A prodrug is a modified drug molecule having no significant biological activity but converts to the parent drug in the biological system. Conventionally, the prodrug is designed and synthesized by modifying a functional group that serves as a ‘synthetic handle’. However, certain drugs do not have any functional group for easy manipulations. For these drugs, it becomes challenging to design or synthesize a prodrug. Herein, we examine a series of methods for bioreversible derivatization of drugs with a pyridine ring to improve their physicochemical properties including water solubility and conjugation with a targeting moiety. Several model prodrugs were synthesized and examined for solubility, stability, and bioreversible conversion. Three water-soluble prodrug models (BW-HIF-352, BW-HIF-354, and BW-HIF-355) showed significant amount of drug activation under physiological conditions. The same method should be applicable to the preparation of prodrugs of other drugs that contain a pyridine ring or even a quinoline ring.