Structure activity relationships of 1,8-disubstituted thioxanthenones.

Becket, Gordon

Abstract

Lucanthone, a thioxanthenone bearing a diethylaminoethylamino substituent, is orally active against Schistosoma mansoni infections in man. The structure-activity relationships of lucanthone and related compounds have been extensively investigated and the need for a 1-dialkylaminoalkylamino substituent and 4-methyl group established. The symmetrical nature of the thioxanthenone ring presents an opportunity for producing 1,8-disubstituted compounds which may possess enhanced biological activity. To investigate this situation a series of 1,8-di(dialkylamino-alkylamino)-4-methylthioxanthen-9-ones and 1,8-dipiperazinyl-4-methylthioxanthen-9-ones have been prepared from l,8-dichloro-4- methylthioxanthen-9-one. The latter compound has been synthesised from 2-chloro-6-nitrotoluene and from 2-amino-4-chlorotoluene. In the course of this work it was established that selective dehalogenation of 1,8-dichloro-4-methylthioxanthen-9-one occurred and this resulted in the isolation of a series of 1-substituted alkylamino-alkylamino- and piperazinyl-5-methylthioxanthen-9-ones. The structures of these compounds were elucidated by their n.m.r. and mass spectral properties. In addition an unambiguous synthesis of the parent l-[[2- (diethylamino)ethyl]amino]-5-methylthioxanthen-9-one from l-chloro-5-methylthioxanthen-9-one confirmed the site of dehalogenation at C-8. The biological activity of these compounds has been examined by means of the heat denaturation profile of native DNA and by assessment of their schistosomicidal activity in experimental S.mansoni infections in mice. The results obtained show that 1,8-di(diethylaminoethylamino)- and 1,8-di(dimethylaminoethylamino)-substitution leads to an increased DNA interaction compared with lucanthone. A mechanism of interaction with DNA consistent with a proposed intercalation model is discussed for the 1,8- and 1-substituted methylthioxanthenones. Enhanced schistosomicidal activity was found for l,8-di[[2- (diethylamino)ethyl]amino]-4-methylthioxanthen-9-one against S.mansoni infection in mice compared with lucanthone. The occurrence of activity with l-[[2-(diethylamino)ethyl]amino]-5-methylthioxanthen-9-one has demonstrated that the presence of a methyl group para to the basic side chain in lucanthone and related compounds is not an absolute requirement for schistosomicidal activity.

Citation

BECKET, G. 1978. Structure activity relationships of 1,8-disubstituted thioxanthenones. Robert Gordon's Institute of Technology, PhD thesis. Hosted on OpenAIR [online]. Available from: https://doi.org/10.48526/rgu-wt-1993230

• Thesis Type: Thesis
• Deposit Date: Oct 16, 2024
• Publicly Available Date: Oct 16, 2024
• DOI: https://doi.org/10.48526/rgu-wt-1993230
• Public URL: https://rgu-repository.worktribe.com/output/1993230
• Award Date: May 31, 1978