We have used a three-dimensional model of deoxyhemoglobin to design potential antisickling agents with an intended binding site in the vicinity of the beta-6 mutation (donor site). Two proline derivatives, (4S)-1-butyryl-4-[(carboxymethyl)amino]-L-proline (9a) and its 1-benzoyl analogue (9b), were designed to interact, via ionic or hydrogen bonds, with polar residues beta His-2, beta Thr-4, and beta Lys-132 of hemoglobin S (HbS). Two other proline derivatives containing a salicylate leaving group, (4S)-1-butyryl-4-[(carboxymethyl)methylamino]-L-proline, 2-ester with salicyclic acid (14a), and its 1-benzoyl analogue (14b), were designed to bind covalently to beta Lys-132, as well as to interact with beta His-2 and beta Thr-4 via ionic and hydrogen bonds. This paper describes the synthesis of these agents, beginning with natural L-hydroxyproline methyl ester, and the testing of their ability to increase or decrease the solubility of dHbS by using a standard solubility assay. The covalent derivatives 14a,b were found to be inactive, while the noncovalent compounds 9a,b showed weak antigelling activity, below that observed for phenylalanine. The presence of only weak activity does not invalidate this approach, since only one structural parameter has been investigated.