Synthesis and analgesic evaluation of 4-(2-heptyloxy)-7-[(Z)-(3-hydroxycyclohexyl)]indole: a caveat on indole-phenol bioisosterism

The synthesis of 4-(2-heptyloxy)-7-[(Z)-(3-hydroxycyclohexyl)]indole (7) is described. Compound 7 was tested for analgesic properties in the phenylbenzoquinone writhing test and was found to be essentially devoid of activity. In contrast, cis-3-[4-(2-heptyloxy)-2-hydroxyphenyl]cyclohexanol (8), the analogue in which the pyrrolo ring is replaced by a hydroxyl group, had an ED50 of 8.3 mg/kg, sc, in the same model. The absence of bioisosterism between the pyrrolo ring and the phenolic hydroxyl group, in this instance, is discussed in terms of the circumstances that control the manifestation of bioisofunctionality between a pyrrolo ring and a phenolic hydroxyl group, which functions as a hydrogen-bond donor.