Synthesis and biological evaluation of pyrimidine analogs of antimycobacterial purines

Read, Matthew Lovell; Brændvang, Morten; Miranda, Pedro O.; Gundersen, Lise‐Lotte

doi:10.1016/j.bmc.2010.04.035

Cited by 37 publications

(21 citation statements)

References 23 publications

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“…1 1-(4 0 -Hydroxy-2 0 -cyclopenten-1 0 -yl)-3-(4‴-hydroxy-2‴-cyclopent-en-1‴-yl)-5-(4″-butylphenylamino) uracil (18) The title compound was obtained as side product in the synthesis of (13). The purification described for compound (13) gave product (18) 1-(4 0 -Hydroxy-2 0 -cyclopenten-1 0 -yl)-3-(4‴-hydroxy-2‴-cyclopenten-1‴-yl)-5-(4″-butyloxyphenylamino) uracil (19) The title compound was obtained as side product in the synthesis of (14). The purification described for compound (14) gave product (19) (20) The title compound was obtained as side product in the synthesis of (15).…”

Section: -(Phenylaminomentioning

confidence: 99%

5‐Arylaminouracil Derivatives: New Inhibitors of Mycobacterium tuberculosis

et al. 2015

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Three series of 5-arylaminouracil derivatives, including 5-(phenylamino)uracils, 1-(4'-hydroxy-2'-cyclopenten-1'-yl)-5-(phenylamino)uracils, and 1,3-di-(4'-hydroxy-2'-cyclopenten-1'-yl)-5-(phenylamino)uracils, were synthesized and screened for potential antimicrobial activity. Most of compounds had a negative effect on the growth of the Mycobacterium tuberculosis H37Rv strain, with 100% inhibition observed at concentrations between 5 and 40 μg/mL. Of those, 1-(4'-hydroxy-2'-cyclopenten-1'-yl)-3-(4‴-hydroxy-2‴-cyclopenten-1‴-yl)-5-(4″-butyloxyphenylamino)uracil proved to be the most active among tested compounds against the M. tuberculosis multidrug-resistant strain MS-115 (MIC90 5 μg/mL). In addition, the thymidylate kinase of M. tuberculosis was evaluated as a possible enzymatic target.

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Section: -(Phenylaminomentioning

confidence: 99%

5‐Arylaminouracil Derivatives: New Inhibitors of Mycobacterium tuberculosis

et al. 2015

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“…A follow‐up optimisation campaign identified MMV687170 ( 419 ) as a promising lead, which maintained its activity inside infected macrophages . A series of related studies which appeared simultaneously assisted in developing a thorough understanding of the SAR of this class, with only compound 420 representing a substantial improvement in in vitro biological activity …”

Section: Tuberculosismentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

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“…One of the Gly derivatives, the methyl ester 7‐Gly‐CH 3 , shows good activity, whereas the other one is a weak inhibitor of M. tuberculosis H37Rv. The favorable effect of aromatic substituents on the antimycobacterial activity has been observed in different purine‐related and non‐purine scaffolds . X‐ray data and docking studies with the target enzyme InhA, an enzyme essential for mycolic acid biosynthesis in M. tuberculosis show that two aromatic moieties connected by a short spacer is a suitable pharmacophore for enzyme inhibition.…”

Section: Discussionmentioning

confidence: 99%

Design, Synthesis, and Antimycobacterial Activity of Novel Theophylline‐7‐Acetic Acid Derivatives With Amino Acid Moieties

et al. 2015

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The theophylline-7-acetic acid (7-TAA) scaffold is a promising novel lead compound for antimycobacterial activity. Here, we derive a model for antitubercular activity prediction based on 14 7-TAA derivatives with amino acid moieties and their methyl esters. The model is applied to a combinatorial library, consisting of 40 amino acid and methyl ester derivatives of 7-TAA. The best three predicted compounds are synthesized and tested against Mycobacterium tuberculosis H37Rv. All of them are stable, non-toxic against human cells and show antimycobacterial activity in the nanomolar range being 60 times more active than ethambutol.

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Synthesis and biological evaluation of pyrimidine analogs of antimycobacterial purines

Cited by 37 publications

References 23 publications

5‐Arylaminouracil Derivatives: New Inhibitors of Mycobacterium tuberculosis

5‐Arylaminouracil Derivatives: New Inhibitors of Mycobacterium tuberculosis

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Design, Synthesis, and Antimycobacterial Activity of Novel Theophylline‐7‐Acetic Acid Derivatives With Amino Acid Moieties

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