Compounds for inhibiting 1-deoxy-D-xylulose-5-phosphate reductoisomerase
Inventors
Boshoff, Helena I. • Dowd, Cynthia S. • Jackson, Emily R. • Kehn-Hall, Kylene • Lee, Richard E. • Lee, Robin • San Jose, Geraldine
Assignees
George Washington University • St Jude Childrens Research Hospital • George Mason University • US Department of Health and Human Services
Publication Number
US-9593136-B2
Publication Date
2017-03-14
Expiration Date
2032-06-29
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Abstract
In particular, the compound is effective to inhibit Dxr in Mycobacterium tuberculosis (Mtb). The present invention relates to compounds having general formula (I) or (II)where X is an acidic group, such as carboxylate, phosphonate, sulfate, and tetrazole; Ar is a substituted or unsubstituted aromatic or heteroaromatic group; and n is 0, 1, 2, 3, or 4, preferably 2, 3, or 4. The compounds inhibits 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr), particularly Dxr in Mycobacterium tuberculosis (Mtb).
Core Innovation
The invention relates to compounds effective in inhibiting the enzyme 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr), specifically in Mycobacterium tuberculosis (Mtb). The compounds have general structural formulas where X is an acidic group such as carboxylate, phosphonate, sulfate, or tetrazole; Ar is a substituted or unsubstituted aromatic or heteroaromatic group; and n is an integer from 0 to 4. The compounds inhibit Dxr by binding simultaneously to the substrate binding site and the NADP+ binding site of the enzyme, preventing both substrate and NADP+ from binding and thereby efficiently inhibiting enzyme activity.
The problem addressed is that current tuberculosis treatments require long regimens and are challenged by multi-drug resistant (MDR-TB) and extensively drug-resistant strains (XDR-TB). Existing anti-TB drugs do not target the nonmevalonate pathway, in which Dxr is an essential enzyme for Mtb survival. Since there are no human homologues for this pathway's enzymes, targeting Dxr provides a promising new mechanism to develop antibiotics that could shorten treatment duration and overcome resistance.
The invention also provides methods for synthesizing these compounds, screening methods to identify effective Dxr inhibitors, and pharmaceutical compositions containing these compounds. The compounds are designed to bridge both substrate and cofactor binding sites on Dxr, mimicking portions of NADP+ and fosmidomycin binding, improving affinity. Examples demonstrate synthesis routes, compound modifications to improve cell penetration, and assays confirming inhibitory activity against purified Mtb Dxr and bacteria.
Claims Coverage
The independent claims define the novel compounds and pharmaceutical compositions, focusing on structural features and their function in Dxr inhibition.
Compound structure with dual binding capability
A compound having the chemical structure of formula (II), characterized by an acidic group X and an aromatic or heteroaromatic group Ar, that inhibits Dxr by binding simultaneously to the substrate and NADP+ binding sites of the enzyme.
Pharmaceutical compositions comprising the dual-site binding compounds
Pharmaceutical compositions containing at least one compound of formula (II), suitable for treating infections by inhibiting the Dxr enzyme.
The claims cover compounds structurally designed to inhibit Dxr via dual-site binding, and pharmaceutical compositions comprising these compounds, thereby providing new anti-TB agents targeting Mtb Dxr distinctly from current drugs.
Stated Advantages
Compounds provide improved inhibition by bridging both substrate and NADP+ binding sites of Dxr, resulting in increased binding affinity compared to existing inhibitors like fosmidomycin.
Targeting Dxr offers a novel mechanism of action, distinct from existing anti-TB drugs, potentially effective against multi-drug resistant and extensively drug resistant Mtb strains.
The compounds' design allows for modification to improve cell penetration, bioavailability, and efficacy, addressing treatment challenges associated with tuberculosis.
Documented Applications
Use of the compounds as antibiotics to treat Mycobacterium tuberculosis infections.
Screening methods for identifying compounds capable of inhibiting Dxr for antibiotic development.
Pharmaceutical compositions formulated for administration via various routes including oral, injectable, and others suitable for targeting Mtb.
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