Synthesis and evaluation of α,β-unsaturated α-aryl-substituted fosmidomycin analogues as DXR inhibitors

Fosmidomycin, which acts through inhibition of 1-deoxy-d-xylulose phosphate reductoisomerase (DXR) in the non-mevalonate pathway, represents a valuable recent addition to the armamentarium against uncomplicated malaria. In this paper, we describe the synthesis and biological evaluation of E- and Z-α,β-unsaturated α-aryl-substituted analogues of FR900098, a fosmidomycin congener, utilizing a Stille or a Suzuki coupling to introduce the aryl group. In contrast with our expectations based on the promising activity earlier observed for several α-substituted fosmidomycin analogues, all synthesized analogues exhibited much lower binding affinity for DXR than fosmidomycin.