Synthesis and biological evaluation of 1,4-benzodiazepin-2-one analogues with antitrypanosomal activity

Rathnam, Rajendra Prasad (2010) Synthesis and biological evaluation of 1,4-benzodiazepin-2-one analogues with antitrypanosomal activity. PhD thesis, University of Greenwich.

Abstract

The 1,4-benzodiazepin-2-one motif has been taken as a privileged skeleton for making antitrypanosomal agents. A library of over sixty 1,4-benzodiazepin-2-one derivatives has been synthesised employing novel synthetic routes. These derivatives were characterised spectroscopically, by mass spectrometry, and by combustion analysis. Five derivatives were characterised, in the solid state, by single crystal X-ray crystallography.

Biological assays of the library of compounds against Trypanosoma brucei brucei (T. b brucei) revealed a range of trypanocidal activities. A first generation library activity showed biological activity as low as 6.25 μM (minimum inhibitory concentration, MIC value). Structure activity relationships in this work revealed that an aromatic substituent at the C3 and N1 positions of the 1,4-benzodiazepin-2-one are important for improved bioactivity.

In order to improve biological activity, putative P-2 transporter motifs were exploited in the 1,4-benzodiazepin-2-ones. Structural activity relationships indicate that the inclusion of a guanidine moiety, a putative P-2 transporter motif, can improve the biological activity of these molecules. In vitro screening of these compounds showed a range of antitrypanosomal activities against T. b.brucei, with a number in the low micromolar range (MIC ≥ 0.78 μm) including (S)-1-(4-((3-benzyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)phenyl)guanidine, (S)-1-(3-((3-benzyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)phenyl)guanidine, (S)-1-(4-((3-benzyl-5-cyclohexyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-1yl)methyl)phenyl)-guanidine and (S)-1-(1-benzyl-5-cyclohexyl-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-7-yl)guanidine)phenylquanidine.

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