Abstract
Taking into consideration the biological activity of the only natural products containing a 1,2,4-oxadiazole ring in their structure (quisqualic acid and phidianidines A and B), the natural product analogs 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl)pyrrolidine-2,5-dione (4) and 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl)-1H-pyrrole-2,5-dione (7) were synthesized starting from 4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)aniline (1) in two steps by isolating the intermediates 4-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenylamino)-4-oxobutanoic acid (3) and (Z)-4-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenylamino)-4-oxobut-2-enoic acid (6). The two natural product analogs 4 and 7 were then tested for antitumor activity toward a panel of 11 cell lines in vitro by using a monolayer cell-survival and proliferation assay. Compound 7 was the most potent and exhibited a mean IC50 value of approximately 9.4 µM. Aniline 1 was synthesized by two routes in one-pot reactions starting from tert-butylamidoxime and 4-aminobenzoic acid or 4-nitrobenzonitrile. The structures of compounds 1, 2, 4, 5 and 6 were confirmed by X-ray crystallography.
Highlights
The five-membered heterocyclic 1,2,4-oxadiazole motif is of synthetic and pharmacological interest
Clapp reviewed the synthesis of 1,2,4-oxadiazoles [33]
The general approach for the synthesis of 1,2,4-oxadiazoles is illustrated in Scheme 1
Summary
The five-membered heterocyclic 1,2,4-oxadiazole motif is of synthetic and pharmacological interest. The 3-substituted indole alkaloids, phidianidines A and B (Figure 1), have been isolated by Carbone et al from the aeolid opisthobranch Phidiana militaris [3] They are selective inhibitors of the dopamine transporter DAT and partial agonists of the μ opioid receptor [4]. These selective molecules are attractive as CNS targets because neither phidianidine A nor B is cytotoxic Another example of a natural product with a oxadiazole core is quisqualic acid (Figure 1). Barrett et al point out that the possibility of performing chemical modifications is a requirement for developing novel drugs, a strong activity is just the starting point [28] Another moiety worth investigation is succinimide, because N-phenylsuccinimides are regarded as some of the most efficacious agricultural fungicides [29,30]. The new derivatives have been tested for in vitro antitumor activity toward a panel of 11 cell lines
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