Phytochemical studies of the Bolivian medicinal plants Lampaya medicinalis and Evanta; synthesis of carbon-14-labeled and analogues of the HIV integrase inhibitor chicoric acid

Nature is still a rich reservoir for drug discovery. The unique geography and ethnomedicinal uses of plants in Bolivia make it a particularly attractive resource for pursuing drug leads. The worldwide reemergence of tuberculosis, particularly due to the development of multi-drug resistant organisms and the HIV/AIDS epidemic, necessitates finding more potent anti-TB drugs. The extracts of two Bolivian plants were tested for anti-tumor and anti-TB activities and their constituents identified by spectroscopic methods. From Lampaya medicinalis four flavonoids, six simple aromatics, five triterpenes and three quinolines were isolated. Among these, 3,11-dioxooleanolic acid and cis-cinnamyl benzoate were isolated from nature the first time. From Evanta four known quinolines and two phytosterols were isolated. Sixteen compounds were tested and found to have anti-TB activity with MIC = 128 to 8 μg/ml. Interestingly, ciscinnamyl benzoate was the most active with an MIC only 32 times larger than Rifampin. A chemotaxonomical examination demonstrated that Evanta is Galipea longiflora instead of Quassia amara as originally designated by our sources and collaborators.; Integrase is an attractive target of HIV therapy, since protease and reverse transcriptase inhibitors fail to eradicate the HIV virus. Chicoric acid is one of the most active inhibitors of HIV-integrase, but the mechanism is not fully understood. Four chicoric acids analogues with the catechol moieties replaced by electron-rich and electron-deficient heterocyclic rings were synthesized for SAR studies, but were inactive. The overall yield and efficiency of the chicoric acid synthesis used previously in our lab was improved and the methodology used to prepare 14C-chicoric acid on a submiligram scale for biological studies. The synthesis of 14C-labeled tartaric acid from 14C-KCN was improved from that in the literature by identifying and removing an impurity in the commercial product that prevented the efficient synthesis of 14C-chicoric acid. Finally, L-tetraacetylchicoric acid was synthesized and its activities against HIV and HIV integrase compared to those in the literature, which claimed that the acetylation of chicoric acid resulted in no loss of activity.