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UBC Theses and Dissertations

Benzisothiazole based anti-viral agents : new chemistry revealed during structure-activity relationship studies Lin, Zheng Sonia


My thesis concerns a study of the fundamental chemistry and reactivity of the benzisothiazole-based antiviral agent “1C8” developed in our laboratory. Initially identified as an anti-HIV agent that blocks HIV replication through perturbation of HIV pre-mRNA alternative splicing, 1C8 also displays activity against adenovirus, influenza, herpes (HSV-1) and hepatitis B infections, by affecting the function of the SR-protein splicing factor SRSF10. However, as there are currently no structural data available for SRSF10, and no detailed knowledge concerning its interactions with other factors in the spliceosome machinery at the molecular level, the optimization of the biological activity of 1C8 could only be achieved through classical Structure-Activity Relationship (SAR) studies (iterative modifications of its structure coupled to biological testing at each step). Chapter 2 describes the SAR studies on 1C8 involving modulation of functional groups in its 1,2-benzisothiazole-amide substructure: Reduction of the potentially bioactivatable nitro group, oxidation of the benzisothiazole sulfur atom, inversion of the central amide function and its replacement by an aminoether motif. A more extensive modification of 1C8 involved the extrusion of the benzisothiazole sulfur atom and incorporation of the amide function and the nitrogen of the isothiazole ring into a conformationally rigid pyrimidine ring. The absence of anti-HIV activity for any of the 1C8 analogs prepared pointed to the importance of the nitro group and to the correct orientation of the amide function in its structure for activity. In Chapter 3, the objective was to prepare a pyridopyrazolone benzisothiazole-type constrained amide analog of 1C8, which mimics a conformation imposed by a crucial H-bonding interaction between the 4-pyridinone C=O and the amide N-H. Pivotal to this effort was the preparation of a 3-hydrazino-5-nitro-1,2-benzisothiazole intermediate through reactions of 3-OMe- and 3-Cl-5-nitrobenzisothiazoles with hydrazine. These reactions resulted in deep-seated rearrangements of the benzisothiazole ring system leading to the formation of (Z)-methyl-2-amino-5-nitrobenzohydrazonate and 3,3'-thiobis-5-nitro-2,1-benzisothiazole, respectively. Support for the proposed mechanisms for the formation of these products was obtained from Density Function Theory calculations. Further investigations using phenylhydrazine revealed the production of aniline from the N-N cleavage of phenylhydrazine. The mechanism for this transformation requires further study.

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