Design, synthesis, and testing of potential antisickling agents. 5. Disubstituted benzoic acids designed for the donor site and proline salicylates designed for the acceptor site.

This paper reports the discovery of a new class of potent antigelling agents. The new compounds, disubstituted benzoic acid derivatives, were designed by using molecular modeling experiments. These molecules contain functional groups positioned to interact with several polar amino acid residues near the Val-6 beta mutation site (donor site) in HbS. The compounds also contain a hydrophobic group designed to occupy a nonpolar ara on the surface of the protein created by several hydrophobic amino acids. The synthesis and testing of these new molecules using a standard solubility assay is reported. A structural comparison is made between one of the most active antigelling agents, compound 13, which has little effect on the oxygen affinity of Hb in solution, and bezafibrate, a known antilipidemic drug that is progelling and has a very potent effect on decreasing Hb oxygen affinity (Perutz, M. F.; Poyart, C. Lancet 1983, 2, 881-882). We also report the synthesis and testing of a series of proline-salicylate molecules designed to react covalently at the mutation acceptor area. This class of molecules did not show significant activity.