ArticleBioorganic & medicinal chemistry letters2014
The effect of chain length and unsaturation on Mtb Dxr inhibition and antitubercular killing activity of FR900098 analogs.
Article in Bioorganic & medicinal chemistry letters, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Design and synthesis of non-hydroxamate lipophilic inhibitors of 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR):RSC advances · 2024Article
- Inhibition of DXR in the MEP pathway with lipophilicRSC medicinal chemistry · 2024Article
- MEPicides: α,β-unsaturated FosmidomycinACS infectious diseases · 2023Article
- The Multifaceted MEP Pathway: Towards New Therapeutic Perspectives.Molecules (Basel, Switzerland) · 2023Review
- Over 40 Years of Fosmidomycin Drug Research: A Comprehensive Review and Future Opportunities.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Phosphoryl Prodrugs: Characteristics to Improve Drug Development.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2022Article
- Antimicrobial Prodrug Activation by the Staphylococcal Glyoxalase GloB.ACS infectious diseases · 2020Article
- Potent, specific MEPicides for treatment of zoonotic staphylococci.PLoS pathogens · 2020Article
- Article
- Phosphonate prodrugs: an overview and recent advances.Future medicinal chemistry · 2019Review
- MEPicides: α,β-Unsaturated Fosmidomycin Analogues as DXR Inhibitors against Malaria.Journal of medicinal chemistry · 2018Article
- The Methylerythritol Phosphate Pathway: Promising Drug Targets in the Fight against Tuberculosis.ACS infectious diseases · 2018Review
- MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis.Scientific reports · 2017Article
- Structure-Activity Relationships of the MEPicides: N-Acyl and O-Linked Analogs of FR900098 as Inhibitors of Dxr from Mycobacterium tuberculosis and Yersinia pestis.ACS infectious diseases · 2016Article
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
Inhibition of the nonmevalonate pathway (NMP) of isoprene biosynthesis has been examined as a source of new antibiotics with novel mechanisms of action. Dxr is the best studied of the NMP enzymes and several reports have described potent Dxr inhibitors. Many of these compounds are structurally related to natural products fosmidomycin and FR900098, each bearing retrohydroxamate and phosphonate groups. We synthesized a series of compounds with two to five methylene units separating these groups to examine what linker length was optimal and tested for inhibition against Mtb Dxr. We synthesized ethyl and pivaloyl esters of these compounds to increase lipophilicity and improve inhibition of Mtb growth. Our results show that propyl or propenyl linker chains are optimal. Propenyl analog 22 has an IC50 of 1.07 μM against Mtb Dxr. The pivaloyl ester of 22, compound 26, has an MIC of 9.4 μg/mL, representing a significant improvement in antitubercular potency in this class of compounds.
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