Synthesis and evaluation of substituted phenyl cycloalkylureas and bioisosteres as IL-6 expression inhibitors

Abstract

Inflammation is an important, normal, and complex host defense response to injury, autoimmune responses or infectious agents. However, chronic inflammation is associated with diseases like rheumatoid arthritis, cancers, cardiovascular diseases, diabetes, and obesity, and over 60% of deaths worldwide. Interleukine-6 is one of the key proinflammatory cytokines involved in inflammation processes and therefore considered as a valuable drug target. We have prepared three series of new drugs referred to as substituted phenyl cycloalkylureas (PcAUs), phenyl cycloalkylthioureas (PcATUs) and phenyl cycloalkylsquaramides (PcASs), respectively. PcAUs and PcATUs were prepared by nucleophilic addition of 3 or 4-tert-butyl, 3- or 4-cyclohexyl and 3- or 4-iodoaniline to a suitable cycloalkylisocyanate or cycloalkylisothiocyanate. PcASs were prepared by nucleophilic addition of the aforementioned anilines to diethoxysquarate. The resulting alkoxysquarates were further reacted with selected cycloalkylamines to produce the desired PcASs. The antiproliferative activity of PcAUs, PcATUs and PcASs was evaluated in human keratinocytes and human skin fibroblasts. Most compounds at the exception of 4f, 4f′, 4f″, 5f, 5f′, 5f″, 6f, and 6f′, 6f″ that are bearing a 3-cyclohexyl group did not exhibit significant antiproliferative activities at concentration <30 µM. At 10 µM, PcAUs 4b-4e, 5b, 5e, and 6e inhibited IL-6 expression by more than 70% in HaCaT cells, which is equivalent to or greater than ibuprofen used as a positive control. These PcAUs showed a good metabolic stability in presence of human liver microsomes. Our results are suggesting PcAUs as a new molecular template for the development of potentially useful IL-6 expression inhibitors for the treatment of inflammation-related diseases.