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diketones 312{1-3,1-2} in yields ranging between 75-93% and 88-99% yields for each step,
respectively. Using an optimized microwave reaction protocol for the pyrrole formation (150 W,
80 °C, 15 min), 214 the six diketones were reacted with the 41 amines outlined in Scheme 4.48. Of
the possible 246 reactions, 210 were performed affording 172 pyrroles 314{1-3,1-2,1-41} in
average yield of 53% after purification. The average amount of each library member obtained
was 14.7 mg, in average purity of 94% (determined by LC/MS analysis with UV detection at
210, 220, 240 nm).
Computational prediction of pharmacologically relevant physico-chemical properties of
small molecule libraries is important in characterizing their potential to to serve as biological
tools or drug candidates. Physico-chemical properties for the tricyclic pyrrole library have been
calculated using QikProp 2.1 215 and are outlined in Table 4.6. y The majority of molecular
descriptors listed (molecular weight, molecular volume, clogP, number of hydrogen bond donors
and acceptors, number of primary metabolites, etc.) fall within the range of values for most
known drugs (first column). The distribution of predicted physico-chemical properties can also
be used to to characterize the diversity of the library members. As can be seen from Figure 4.2,
the pyrroles display broad distribution of molecular weights (472-763 g/mol), clogP values (3.3-
8.9) and number of hydrogen bond acceptors (7-13). Less distribution is seen in the number of
hydrogen bond donors (0-2). The number of rotatable bonds ranges from 5-12, whereas FISA
(hydrophilic component of the solvent accessible surface area) ranges between 15.4-153.1 Å 2 .
y Calculations were performed by Dr. Stefan Werner.
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