The effect of varying the chain length on the solid state conformation and packing of 6,12-dialkoxy- and 6,12-dialkylsulfanyl-benzo[1,2-b:4,5-b′]bis[b]benzothiophenes has been studied. The compounds were prepared by SNAr reaction of 6,12-difluorbenzo[1,2-b:4,5-b′]bis[b]benzothiophene with alkoxides or alkanethiolates derived from C7-C10 alcohols and alkanethiols. Single crystal X-ray diffraction analysis revealed that all but two compounds crystallize in the triclinic space group P1. Two compounds were obtained as monoclinic crystals with space group P21/c. The alkoxy substituted compounds adopted a molecular conformation with a step from the core and a gauche conformation about the C1′-C2′ bond placing the alkyl chains close to parallel with the pentacyclic arene ring system, whereas in the alkylsufanyl derivatives, the alkyl chains were arranged strongly deviated from the plane of the ring, with the sulfur atom antiperiplanar to C3′ of the alkyl chain. NMR measurement of T1 relaxation in CDCl3 showed both the alkoxy and alkylsulfanyl substituents to be freely rotating at ambient temperature in solution, indicating the orientation of the chains in the solid state was due to packing interactions during crystallization.

Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense and is invariably fatal unless treated. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work, informed by previous findings, presents novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives with promising antitrypanosomal activity. In particular, 32 exhibits an in vitro EC₅₀ value of 0.5 µM against Trypanosoma brucei rhodesiense, and analogues 29, 30 and 33 show antitrypanosomal activities in the <1 µM range. We have demonstrated that substituted 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidines present promising antitrypanosomal hit molecules with potential for further preclinical development.