Lead compounds analog design

The pyrrole nucleus is commonly found in biologically active lead compounds and designed analogs, and two out of many recently published examples will be mentioned here. The pyrrole core structures of roseophilin and prodigiosin have been studied as protein tyrosine phosphatase inhibitors <04CBC1575>. A new class of 2-vinylpyrroles, 6-pyrrolyl-2,4-dioxo-5-hexenoic acids, were found to be active HIV-1 integrase inhibitors <04BMCL1745>. 

This two-step strategy starts with the synthesis of numerous analogs of the lead compound. This is meant to explore the structural diversity of the lead compound. Next, QSAR studies are employed to correlate these structural diversities with bioactivity. The results of the QSAR smdies are then used to design new and, hopefully, improved analogs. 

Incorporation of the ferrocene core in the lateral side chain of CQ between the two amine atoms has led to the design of Ferroquine (FQ, SR97193). This compound was shown to be extremely active against both CQ-sensitive and CQ-resistant P. falciparum. FQ was also the most active derivative in vivo and was considered as a lead compound early on (More details in Sect. 3) [121], As 1,2-unsymmetri-cally substituted ferrocenes are chiral molecules, an effort was made to design an achiral version of these derivatives. The easiest solution was to move the second substituent to the other cyclopentadienyl cycle. These achiral 1,1 -substituted ferrocene analogs (Fig. 19) were much more active than CQ but exhibited four times lower activity against the K1 CQ-resistant strain than against the DIO CQ sensitive strain [122], Unfortunately, no in vivo data were available for the comparison of the substitution patterns 1,2 vs. 1,1. ... 

Structure-activity relationships may be estabhshed if several analogs are available. This step is a necessary step in drug design that leads to optimizing the properties of the therapeutic agent and developing a lead compound. 

In analog design, molecular modification of the lead compound can involve one or more of the following strategies ... 

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