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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]

Fosmidomycin inhibits IspC (1-deoxy-d-xylulose 5-phosphate reductoisomerase), the first committed enzyme in the methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis. The MEP pathway of isoprenoid biosynthesis is essential to the causative agent of the plague, Yersinia pestis , and is entirely distinct from the corresponding mammalian pathway. To further drug development, we established structure-activity relationships of fosmidomycin analogues by assessing a suite of 17 α-phenyl-substituted reverse derivatives of fosmidomycin against Y. pestis IspC. Several of these compounds showed increased potency over fosmidomycin with IC 50 values in the nanomolar range. Additionally, we performed antimicrobial susceptibility testing with Y. pestis A1122 ( Yp A1122). The bacteria were susceptible to several compounds with minimal inhibitory concentration (MIC) values ranging from 128 to 512 μg/mL; a correlation between the IC 50 and MIC values was observed., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)