All parasitic protozoa obtain purine nucleotides exclusively via salvage pathways for purine bases and/or nucleosides from their host. De novo biosynthesis of purines is absent in these organisms. Thus, inhibition of purine salvage may be a good target for antiprotozoan drugs. Rational design of a novel antimicrobial containing a phthalic anhydride moiety has been reported previously. We are modifying the scaffold to phthalimide which is expected to greatly increase bioavailability of the inhibitors. We have also been working on designing a combinatorial library using computational methods by docking a virtual computer-generated combinatorial library to the target protein and using this approach to efficiently reduce library size. Synthesis of these inhibitors is expected to yield low micromolar or better inhibitors of purine salvage in protozoa.
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