Parallel synthesis and screening of bioactive pharmacophore libraries

Parallel synthesis and screening of bioactive pharmacophore libraries 

The extension of the application of combinatorial chemistry from lead discovery to lead optimization has resulted in a gradual shift from split-pool protocol-based libraries generating mixtures of compounds to the parallel synthesis of discrete analogs (see Fig. 5). The emphasis in the latter case is not on the size of the libraries but rather on the yield, purity, 

Aldol condensation of the zinc enolate of resin-bound alkyl ester 29 with aromatic aldehyde or ketone forms a P-hydroxy ester, which upon treatment with DIBAL-H leads to simultaneous reduction and cleavage of the ester moiety from the resin to give a soluble 1,3-diol 31 [31], Parallel synthesis utilizing three ester and nine carbonyl building blocks afforded a library of 27 analogs which was screened for antioxidative efficiency using a ferric thiocyanate assay. 

A 24-analog hydroxystilbene library 34 was constructed from the Horner-Emmons olefination of four resin-bound hydroxybenzaldehyde BBs 33 and six different benzyl phosphonate anions [32], Screening for activity in a cell-based estrogenic assay identified several analogs such as 35 with IC50 values in the 5-15 pM range. 

Using a set of six o-cyanoaniline 39 and 12 cyclohexanone 40 BBs, Pirrung and coworkers prepared two orthogonal sets of a 72-member tetrahydroacridine library 41. Screening against acetylcholinesterase led to the identification of 7-nitrotacrine 42 as a 10-fold more potent analog (Kj =10 nM) than the parent compound tacrine [34], 

---