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Paper | Special issue | Vol 101, No. 1, 2020, pp.145-164
Published online, 20th June, 2019
DOI: 10.3987/COM-19-S(F)5
Synthesis of 1,3,4-Oxadiazoles as Selective T-Type Calcium Channel Inhibitors

Man Zhang, Bende Zou, Medha J. Gunaratna, Sahani Weerasekara, Zongbo Tong, Thi D. T. Nguyen, Serkan Koldas, William S. Cao, Conrado Pascual, Xinmin Simon Xie,* and Duy H. Hua*

*Department of Chemistry, Kansas State University, 1212 Mid Campus Drive, Manhattan, KS 66506, U.S.A.

Abstract

Neuropathic pain, epilepsy, insomnia, and tremor disorder may arrive from an increase of intracellular Ca2+ concentration through a dysfunction of T-type Ca2+ channels. Thus, T-type calcium channels could be a target in drug discovery for the treatments of neuropathic pain and epilepsy. From rational drug design approach, a group of 2,5-disubstituted 1,3,4-oxadiazole molecules was synthesized and their selective T-type channel inhibitions were evaluated. The synthetic strategy consists of a short sequence of three reactions: (i) condensation of thiosemicarbazide with acid chlorides; (ii) ring closing by 1,3-dibromo-5,5-dimethylhydantoin; and (iii) coupling with various acid chlorides. 5-Chloro-N-(5-phenyl-1,3,4-oxadiazol-2-yl)thiophene-2-carboxamide (11) was found to selectively inhibit T-type Ca2+ channel over Na+ and K+ channels in mouse dorsal root ganglion neurons and/or human embryonic kidney (HEK)-293 cells and to suppress seizure-induced death in mouse model. Consequently, compound 11 is a useful probe for investigation of physiologic and pathophysiologic roles of the T-channel, and provides a basis to develop a novel therapeutic to treat chronic neuropathic and inflammatory pains.