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

Aziz-Ur- Rehman,Sz Siddiqui,Saa Shah,Ta Chohan,Ma Abbasi,S Saleem,N Ahtzaz,J Iqbal,S Manzoor,Na Virk

doi:10.4314/tjpr.v17i6.22

Abstract

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 IC 50 (±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. Keywords : Ethyl isonipecotate, Propanamides, 1,3,4-Oxadiazole, Anti-cancer activity

Highlights

Heterocyclic compounds have gained great interest by chemists in the quest for new significant therapeutic and pharmacological agents [1]
The methodology of all N-substituted propanamide derivatives of 1,3,4-oxadiazole have been summarized in scheme-1
Compound 6c, light brown amorphous solid, having melting point 150-152 °C with 85 % yield was selected randomly for single molecule discussion to explain the structural elucidation of synthesized compound

Summary

INTRODUCTION

Heterocyclic compounds have gained great interest by chemists in the quest for new significant therapeutic and pharmacological agents [1]. The synthesis of targeted compounds 6a-l is significant, as it has different heterocyclic systems submerged in one unit in order to enhance their biological applications, in the evaluation of anticancer activity. The product in the form of precipitates was attained by addition of distilled water. The precipitates of target compound 2 were acquired by the water addition followed by the filtration and washing. The reaction mixture was stirred vigorously to attain the precipitates. Compound 4 (0.006 mol) was stirred with lithium hydride in the presence of DMF for 30 minutes N-substituted propanamides (5a-l) were subsequently added. The reaction mixture stirred for 4 hours at the room temperature. Following the addition of cold distilled water, the target compounds (6a-l) were obtained in the form of precipitates that were filtered, washed and dried. The results for 50% inhibitory concentration (IC50) were obtained at different dilutions (μg/well) and analyzed by EZ-Fit software (Perrella Scientific Inc, Amherst, USA)

RESULTS

DISCUSSION

CONCLUSION