Question

1. Draw out the SAR of the quinazoline scaffold from this section (EGF-R kinase inhibitors) and show all the resulting features

2. Draw out the SAR diagram of the fused ring analysis of the quinazoline scaffold (EGF-R kinase inhibitors) from this section and show all the resulting features

3. In the analysis of different analogues from the quinazoline EGF-R kinase inhibitors a significant difference was shown by the introduction of a second nitrogen atom into the aromatic ring. Draw out the structures and use electron pushing arrows to explain the effect. Note: you may have to consult a chemistry textbook (1st year will do) and/or the attached paper below. Explain also why the most potent analogue resulted.

4. Draw out a SAR diagram of the salicylamide inhibitors of scytalone dehydratase. Point out the dominant feature(s) observed in the section and also all the potential other interactions suggested by the chemical structures.

5. In the development of a potent carbonic anhydrase inhibitor what important discoveries were made as a) regards the bioactive conformations? b) what modifications were made to enhance the binding?

Answer 1

1.

The substituent in the C-4 position in the quinazoline scaffold is to inhibit the tyrosine kinase activity of the epidermal growth factor receptor (EGF-R). This shows structure-activity relationship (SAR) for the basic ring system, with quinazoline as the preferred chromophore and benzylamino and anilino as the preferred side chains. In the 4-anilino series, substitution on the 3-position of the phenyl ring with small lipophilic electron-withdrawing groups provide the analogs with enhanced potency. For example, a more active 4-(3-bromophenyl)amino series, electron-donating groups (NH₂, OMe) at the 6- or 7-position increases activity, in a pattern consistent with a requirement for high electron density in the vicinity of the 8-position of the quinazoline ring.