Design and synthesis of coumarin analogs as anti-HIV agents

Numerous plant compounds have been evaluated for inhibitory effects against HIV replication, including the coumarin compounds suksdorfin and imperatorin, which were discovered in our laboratory. To develop these moderately active compounds into a drug candidate, structural optimizations are required to improve biological activities as well as pharmacokinetic properties.; Activity-guided structural modification of suksdorfin previously led to the analogs 3',4'-di- O-(-)-camphanoyl-(+)-cis-khellactone (DCK) and 3',4'-di-O-(-)-camphanoyl-2 ',2'-dimethyldihydropyrano[2,3-f]chromone (DCP), which exhibited significantly improved in vitro anti-HIV activity. Many DCK and DCP analogs (DCKs and DCPs, respectively) were subsequently synthesized and structure-activity relationships were well established for these compounds. However, in vivo animal studies suggested low bioavailability of the DCKs, partially due to rapid metabolism, and the same property may be assumed for the structurally similar DCPs. In order to guide further structural design of these compounds as bioavailable anti-HIV drug leads, my studies established metabolic profiles of DCKs and DCPs. In vitro metabolic stabilities of DCKs and DCPs in human liver microsomes were assessed using high performance liquid chromatography (HPLC) with UV detection to establish structure-metabolism relationships (SMR). In addition, HPLC coupled with mass spectrometry (LC-MS) was used to identify metabolically vulnerable sites of DCKs and DCPs. The SMR results suggested that either replacing the heteroatom in the dimethylpyran ring or introduction of aromatic substituents in the benzopyran ring may be beneficial for improving metabolic stability. Alternatively, structural analysis of the metabolites suggested that camphanoyl moiety is the major site of oxidative metabolism and, thus, structural alteration of the two ester regions may also be beneficial for improving the metabolic stability.; Systematic structural modifications of imperatorin at the ether moiety and the coumarin ring gave over twenty synthetic psoralen analogs in order to establish structure-activity relationships; however, none showed significant anti-HIV activity.; In summary, the investigation of metabolic properties of DCKs and DCPs offered avenues for design of better lead structures, while the activity of imperatorin needs re-investigation. The study also is a good indication that the synthetic approach should be coupled with the simultaneous evaluation of in vitro activity and metabolic stability in order to provide a successful drug candidate.