]-4-piperidinecarboxylate (1) was synthesized from 4-methylbenzenesulfonylchloride (a) and ethyl 4-piperidinecarboxylate (b). Compound (1) was converted into ethyl 1-[(4-methylphenyl)sulfonyl]-4-piperidine carbohydrazides (2) and 5-{1-[(4-methylphenyl)sulfonyl]-4-piperidinyl}-1,3,4-oxadiazole-2-thiol (3) respectively. A variety of aryl amine (4a-l) were treated with 2-bromopropionylbromide to synthesize an array of propanamide (5a-l). Finally, 5-{1-[(4-methylphenyl)sulfonyl]-4-piperidinyl}-1,3,4-oxadiazole-2-thiol (3) and propanamides (5a-l) were reacted to synthesize target compounds (6a-l). Purity compounds 6a-l was confirmed by spectroscopic techniques like (1 H-NMR), (13 C-NMR) and EI-MS. To determine their anticancer potential, the change in absorbance of mixture and cell line before and after incubation was determined. Results: All the compounds 6a-l were successfully synthesized in 73-85 % yield. Compounds 6h, 6j and 6e have low IC50 (±SD) values of 20.12 ± 6.20, 10.84 ± 4.2 and 24.57 ± 1.62 µM to act as strong anticancer agents relative to doxorubicin (0.92 ± 0.1 µM) used as a reference. Conclusion: The synthesized propanamide derivatives bearing 4-piperidinyl-1,3,4-oxadiazole are potential anticancer agents, but further studies, especially in vivo, are required to ascertain their therapeutic usefulness. © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria and 2018 The authors.