The synthesis of potential anti parasitic compounds

Abstract

Novel members of a homologous series of N', N'-di-(2,6-dinitro-4-trifluoromethylphenyl) diamine dimers related to the anti-malarial compound trifluralin (2,6-dinitro-(N, Ndipropylamino- 4-trifluoromethyl)benzene) have been synthesised in good yields for screening against several tropical diseases such as Leishmaniasis, Trypanosomiais, and Malarial in both humans and animals. This was achieved in a single step reaction where the starting material chloralin (1-chloro-2,6-dinitro-4-trifluoromethylbenzene) was reacted with various aliphatic and aromatic diamines via the key step involving nucleophilic aromatic ipso-substitution. The final compounds were obtained via the intermediate Jackson-Meisenheimer complexes. The formation of the corresponding tri- and tetrasubstituted hydrazines were, however, not successful due to unfavourable steric interactions. Previous investigations by other researchers have postulated tubulin (a dimeric protein) as a potential site of drug action. Based on this theory such compounds were synthesised that may play a role in mapping distances between tubulin binding sites. As both the herbicides, trifluralin and oryzalin (3,5-dinitro-4-(N, N-dipropylamino) - benzenesulphonamide) have been shown to possess anti-leishmanial and anti-malarial activities against Leishmania mexicana (in vivo) and Plasmodium falciparum (in vitro) respectively, a new analogue of oryzalin, 4-(N, N-dipropylsulphamoyl)-2,6-dinitro-l- (N, N-dipropylamino)benzene has been synthesised for possible screening. The study was extended to the synthesis of julolidine (2,3,6,7-tetrahydro-IH, 5H-benzo[ij] quinolizine) and lilolidine (1,4,5,6-tetrahydro-2H-pyrrolo[3,2,1[ij]quinoline) analogues since the parent ring structures are known to exhibit anti-leishmanial activities. This was achieved by reacting several aromatic amines with a series of a, ß-ketoesters to give the intermediate amides, which were then cyclised (in situ) via Friedel-Crafts acylation using polyphosphoric acid to the corresponding substituted julolidine and lilolidine analogues. Spectroscopic data on trifluralins, julolidines and related compounds is presented in this thesis and were found to be consistent with the proposed structures. Although in this study the emphasis lies on synthetic aspects and spectroscopic evaluations some preliminary biological data is summarised in the Appendix, while the remaining testing will form part of an ongoing programme of work by others.