Antimycobacterial Activities of the Zanthoxylum leprieurii Metabolite Adubangoamide and Non-Natural Fagaramide Analogues.

trans-Fagaramide (1) and adubangoamide (2) are natural products with a cinnamic acid amide skeleton that have recently been isolated from Zanthoxylum leprieurii, a medicinal plant used locally in Uganda for the treatment of tuberculosis. Insufficient quantities of material from the natural source originally prevented the antimycobacterial evaluation of the new natural product 2. Herein, a synthesis of 2 is reported, and its antimycobacterial activity was determined using the synthetic material. Adubangoamide (2) is three times more active against the drug-susceptible M. tuberculosis strain H₃₇Rv than trans-fagaramide (1), with an MIC value of 10.0 μM. In addition, we synthesized eight non-natural analogues of trans-fagaramide (1, MIC = 32.0 μM against H₃₇Rv strain), in which benzylamide groups mimic the isobutylamide part of the trans-fagaramide structure. Five out of eight synthetic analogues are more active than the parent natural product: 11b (MIC = 6.0 μM), 11d (21.0 μM), 11e (6.1 μM), 11g (17.0 μM), and 11h (4.5 μM).