AI Article Synopsis
- Researchers are exploring the inhibition of the nonmevalonate pathway (NMP) in isoprene biosynthesis as a potential new avenue for developing antibiotics with unique mechanisms.
- The most studied enzyme in this pathway is Dxr, and many effective inhibitors have been found that are chemically similar to natural products like fosmidomycin and FR900098.
- A series of new compounds were synthesized with varying linker lengths, and the results indicated that compounds with propyl or propenyl linkers were most effective at inhibiting Mtb Dxr, with one compound showing a noteworthy improvement in killing Mtb.
Article 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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Source |
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927493 | PMC |
| http://dx.doi.org/10.1016/j.bmcl.2013.11.067 | DOI Listing |
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