Elaboration of a proprietary thymidylate kinase inhibitor motif towards anti-tuberculosis agents

Song, Lijun; Risseeuw, Martijn; Froeyen, Matheus; Karalić, Izet; Goeman, Jan; Cappoen, Davie; Eycken, Johan Van der; Cos, Paul; Munier‐Lehmann, Hélène; Calenbergh, Serge Van

doi:10.1016/j.bmc.2016.08.041

Cited by 11 publications

(35 citation statements)

References 34 publications

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“…Replacement of the thymine ring by a phenyl ( 27 ) led to a complete loss of the inhibitory potency. Additionally, repositioning of the thymine ring from the para to the meta -position of the piperidine ring [ 20 , 22 ] (racemic compound 23 ) resulted in a substantial (>10-fold) loss in the inhibitory potency. In-line with earlier observations, with a one-carbon linker [ 14 , 21 ], amide analog 26 displayed a weak enzyme inhibition.…”

Section: Resultsmentioning

confidence: 99%

“… Structures of reported Mtb TMPK inhibitors 1 , 2 and 3 and their TMPK inhibitory potency and antitubercular activity [ 14 , 20 ]. Compound 3 was resynthesized and re-evaluated herein as a reference.…”

Section: Figures Schemes and Tablesmentioning

confidence: 99%

“…Further modifications led to the identification of 1-(1-arylethylpiperidin-4yl)thymine analog 3, which, compared to 1, displayed a nine-fold lower minimum inhibitory concentration (MIC) value for H37Rv [14]. [14,20]. Compound 3 was resynthesized and re-evaluated herein as a reference.…”

Section: Introductionmentioning

confidence: 99%

“…An overview of the synthesized analogs is presented in Figure 2. [14,20]. Compound 3 was resynthesized and re-evaluated herein as a reference.…”

Section: Introductionmentioning

confidence: 99%

“…Thymidylate kinase, a key enzyme for the synthesis of the DNA building block thymidine-5′-triphosphate, is indispensable for bacterial survival [ 9 , 10 , 11 ]. The availability of co-crystal structures of Mtb TMPK [ 12 , 13 , 14 , 15 , 16 ] has aided the discovery of Mtb TMPK inhibitors, featuring both nucleoside [ 14 , 17 , 18 , 19 , 20 ] and non-nucleoside [ 14 , 15 , 20 , 21 ] structures.…”

Section: Introductionmentioning

confidence: 99%

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1-(1-Arylethylpiperidin-4-yl)thymine Analogs as Antimycobacterial TMPK Inhibitors

et al. 2020

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A series of Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors based on a reported compound 3 were synthesized and evaluated for their capacity to inhibit MtbTMPK catalytic activity and the growth of a virulent M. tuberculosis strain (H37Rv). Modifications of the scaffold of 3 failed to afford substantial improvements in MtbTMPK inhibitory activity and antimycobacterial activity. Optimization of the substitution pattern of the D ring of 3 resulted in compound 21j with improved MtbTMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold). Moving the 3-chloro substituent of 21j to the para-position afforded isomer 21h, which, despite a 10-fold increase in IC50-value, displayed promising whole cell activity (minimum inhibitory concentration (MIC) = 12.5 μM).

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Section: Resultsmentioning

confidence: 99%

Section: Figures Schemes and Tablesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…An overview of the synthesized analogs is presented in Figure 2. [14,20]. Compound 3 was resynthesized and re-evaluated herein as a reference.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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1-(1-Arylethylpiperidin-4-yl)thymine Analogs as Antimycobacterial TMPK Inhibitors

et al. 2020

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Synthesis and structure activity relationships of cyanopyridone based anti-tuberculosis agents

Jian

Hulpia

Risseeuw

et al. 2020

European Journal of Medicinal Chemistry

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Endeavors towards transformation of M. tuberculosis thymidylate kinase (MtbTMPK) inhibitors into potential antimycobacterial agents

Jian

Merceron

Munck

et al. 2020

European Journal of Medicinal Chemistry

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As the last enzyme in nucleotide synthesis as precursors for DNA replication, thymidylate kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor bacterial uptake. To address this, we herein describe our efforts to equip previously reported MtbTMPK inhibitors with targeting moieties to increase the whole cell activity of the hybrid analogues. Introduction of a simplified Fe-chelating siderophore motif gave rise to analogue 17 that combined favorable enzyme inhibitory activity with significant activity against M. tuberculosis (MIC of 12.5 μM). Conjugation of MtbTMPK inhibitors with an imidazo[1,2a]pyridine or 3,5-dinitrobenzamide scaffold afforded analogues 26, 27 and 28, with moderate MtbTMPK enzyme inhibitory potency, but sub-micromolar activity against mycobacteria without significant cytotoxicity. These results indicate that conjugation with structural motifs known to favor mycobacterial uptake may be a valid approach for discovering new antimycobacterial agents.

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Elaboration of a proprietary thymidylate kinase inhibitor motif towards anti-tuberculosis agents

Cited by 11 publications

References 34 publications

1-(1-Arylethylpiperidin-4-yl)thymine Analogs as Antimycobacterial TMPK Inhibitors

1-(1-Arylethylpiperidin-4-yl)thymine Analogs as Antimycobacterial TMPK Inhibitors

Synthesis and structure activity relationships of cyanopyridone based anti-tuberculosis agents

Endeavors towards transformation of M. tuberculosis thymidylate kinase (MtbTMPK) inhibitors into potential antimycobacterial agents

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