Synthesis and evaluation of trypanocidal activity of derivatives of naturally occurring 2,5-diphenyloxazoles.

African trypanosomiasis is a zoonotic protozoan disease affecting the nervous system. Various natural products reportedly exhibit trypanocidal activity. Naturally occurring 2,5-diphenyloxazoles present in Oxytropis lanata, and their derivatives, were synthesized. The trypanocidal activities of the synthesized compounds were evaluated against Trypanosoma brucei brucei, T. b. gambiense, T. b. rhodesiense, T. congolense, and T. evansi. Natural product 1 exhibited trypanocidal activity against all the species/subspecies of trypanosomes, exhibiting half-maximal inhibitory concentrations (IC50) of 1.1-13.5 µM. Modification of the oxazole core improved the trypanocidal activity. The 1,3,4-oxadiazole (7) and 2,4-diphenyloxazole (9) analogs exhibited potency superior to that of 1. However, these compounds exhibited cytotoxicity in Madin-Darby bovine kidney cells. The O-methylated analog of 1 (12) was non-cytotoxic and exhibited selective trypanocidal activity against T. congolense (IC50 = 0.78 µM). Structure-activity relationship studies of the 2,5-diphenyloxazole analogs revealed aspects of the molecular structure critical for maintaining selective trypanocidal activity against T. congolense.

Concise Syntheses of Violaceoids A and C.

The concise syntheses of two alkylated hydroquinone natural products, violaceoids A and C, were accomplished by a protecting-group-free method employing the commercially available 2,5-dihydroxybenzaldehyde as the starting material. The key strategy of the syntheses is the utilization of alkenylboronic acid as both the coupling and temporary protective reagents to efficiently introduce the requisite alkenyl side chain of violaceoid A. Moreover, the synthesis of violaceoid C is reported here for the first time.