Bicyclononane-2,8-bis(trifluoromethyl)quinoline hybrids: synthesis, antiplasmodial and antitrypanosomal activity.

With the aim to design dual-acting antiprotozoals, a set of hybrid-molecules was prepared. Amino-substituted 2-aza- and 3-azabicyclo[3.2.2]nonanes with antiplasmodial and antitrypanosomal activity were linked via aminoalkyl linkers to the 2,8-bis(trifluoromethyl)quinoline scaffold of mefloquine. All newly synthesized compounds were characterized by IR spectroscopy, NMR spectroscopy, and HRMS. Their antiplasmodial activities were examined in vitro against the NF54 strain of Plasmodium falciparum and their antitrypanosomal activity against the STIB900 strain of Trypanosoma brucei rhodesiense. Most of the compounds showed antiprotozoal activity in submicromolar concentration. Structure-activity relationships concerning the linker length as well as the amino substituent and ring position of the nitrogen in the bicyclic ring system were discussed. The most promising of the newly synthesized compounds was a 2-azabicyclononane with an aminopropyl linker and a 4-methylpiperazinyl substituent at a bridgehead atom. It showed excellent antiplasmodial and antitrypanosomal activity (IC50 ≤ 0.065 µM). Two chemical compounds labeled 8d and 9c are shown with their molecular structures and activity data. Compound 8d has a half-maximal inhibitory concentration (IC50) of 0.050 micromolar against P.f NF54, 0.065 micromolar against T. b. r., and 2.860 micromolar cytotoxicity in L6 cells. Compound 9c has an IC50 of 0.051 micromolar against P.f. NF54, 0.537 micromolar against T. b. r., and 1.845 micromolar cytotoxicity in L6 cells. The structures share a common core with variations in the nitrogen-containing ring and side chains.