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1-Deoxy-d-xylulose 5-phosphate reductoisomerase of Plasmodiumfalciparum(PfIspC, PfDxr), believed to be the rate-limiting enzyme of the nonmevalonatepathway of isoprenoid biosynthesis (MEP pathway), is a clinicallyvalidated antimalarial target. The enzyme is efficiently inhibitedby the natural product fosmidomycin. To gain new insights into thestructure activity relationships of reverse fosmidomycin analogs,several reverse analogs of fosmidomycin were synthesized and biologicallyevaluated. The 4-methoxyphenyl substituted derivative 2cshowed potent inhibition of PfIspC as well as of P. falciparumgrowth and was more than one orderof magnitude more active than fosmidomycin. The binding modes of three new derivatives in complexwith PfIspC, reduced nicotinamide adenine dinucleotidephosphate, and Mg2+were determined by X-ray structureanalysis. Notably, PfIspC selectively binds the S-enantiomers of the study compounds. [ABSTRACT FROM AUTHOR]