Aminomethyl phosphonate DXR inhibitors: potent anti-infective compounds with antimalarial activity
Library of beta-aza aminomethyl phosphonate analogues designed as DXR inhibitors for anti-infective applications. Compounds show low to subnanomolar IC50 potency, in vitro antimalarial activity, and no cytotoxicity on HepG2 cells. Synthesized with >95% purity via the Kabashnik-Fields reaction.
Overview
This offering presents a focused chemical library of aminomethyl phosphonate compounds developed as competitive inhibitors of DXR (1-deoxy-D-xylulose-5-phosphate reductoisomerase), a key enzyme in the non-mevalonate isoprenoid biosynthesis pathway. The library was designed using medicinal chemistry and molecular modelling approaches, building on the structural framework of fosmidomycin—a known DXR inhibitor with established antimalarial and herbicidal properties. By introducing beta-aza modifications through the Kabashnik-Fields reaction, the researchers explored broad chemical diversity to optimize structure-activity and structure-property relationships.
The lead compounds demonstrate low to subnanomolar IC50 values against DXR, significant in vitro antimalarial activity, and a clean cytotoxicity profile on HepG2 cells. These results position the library as a promising starting point for anti-infective drug discovery, particularly for malaria therapeutics, and potentially for herbicidal applications targeting the same pathway.
Technical specifications
- Target enzyme: DXR (1-deoxy-D-xylulose-5-phosphate reductoisomerase), a validated anti-infective target in the non-mevalonate pathway
- Compound class: Beta-aza aminomethyl phosphonate analogues of fosmidomycin
- Synthesis route: Kabashnik-Fields reaction enabling systematic exploration of chemical diversity
- Purity: All compounds obtained with >95% purity by organic synthesis
- Potency: Low to subnanomolar IC50 values as competitive DXR inhibitors
- Biological activity: Demonstrated in vitro antimalarial activity
- Safety profile: No cytotoxicity observed on HepG2 cells
- Design approach: Structure-activity relationship (SAR) and structure-property relationship (SPR) analysis supported by molecular modelling
Technology readiness level
The library is at an early-stage research and discovery phase. Compounds have been synthesized, purified to >95%, and validated in biochemical (DXR inhibition) and cellular (antimalarial activity, HepG2 cytotoxicity) assays. Further validation steps would include expanded SAR studies, pharmacokinetic profiling, and in vivo efficacy testing to advance toward lead optimization and preclinical development.
About Ghent University
Ghent University is a comprehensive public research university with a strong applied research and innovation culture. Industry collaborates through the Tech Lane Ghent Science Park, where corporate R&D, public research institutes and UGent labs are co‑located, and via a second science park in Ostend. Integration with Ghent University Hospital enables clinical translation and access to patient care environments. Research is backed by competitive European programmes such as Horizon Europe and the ERC, alongside national and regional support from FWO and VLAIO. UGent’s TechTransfer office, working with an Industrial Liaison Network and a central EU funding team, supports IP, licensing, spin‑offs and contract research to accelerate partnerships.
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