Structural studies, lead compounds

The in vitro and in vivo antibacterial evaluations of these compounds revealed that the active compounds are those that correspond to structure 106, with the 3-pyridyl analogue being the most active. Unfortunately, the 30-day toxicological evaluation of this compound in mice demonstrated severe toxicity, and therefore further development of this compound was halted. Compound 103 (PNU-86093), although weaker than Dup-721, has a promising toxicological profile and is considered as a lead compound for future studies [51]. 

Fig. 4 Gas chromatographic traces of extracts from females of the pale brown chafer Phyl-lopertha diversa monitored by a conventional detector, flame-ionization detector (FID), and a biosensor, electroantennographic detector (EAD), using a male antenna as the sensing element. Although the peak of the sex pheromone (arrow) is hardly seen in the FID trace, its pheromonal activity was initially indicated by the strong EAD peak. Structural elucidation, followed by synthesis and behavioral studies lead to the identification of an unusual sex pheromone, l,3-dimethyl-2,4-(lff,3ff)-quinazolinedione [124]. It is unlikely that this minor compound would be fished out by a bioassay-oriented isolation procedure...

Currently, this is a major application of protein crystallography in most of the major drug companies. One of the best examples of this approach is the design of inhibitors for HIV protease (Dash et al., 2003). In brief, once the 3-D structure of HIV protease was determined, the active site was identified and used to screen small molecule libraries for potential compounds that could bind to HIV protease. These compounds were then tested for their ability to inhibit the protease. Lead compounds were then used to iteratively improve the inhibitors, using crystallographic studies, computational modeling, and biochemical tests. 

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